Faculty Bibliography

BACKGROUND:The comparative benefits and harms of available interventions for ADHD in adults remain unclear. We aimed to address these important knowledge gaps. METHODS:In this systematic review and component network meta-analysis (NMA), we searched multiple databases for published and unpublished randomised controlled trials (RCTs) investigating pharmacological and non-pharmacological interventions for ADHD in adults from database inception to Sept 6, 2023. We included aggregate data from RCTs comparing interventions against controls or any other eligible active intervention for the treatment of symptoms in adults (ages ≥18 years) with a formal diagnosis of ADHD. Pharmacological therapies were included only if their maximum planned doses were considered eligible according to international guidelines. We included RCTs of at least 1-week duration for medications, of at least four sessions for psychological therapies, and of any length deemed appropriate for neurostimulation. For RCTs of medications, cognitive training, or neurostimulation alone, we included only double-blind RCTs. At least two authors independently screened the identified records and extracted data from eligible RCTs. Our primary outcomes were efficacy (change in ADHD core symptom severity on self-rated and clinician-rated scales at timepoints closest to 12 weeks) and acceptability (all-cause discontinuation). We estimated standardised mean differences (SMDs) and odds ratios (ORs) using random effects pairwise and component NMA, dismantling interventions into specific therapeutic components. This study was registered with PROSPERO (CRD42021265576). People with relevant lived experience were involved in the conduct of the research and writing process. FINDINGS/RESULTS:Of 32 416 records, 113 unique RCTs encompassing 14 887 participants were eligible for analysis (6787 [45·6%] females, 7638 [51·3%] males, 462 [3·1%] sex not reported). The RCTs encompassed pharmacological therapies (63 [55·8%] of 113 RCTs; 6875 participants), psychological therapies (28 [24·8%] of 113 RCTs; 1116 participants), neurostimulatory therapy and neurofeedback (ten [8·8%] of 113 RCTs; 194 participants), and control conditions (97 [85·8%] of 113 RCTs; 5770 participants). For reduction of ADHD core symptoms at 12 weeks on both self-reported and clinician-reported rating scales, atomoxetine (self-reported scale SMD -0·38, 95% CI -0·56 to -0·21; clinician-reported scale -0·51, -0·64 to -0·37) and stimulants (0·39, -0·52 to -0·26; -0·61, -0·71 to -0·51) had higher efficacy than placebo (Confidence in Network Meta-Analysis [CINeMA] ranging between very low and moderate). Cognitive behavioural therapy (-0·76, -1·26 to -0·26), cognitive remediation (-1·35, -2·42 to -0·27), mindfulness (-0·79, -1·29 to -0·29), psychoeducation (-0·77, -1·35 to -0·18), and transcranial direct current stimulation (-0·78; -1·13 to -0·43) were better than placebo only on clinician-reported measures. Regarding acceptability, all therapeutic components were similar to placebo other than atomoxetine (OR 1·43, 95% CI 1·14 to 1·80; CINeMA moderate) and guanfacine (3·70, 1·22 to 11·19; high), which had lower acceptability compared with placebo. Baseline severity of self-reported ADHD core symptoms, year of publication, percentage of male individuals, and percentage of individuals with ADHD and another mental health condition did not explain the heterogeneity observed in unadjusted non-component models of self-reported ADHD core symptoms. Treatment length had little effect on heterogeneity. INTERPRETATION/CONCLUSIONS:Stimulants and atomoxetine were the only interventions with evidence of beneficial effects in terms of reducing ADHD core symptoms in the short term, supported by both self-reported and clinician-reported ratings. However, atomoxetine was less acceptable than placebo. Medications for ADHD were not efficacious on additional relevant outcomes, such as quality of life, and evidence in the longer term is underinvestigated. The effects of non-pharmacological strategies were inconsistent across different raters. Our network meta-analysis represents the most comprehensive synthesis of available evidence to inform future guidelines in the field. FUNDING/BACKGROUND:UK National Institute for Health and Care Research.

BACKGROUND:COVID infection has been associated with long term sequalae (Long COVID) which include neurological and behavioral effects in thousands of patients, but the etiology and scope of symptoms is not well understood. This paper reviews long term sequelae of COVID on brain and mental health in patients with the Long COVID syndrome. METHODS:This was a literature review which queried databases for Pubmed, Psychinfo, and Medline for the following topics for January 1, 2020-July 15, 2023: Long COVID, PASC, brain, brain imaging, neurological, neurobiology, mental health, anxiety, depression. RESULTS:Tens of thousands of patients have developed Long COVID, with the most common neurobehavioral symptoms anosmia (loss of smell) and fatigue. Anxiety and mood disorders are elevated and seen in about 25% of Long COVID patients. Neuropsychological testing studies show a correlation between symptom severity and cognitive dysfunction, while brain imaging studies show global decreases in gray matter and alterations in olfactory and other brain areas. CONCLUSIONS:Studies to date show an increase in neurobehavioral disturbances in patients with Long COVID. Future research is needed to determine mechanisms.

Palliative care improves the quality of life for seriously ill patients, but misconceptions and knowledge gaps hinder its implementation in home healthcare (HHC). This study developed and pilot-tested HHC-specific questionnaires to measure palliative care knowledge, attitudes, and confidence (PC-KAC) among clinicians, patients, and caregivers. Using literature reviews, expert input, and cognitive interviews, the questionnaires were refined to ensure clarity, practical relevance, and content validity. Pilot testing revealed widespread confusion about palliative care, with patients and caregivers often conflating it with hospice care and holding misconceptions about opioid use for pain and symptom management. While clinicians demonstrated adequate knowledge, gaps in pain management and confidence in handling emergencies were evident. These findings highlight the need for targeted education and training to integrate palliative care effectively into HHC, improving patient outcomes and supporting interdisciplinary collaboration.

Preterm birth poses a major public health challenge, with significant and heterogeneous developmental impacts. Latent profile analysis was applied to the National Institutes of Health Toolbox performance of 1891 healthy prematurely born children from the Adolescent Brain and Cognitive Development study (970 boys, 921 girls; 10.00 ± 0.61 years; 1.3% Asian, 13.7% Black, 17.5% Hispanic, 57.0% White, 10.4% Other). Three distinct neurocognitive profiles emerged: consistently performing above the norm (19.7%), mixed scores (41.0%), and consistently performing below the norm (39.3%). These profiles were associated with lasting cognitive, neural, behavioral, and academic differences. These findings underscore the importance of recognizing diverse developmental trajectories in prematurely born children, advocating for personalized diagnosis and intervention to enhance care strategies and long-term outcomes for this heterogeneous population.

INTRODUCTION/BACKGROUND:Maternal undernutrition and inflammation in utero may significantly impact the neurodevelopmental potential of offspring. However, few studies have investigated the effects of pregnancy interventions on long-term child growth and development. This study will examine the effects of prenatal nutrition and infection management interventions on long-term growth and neurodevelopmental outcomes of offspring. METHODS:The Enhancing Nutrition and Antenatal Infection Treatment ('ENAT') study (ISRCTN15116516) was a pragmatic, open-label, 2×2 factorial, randomised clinical effectiveness study implemented in 12 rural health centres in Amhara, Ethiopia. The study enrolled 2399 pregnant women who were randomised to receive routine care, an enhanced nutrition package (iron and folic acid, monthly household supply of iodised salt, and micronutrient-fortified balanced energy protein supplement for undernourished women), an enhanced infection management package (genitourinary tract infection screening and treatment, and enhanced deworming), or both packages. In the present Longitudinal Infant Development and Growth study, a subset of 480 children of mothers from ENAT will be recruited equally from each of the four study arms and visited at 12, 18, and 24 months of postnatal age. We will evaluate a range of domains and deploy multiple measures to assess child neurodevelopment, including resting electroencephalography and visual evoked potentials, Hammersmith Infant Neurological Examination, eye-tracking, Bayley Scales of Infant and Toddler Development (Bayley-III), and Magnetic Resonance Imaging (MRI). DISCUSSION/CONCLUSIONS:This study will advance understanding of the impact of nutrition and inflammation in pregnancy on long-term offspring neurodevelopment. This study aims to fill a critical knowledge gap on the benefits of prenatal interventions to promote the health of mothers and their offspring. ETHICS AND DISSEMINATION/BACKGROUND:This study was approved by the Institutional Review Boards of Addis Continental Institute of Public Health (ACIPH/IRB/002/2022) and Mass General Brigham (2023P000461). Results will be disseminated to local and international stakeholders. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT06296238.

PURPOSE/OBJECTIVE:Children and adolescents are experiencing a mental health crisis. Neurodiverse patients have high rates of mental health conditions and worse outcomes. To address this disparity, the Autism Spectrum Disorder Care Pathway was applied to a pediatric emergency department (PED) and Observation Unit (OU) in order to decrease agitation experienced by these patients. METHODS:This prospective cohort study was in a community-based PED and OU from June 2023 to February 2024. A medical education curriculum consisting of a multidisciplinary champion training and toolkit rollout was completed. Agitation was measured by the Behavioral Activity Rating Scale. The primary aim was to decrease frequency of agitation experienced by neurodiverse patients at any point in the PED/OU. The secondary outcome was to decrease pharmacologic intervention and physical restraint use. RESULTS:We captured data from a total of 45 patients, with 19 baseline patients and 26 patients in the intervention group. At baseline, 9 out of 19 (47%) patients experienced agitation at some point in their PED/OU stay. After implementation of the curriculum, agitation levels decreased to 6 out of 26 (23%) patients (p = 0.04). Inter-rater reliability was 0.95. There were 3 incidences of pharmacologic intervention and no physical restraint use. CONCLUSIONS:This pilot medical education curriculum for PED and OU staff members decreased agitation in neurodiverse patients who presented for mental health complaints. This study is the foundation for expansion of the curriculum for use in general emergency departments.

Systematic reviews and meta-analyses have become crucial for evidence-based decision-making in recent decades. However, it is common for the results of multiple reviews on the same topic to be inconsistent, and it is widely recognised that the results of the reviews are not always effectively communicated to healthcare professionals and the lay public. This manuscript proposes a strategy to summarise and communicate the findings of previous systematic reviews and meta-analyses to wider audiences. The proposed approach couples the findings of umbrella reviews with the creation of open-access online platforms that present the results of these umbrella reviews in an accessible way to various stakeholders. The key potential methodological avenues of this approach are presented, and specific examples from the author's own works and those from other teams are provided. An accompanying website (https://u-reach.org/) has been designed to present this Umbrella-Review, Evaluation, Analysis, and Communication Hub (U-REACH) approach and to overcome the technical challenges associated with this type of project (by sharing the code used to build existing U-REACH projects). The present document is intended to serve as a methodological and technical guide for the creation of large-scale projects designed to synthesise and disseminate scientific information to a broad audience.

Numerous recommendations have been made to address the high rates of mental health disorders among justice-involved youth. Few data are available on the use, quality, appropriateness, or availability of services to address these needs. This study examined the relationship between trauma-informed mental health screening, other referral pathways for diagnostic evaluation, subsequent DSM-5 diagnoses, and treatments for evaluated youth. Eligible participants were all youth admitted to New York City secure juvenile detention facilities from September 17, 2015 to October 30, 2016 who remained in the facility for at least five days (N = 786). Of those, 581 (73.9%) were voluntarily screened and 309 (53.2%) later received a diagnostic evaluation. Youth who screened positive for depression, posttraumatic stress disorder, and problematic substance use were more likely to be evaluated. Treatment received was related to diagnosis rather than reason for referral. For youth who were referred for behavioral or emotional concerns, 99.1 percent (114 of 115) of those diagnosed with a neurodevelopmental disorder had attention-deficit/hyperactivity disorder (ADHD). These data are among the first to describe DSM-5 diagnoses and treatment among youth detainees. They highlight the prevalence of ADHD in detained youth and argue for the coordination of universal trauma-informed mental health screening and a structured referral system for this population.

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 a sample of 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 clinician-based dimensional measures of autism and ADHD symptoms and whole-brain low motion intrinsic functional connectivity (iFC). 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: the middle frontal gyrus of the frontoparietal network and 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 symptoms. Results from segregation analyses were consistent with primary findings, underscoring the significance of internetwork iFC interactions 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 projection, suggesting shared genetic mechanisms for this specific brain-clinical phenotype. Overall, these findings underscore the relevance of transdiagnostic dimensional approaches in linking clinically-defined phenomena to shared presentations at the macroscale circuit- and genomic-levels among children with diagnoses of autism and ADHD.

IMPORTANCE/UNASSIGNED:Neurofeedback has been proposed for the treatment of attention-deficit/hyperactivity disorder (ADHD) but the efficacy of this intervention remains unclear. OBJECTIVE/UNASSIGNED:To conduct a meta-analysis of randomized clinical trials (RCTs) using probably blinded (ie, rated by individuals probably or certainly unaware of treatment allocation) or neuropsychological outcomes to test the efficacy of neurofeedback as a treatment for ADHD in terms of core symptom reduction and improved neuropsychological outcomes. DATA SOURCES/UNASSIGNED:PubMed (MEDLINE), Ovid (PsycInfo, MEDLINE, Embase + Embase Classic), and Web of Science, as well as the reference lists of eligible records and relevant systematic reviews, were searched until July 25, 2023, with no language limits. STUDY SELECTION/UNASSIGNED:Parallel-arm RCTs investigating neurofeedback in participants of any age with a clinical ADHD or hyperkinetic syndrome diagnosis were included. DATA EXTRACTION AND SYNTHESIS/UNASSIGNED:Standardized mean differences (SMDs) with Hedges g correction were pooled in random effects meta-analyses for all eligible outcomes. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was ADHD total symptom severity assessed at the first postintervention time point, focusing on reports by individuals judged probably or certainly unaware of treatment allocation (probably blinded). Secondary outcomes were inattention and/or hyperactivity-impulsivity symptoms and neuropsychological outcomes postintervention and at a longer-term follow-up (ie, after the last follow-up time point). RCTs were assessed with the Cochrane risk of bias tool version 2.0. RESULTS/UNASSIGNED:A total of 38 RCTs (2472 participants aged 5 to 40 years) were included. Probably blinded reports of ADHD total symptoms showed no significant improvement with neurofeedback (k = 20; n = 1214; SMD, 0.04; 95% CI, -0.10 to 0.18). A small significant improvement was seen when analyses were restricted to RCTs using established standard protocols (k = 9; n = 681; SMD, 0.21; 95% CI, 0.02 to 0.40). Results remained similar with adults excluded or when analyses were restricted to RCTs where cortical learning or self-regulation was established. Of the 5 neuropsychological outcomes analyzed, a significant but small improvement was observed only for processing speed (k = 15; n = 909; SMD, 0.35; 95% CI, 0.01 to 0.69). Heterogeneity was generally low to moderate. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Overall, neurofeedback did not appear to meaningfully benefit individuals with ADHD, clinically or neuropsychologically, at the group level. Future studies seeking to identify individuals with ADHD who may benefit from neurofeedback could focus on using standard neurofeedback protocols, measuring processing speed, and leveraging advances in precision medicine, including neuroimaging technology.