Faculty Bibliography

INTRODUCTION/BACKGROUND:Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders. METHODS AND ANALYSIS/METHODS:We will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses. ETHICS AND DISSEMINATION/BACKGROUND:We do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.

Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. The existing data suggest that early diagnosis and intervention can improve ASD outcomes. The causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. There is an increasing recognition that ASD might be associated with oxidative stress through several mechanisms including abnormal metabolism (lipid peroxidation) and the toxic buildup of reactive oxygen species (ROS). Glutathione acts as an antioxidant, a free radical scavenger and a detoxifying agent. This open-label pilot study investigates the tolerability and effectiveness of oral supplementation with Opitac^TM gluthathione as a treatment for patients with ASD. The various aspects of glutathione Opitac^TM glutathione bioavailability were examined when administered by oral routes. The absorption of glutathione from the gastrointestinal tract has been recently investigated. The results of this case series suggest that oral glutathione supplementation may improve oxidative markers, but this does not necessarily translate to the observed clinical improvement of subjects with ASD. The study reports a good safety profile of glutathione use, with stomach upset reported in four out of six subjects. This article discusses the role of the gut microbiome and redox balance in ASD and notes that a high baseline oxidative burden may make some patients poor responders to glutathione supplementation. In conclusion, an imbalance in redox reactions is only one of the many factors contributing to ASD, and further studies are necessary to investigate other factors, such as impaired neurotransmission, immune dysregulation in the brain, and mitochondrial dysfunction.

UNLABELLED:Interictal spikes (IIS) and seizures are well-documented in Alzheimer's disease (AD). IIS typically outnumber seizures, supporting their role as a prominent EEG biomarker in AD. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) also occur, but it is currently unknown how HFOs compare to IIS. Therefore, we asked whether the incidence of HFOs and IIS differed and if they are differentially affected by behavioral state. We used three mouse lines that simulate aspects of AD: Tg2576, presenilin 2 knockout, and Ts65Dn mice. We recorded and quantified HFOs and IIS in the hippocampus during wakefulness, slow-wave sleep, and rapid eye movement sleep. In all three mouse lines, HFOs were more frequent than IIS. High numbers of HFOs correlated with fewer IIS, suggesting for the first time possible competing dynamics among them in AD. Notably, HFOs occurred in more behavioral states than IIS. In summary, HFOs were the most abundant EEG abnormality when compared to IIS, and occurred in all behavioral states, suggesting they are a better biomarker than IIS. These findings pertained to three mouse lines, which is important because they simulate different aspects of AD. We also show that HFOs may inhibit IIS. SHORT SUMMARY/OBJECTIVE:Interictal spikes (IIS) and seizures are common in Alzheimer's disease (AD). IIS are more frequent than seizures and occur during earlier disease stages. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) occur, but a comparison between IIS and HFOs is lacking. Here we used 3 mouse lines with AD features and local field potential recordings to quantify IIS and HFOs. We found that HFOs outnumbered IIS and that their total numbers were inversely correlated with IIS. HFOs occurred during more behavioral states than IIS. Therefore, HFOs were the most abundant EEG abnormality, and this was generalizable across 3 types of preclinical AD.

BACKGROUND:The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. METHODS:71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. RESULTS: = 0.486, p < 0.001). CONCLUSIONS:Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.

When children first meet a stranger, there is great variation in how much they will approach and engage with the stranger. While individual differences in this type of behavior-called social wariness-are well-documented in temperament research, surprisingly little attention has been paid to the social groups (such as race) of the stranger and how these characteristics might influence children's social wariness. In contrast, research on children's social bias and interracial friendships rarely examines individual differences in temperament and how temperament might influence cross-group interactions. The current study bridges the gap across these different fields of research by examining whether the racial group of an unfamiliar peer or adult moderates the association between temperament and the social wariness that children display. Utilizing a longitudinal dataset that collected multiple measurements of children's temperament and behaviors (including parent-reported shyness and social wariness toward unfamiliar adults and peers) across early childhood, we found that 2- to 7-year-old children with high parent-reported shyness showed greater social wariness toward a different-race stranger compared to a same-race stranger, whereas children with low parent-reported shyness did not. These results point to the importance of considering racial group membership in temperament research and the potential role that temperament might play in children's cross-race interactions. RESEARCH HIGHLIGHTS: Previous research on temperament has not considered how the race of strangers could influence children's social wariness. We find evidence that 2- to 7-year-old children with high parent-reported shyness show greater social wariness toward a different-race stranger compared to a same-race stranger. These results point to the importance of considering racial group membership in temperament research. Our findings also suggest temperament may play a role in children's cross-race interactions.

Caregivers often tailor their language to infants' ongoing actions (e.g., "are you stacking the blocks?"). When infants develop new motor skills, do caregivers show concomitant changes in their language input? We tested whether the use of verbs that refer to locomotor actions (e.g., "come," "bring," "walk") differed for mothers of 13-month-old crawling (N = 16) and walking infants (N = 16), and mothers of 18-month-old experienced walkers (N = 16). Mothers directed twice as many locomotor verbs to walkers compared to same-age crawlers, but mothers' locomotor verbs were similar for younger and older walkers. In real-time, mothers' use of locomotor verbs was dense when infants were locomoting, and sparse when infants were stationary, regardless of infants' crawler/walker status. Consequently, infants who spent more time in motion received more locomotor verbs compared to infants who moved less frequently. Findings indicate that infants' motor skills guide their in-the-moment behaviors, which in turn shape the language they receive from caregivers. RESEARCH HIGHLIGHTS: Infants' motor skills guide their in-the-moment behaviors, which in turn shape the language they receive from caregivers. Mothers directed more frequent and diverse verbs that referenced locomotion (e.g., "come," "go," "bring") to walking infants compared to same-aged crawling infants. Mothers' locomotor verbs were temporally dense when infants locomoted and sparse when infants were stationary, regardless of whether infants could walk or only crawl.

OBJECTIVES/OBJECTIVE:Developmentally specified measures that identify clinically salient irritability are needed for early school-age youth to meaningfully capture this transdiagnostic risk factor for psychopathology. Thus, the current study modeled the normal:abnormal irritability spectrum and generated a clinically optimized screening tool for this population. METHODS:The irritability spectrum was modeled via the youth version of the Multidimensional Assessment Profile Scales-Temper Loss Scale (MAPS-TL-Youth) in children (n = 474; 6.0-8.9 years) using item response theory (IRT). Both cross-cutting core irritability items from the early childhood version and new developmentally specific items were included. Items uniquely associated with impairment were identified and used to derive a brief, clinically optimized irritability screener. Longitudinal data were then utilized to test the predictive utility of this clinically optimized screener in preadolescence (n = 348; 8.0-12.9 years). RESULTS:Most children exhibit irritability regularly, but daily occurrence was rare. Of the top 10 most severe items from the IRT analyses, 9 were from the developmentally specific items added for the MAPS-TL Youth version. Two items associated with concurrent impairment were identified for the clinically optimized irritability screener ("Become frustrated easily" and "Act irritable"). The MAPS-TL-Youth clinically optimized screener demonstrated good sensitivity (69%) and specificity (84%) in relation to concurrent DSM 5 irritability-related diagnoses. Youth with elevated scores on the screener at early school age (ESA) had more than 7x greater odds of irritability-related psychopathology at pre-adolescence. CONCLUSIONS:The MAPS-TL-Youth characterized the developmental spectrum of irritability at ESA and a clinically optimized screener showed promise at predicting psychopathology risk. Rigorous testing of clinical applications is a critical next step.