Faculty Bibliography

BACKGROUND:The mechanisms underlying placebo effects of psychotropic drugs remain poorly understood. We carried out the first systematic review of functional neuroimaging correlates of placebo response in adults with anxiety/depressive disorders. METHODS:We systematically searched a large set of databases up to February 2021 based on a pre-registered protocol (PROSPERO CRD42019156911). We extracted neuroimaging data related to clinical improvement following placebo or related to placebo mechanisms. We did not perform a meta-analysis due to the small number of included studies and significant heterogeneity in study design and outcome measures. RESULTS:We found 12 relevant studies for depressive disorders and four for anxiety disorders. Activity in the ventral striatum, rostral anterior cingulate cortex and other default mode network regions, orbitofrontal cortex, and dorsolateral prefrontal cortex correlated with placebo antidepressant responses. Activity in regions of the default mode network, including posterior cingulate cortex, was associated with placebo anxiolysis. There was also evidence for possible involvement of the endogenous opioid, dopamine and serotonin systems in placebo antidepressant and anxiolytic effects. CONCLUSIONS:Several brain regions and molecular systems may be involved in these placebo effects. Further adequately powered studies exploring causality and controlling for confounders are required.

BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) has been associated with reduced resting state connectivity in the core subsystem of the default mode network (DMN; medial prefrontal cortex - posterior cingulate cortex). However, the neuropsychological consequences of this hypoconnectivity remain to be determined. Building on recent theoretical models of DMN function, we tested the association between DMN hypo-connectivity and three neuropsychological processes previously implicated in ADHD: (i) excessive task-unrelated spontaneous thought (i.e., mind-wandering); (ii) sub-optimal decision-making due to exaggerated temporal discounting; and (iii) delay aversion - a heightened emotional response to the imposition or experience of delay. METHODS:Twenty male adolescents with a clinical diagnosis of ADHD and 18 typically developing adolescents (all aged 11-16 years) underwent a resting-state fMRI scan to assess DMN connectivity. An experimental paradigm was used to assess temporal discounting and self-report questionnaires were used to measure mind wandering and delay aversion. RESULTS:ADHD was significantly associated with DMN hypo-connectivity specifically in the core subsystem, elevated levels of mind-wandering, delay aversion, and temporal discounting. Mediation analysis suggested that DMN hypoconnectivity mediated the link between ADHD and delay aversion. CONCLUSION/CONCLUSIONS:The results provide initial evidence that disturbances in the DMN may impair ability to regulate delay-related negative affect in adolescents with ADHD.

Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose-response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose-response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice.

BACKGROUND:In the UK, children with high levels of hyperactivity, impulsivity and inattention referred to clinical services with possible attention-deficit/hyperactivity disorder (ADHD) often wait a long time for specialist diagnostic assessment. Parent training (PT) has the potential to support parents during this difficult period, especially regarding the management of challenging and disruptive behaviours that often accompany ADHD. However, traditional face-to-face PT is costly and difficult to organise in a timely way. We have created a low-cost, easily accessible PT programme delivered via a phone app, Structured E-Parenting Support (STEPS), to address this problem. The overall OPTIMA programme will evaluate the efficacy and cost-effectiveness of STEPS as a way of helping parents manage their children behaviour while on the waitlist. To ensure the timely and efficient evaluation of STEPS in OPTIMA, we have worked with children's health services to implement a remote strategy for recruitment, screening and assessment of recently referred families. Part of this strategy is incorporated into routine clinical practice and part is OPTIMA specific. Here, we present the protocol for Phase 1 of OPTIMA-a study of the feasibility of this remote strategy, as a basis for a large-scale STEPS randomised controlled trial (RCT). METHODS:This is a single arm observational feasibility study. Participants will be parents of up to 100 children aged 5-11 years with high levels of hyperactivity/impulsivity, inattention and challenging behaviour who are waiting for assessment in one of five UK child and adolescent mental health or behavioural services. Recruitment, consenting and data collection will occur remotely. The primary outcome will be the rate at which the families, who meet inclusion criteria, agree in principle to take part in a full STEPS RCT. Secondary outcomes include acceptability of remote consenting and online data collection procedures; the feasibility of collecting teacher data remotely within the required timeframe, and technical difficulties with completing online questionnaires. All parents in the study will receive access to STEPS. DISCUSSION/CONCLUSIONS:Establishing the feasibility of our remote recruitment, consenting and assessment strategy is a pre-requisite for the full trial of OPTIMA. It can also provide a model for future trials conducted remotely.

INTRODUCTION:Attention-deficit/hyperactivity disorder (ADHD) is associated with binge eating (BE), food addiction (FA), and obesity/higher BMI in individuals without alcohol use disorder (AUD). ADHD is highly prevalent in patients with AUD, but it is unknown whether the presence of comorbid AUD might change the nature of the association between ADHD, BE, FA and BMI (food and alcohol may either compete for the same brain neurocircuitry or share vulnerability risk factors). Here, we filled this gap by testing the association between ADHD and FA/BE in adult patients hospitalized for AUD, with the strength of simultaneously assessing childhood and adult ADHD. We also investigated the association between ADHD and BMI, and the other factors associated with BMI (FA/BE, AUD severity). METHODS:We included 149 AUD inpatients between November 2018 and April 2019. We assessed both childhood and adulthood ADHD (Wender Utah Render Scale and Adult ADHD Self-Report Scale), FA (modified Yale Food Addiction Scale 2.0), BE (Binge Eating Scale), and BMI and AUD (clinical assessment). RESULTS:In multivariable analyses adjusted for age, adult ADHD was associated with higher BE scores (p = .048), but not significant BE (9% vs. 7%; p = .70). ADHD was also associated with FA diagnosis and the number or FA symptoms, with larger effect size for adult (ORs: 9.45[95%CI: 2.82-31.74] and 1.38[1.13-1.69], respectively) than childhood ADHD (ORs: 4.45[1.37-14.46] and 1.40[1.13-1.75], respectively). In multivariable analysis, BMI was associated with both significant BE (p < .001) and FA diagnosis (p = .014), but not adult ADHD nor AUD severity. CONCLUSION:In patients hospitalized for AUD, self-reported adult ADHD was associated with FA and BE, but not BMI. Our results set the groundwork for longitudinal research on the link between ADHD, FA, BE, and BMI in AUD inpatients.

OBJECTIVE:We meta-analyzed studies comparing perceptual timing abilities in the range of milliseconds to several seconds in individuals with ADHD and neurotypical participants, using the well-established time discrimination, time estimation, time production, and time reproduction paradigms. METHOD/METHODS:We searched Pubmed, OVID databases and WEB OF KNOWLEDGE through September 17, 2020. From 2,266 records, 55 studies were retained and meta-analyzed with random effects models. We conducted meta-regression analyses to explore moderating effects of task parameters and neuropsychological measures of working memory, attention, and inhibition on timing performance. RESULTS:Compared with those without ADHD, individuals with ADHD had significantly more severe difficulties in discriminating stimuli of very brief durations, especially in the sub-second range. They also had more variability in estimating the duration of stimuli lasting several seconds. Moreover, they showed deficits in time estimation and time production accuracy, indicative of an accelerated internal clock. Additional deficits in individual with ADHD were also found in the time reproduction paradigm, involving attentional (slower counting at short time intervals due to distraction) and motivational (faster counting at long time intervals due to increased delay aversion) functions. CONCLUSION/CONCLUSIONS:There is meta-analytic evidence of a broad range of timing deficits in individuals with ADHD. Results have implications for advancing our knowledge in the field (e.g., for refinement of recent timing models in ADHD) and clinical practice (e.g., testing timing functions to characterize the clinical phenotype of the patient and implementation of interventions to improve timing abilities).

Children with autism spectrum disorder (ASD) are frequently diagnosed with co-occurring medical conditions including inflammatory bowel disease (IBD). To investigate the association, we conducted a systematic review registered in PROSPERO (ID:CRD42021236263) with a random-effects meta-analysis. We searched PubMed, Embase, and PsycInfo (last search on January 25, 2021), and manually searched relevant publications. We included observational studies measuring the association between ASD and IBD. The primary outcome was the association (odds ratio, OR) between ASD and later development of IBD. Sensitivity analyses were conducted by quality, confounding adjustment, and study design. We performed meta-regression analyses and assessed heterogeneity, publication bias, and quality of studies with the Newcastle-Ottawa Scale. Overall, we included six studies consisting of eight datasets, including over 11 million participants. We found that ASD was significantly associated with subsequent incident IBD (any IBD, OR = 1.66, 95% confidence interval[CI] = 1.25-2.21, p < 0.001; ulcerative colitis, OR = 1.91, 95%CI = 1.41-2.6, p < 0.001; Crohn's disease, OR = 1.47, 95%CI = 1.15-1.88, p = 0.002). ASD and IBD were also associated regardless of temporal sequence of diagnosis (any IBD, OR = 1.57, 95%CI = 1.28-1.93, p < 0.001; ulcerative colitis, OR = 1.7, 95%CI = 1.36-2.12, p < 0.001; Crohn's disease, OR = 1.37, 95%CI = 1.12-1.69, p = 0.003). Sensitivity analyses confirmed the findings of the main analysis. Meta-regression did not identify any significant moderators. Publication bias was not detected. Quality was high in four datasets and medium in four. In conclusion, our findings highlight the need to screen for IBD in individuals with ASD, and future research should identify who, among those with ASD, has the highest risk of IBD, and elucidate the shared biological mechanisms between ASD and IBD.

This editorial perspective focuses on the challenges of research on child and adolescent mental health during the COVID-19 pandemic. Common limitations of published/ongoing studies are (i) being conducted in one or few countries, (ii) the survey being available in one or few languages, (iii) targeting selected samples (e.g., clinical populations and health workers) rather than the general population, (iv) only recruiting/reporting on non-representative samples, (v) focusing often on a restricted set of mental health outcomes, missing the broader picture of mental and physical health, quality of life and functioning, (vi) failing to use a longitudinal design and (vii) collecting only parental ratings or self-rated questionnaires from children and adolescents, but not both. We discuss how the Collaborative Outcomes Study on Health and Functioning during Infection Times (COH-FIT) was designed to address some of these challenges, also highlighting its limitations.

Problematic Usage of the Internet (PUI) has been linked to diverse structural gray matter changes in individual data studies. However, no quantitative synthesis across studies has been conducted. We aimed to identify gray matter regions showing significant spatial convergence across neuroimaging studies in PUI. We searched PubMed and PsycINFO up to 10/03/2021 and included original, cross-sectional comparative studies that examined structural gray matter imaging in PUI versus control groups; reported a whole-brain analysis; and provided peak coordinates for gray matter differences. From a total of 624 potentially relevant studies, 15 (including 355 individuals with PUI and 363 controls) were included in a meta-analysis of voxel-based morphometry studies. Anatomical likelihood estimation (ALE) meta-analysis was performed using extracted coordinates and identified significant spatial convergence in the medial/superior frontal gyri, the left anterior cingulate cortex/cingulate gyrus, and the left middle frontal/precentral gyri. Datasets contributing to these findings all indicated reduced gray matter in cases compared to controls. In conclusion, voxel-based morphometric studies indicate replicable gray matter reductions in the dorsolateral prefrontal cortex and anterior cingulate cortex in PUI, regions implicated in reward processing and top-down inhibitory control. Further studies are required to understand the nature of gray matter differences across PUI behaviors, as well as the contribution of particular mental health disorders, and the influence of variation in study and sample characteristics.