Faculty Bibliography

A large number of studies have examined the association between advanced paternal age (APA) and risk of schizophrenia in offspring. Here we present an overview of epidemiological studies on this subject published since 2000, and systematically summarize their methodologies and results. Next, we discuss evidence to elucidate the potential mechanisms contributing to the association between APA and offspring schizophrenia, considering paternal psychiatric morbidity and genetic liability, maternal factors, and findings from family design studies. We propose that multiple mechanisms, including causal and non-causal pathways, contribute to the observed relationship between APA and schizophrenia in offspring, and conclude by highlighting the need for multi-disciplinary studies in disentangling these complex, non-mutually exclusive mechanisms.

Many everyday objects require "hidden" affordances to use as designed (e.g., twist open a water bottle). Previous work found a reliable developmental progression in children's learning of designed actions with adult objects such as containers and zippers-from non-designed exploratory actions, to the basics of the designed action, to successful implementation. Many objects designed for children (e.g., toys) also entail designed actions (e.g., interlocking bricks) but might not require a protracted period of discovery and implementation. We encouraged 12- to 60-month-old children (n = 91) and a comparative sample of 20 adults to play with six Duplo bricks to test whether the developmental progression identified for children's learning of adult objects with hidden affordances holds for a popular toy expressly designed for children. We also examined whether children's moment-to-moment behaviors with Duplo bricks inform on general processes involved in discovery and implementation of hidden affordances. With age, children progressed from non-designed exploratory actions, to attempts to interlock, to success, suggesting that the three-step developmental progression revealed with everyday adult objects broadly applies to learning hidden affordances regardless of object type. Detailing the process of learning (the type and timing of children's non-designed actions and attempts to interlock) revealed that the degree of lag between steps of the progression depends on the transparency of the required actions, the availability of perceptual feedback, and the difficulty of the perceptual-motor requirements. Findings provide insights into factors that help or hinder learning of hidden affordances.

Background/Purpose: The gut microbiome and its metabolites are dysregulated in rheumatoid arthritis. Short chain fatty acids (SCFAs), microbial fermentation byproducts of certain gut microbes, induce regulatory T cells (Treg) that exhibit antiinflammatory properties. Unsurprisingly, SCFA are found at reduced levels in both murine models of RA and patients. The SCFA butyrate has been shown to increase levels of gut and circulating Treg and ameliorate inflammatory arthritis in murine models. Additionally, we previously noted that SCFA supplementation in WT mice led to significant perturbations in gut bacterial composition with a significant increase in SCFA-producing commensals. Similarly, others have shown that a high-fiber diet increases circulating levels of SCFAs and decreases pro-arthritogenic cytokines (Durholz et al. Nutrients. 2020). We therefore hypothesized that butyrate supplementation may promote favorable gut microbial changes and increase tolerogenic adaptive immune response in RA patients.
Method(s): We designed an ongoing, prospective, proof-of-principle study to determine the effects of butyrate supplementation in new-onset RA (NORA) patients. First, we evaluated the effects of butyrate supplementation in healthy subjects (n=7; 1 gm 3 times daily for 14 days). Next, we evaluated the effects of butyrate on new-onset RA (n=5; 1 gm 3 times daily for 30 days) compared to methotrexate (n=20). Clinical history and joint exam were performed at baseline and follow up. Peripheral blood and fecal samples were collected at baseline and follow up for flow cytometric analysis of Treg and 16s rRNA sequencing, respectively. Wilcoxon signed-rank test was used to compare differences in Treg before and after butyrate administration.
Result(s): Although butyrate supplementation in healthy subjects did not lead to significant community changes by 7 days, it did lead to a significant increase in the percentage of circulating CD4+CD25+FoxP3+ Treg (p=0.02) followed by a significant increase in highly activated CD39+ Treg by 14 days (p < 0.0001). Gut bacterial alpha diversity (Shannon index) was significantly lower in NORA patients compared to healthy subjects at baseline (p=0.04; wilcox-test). After butyrate supplementation, NORA alpha diversity increased to levels approaching those of healthy subjects, with a modest increase in abundance of both Firmicutes and Bacteroidetes. LDA Effect Size analysis recapitulated previous studies where healthy subjects had greater abundance of SCFA producing commensals compared to NORA.
Conclusion(s): In both health and new-onset RA, butyrate supplementation is associated with changes in human gut microbiota composition and in peripheral Treg abundance and markers of Treg activation. In preliminary analyses of this ongoing prospective study, butyrate increased gut microbial diversity in NORA, suggesting that gut microbial composition may shift towards a healthier level of diversity. As seen in murine models, butyrate also increased Treg in healthy subjects. We hypothesize that, in patients, butyrate will induce modifications in gut microbial communities that favor a regulatory adaptive immune response that may ultimately lead to better clinical response

Hyperserotonemia, or elevated levels of whole blood serotonin (WB5-HT), was the first biomarker linked to autism spectrum disorder (ASD). Despite numerous studies investigating the etiology of hyperserotonemia, results have been inconsistent. Recent findings suggest a relationship between the immune system and hyperserotonemia. The current study investigated whether intestinal 5-HT levels, 5-HT gene expression, or intestinal cell types predict WB5-HT. Participants included thirty-one males aged 3-18 who were classified into one of three groups: ASD and functional GI issues, typically developing with GI issues, and typically developing without GI issues. Samples from a lower endoscopy were analyzed to examine the pathways in predicting WB-5HT. Results demonstrated an association between T-Lymphocytes and WB5-HT.

BACKGROUND:Early-onset (3-8 years old) disruptive behavior disorders (DBDs) have been linked to a range of psychosocial sequelae in adolescence and beyond, including delinquency, depression, and substance use. Given that low-income families are overrepresented in statistics on early-onset DBDs, prevention and early-intervention targeting this population is a public health imperative. The efficacy of Behavioral Parent Training (BPT) programs such as Helping the Noncompliant Child (HNC) has been called robust; however, given the additional societal and structural barriers faced by low-income families, family engagement and retention barriers can cause effects to wane with time. This study extends preliminary work by examining the potential for a Technology-Enhanced HNC (TE-HNC) program to improve and sustain parent skill proficiency and child outcomes among low-income families. METHODS:A randomized controlled trial with two parallel arms was the design for this study. A total of 101 children (3-8-years-old) with clinically significant problem behaviors from low-income households were randomized to HNC (n = 54) or TE-HNC (n = 47). Participants were assessed at pre-treatment, post-treatment, 3-month, and 6-month follow-ups. Primary outcomes were parent-reported and observed child behavior problems. Secondary outcomes included observed parenting skills use (ClinicalTrials.gov Identifier: NCT02191956). RESULTS:Primary analyses used latent curve modeling to examine treatment differences in the trajectory of change during treatment, maintenance of treatment gains, and levels of outcomes at the 6-month follow-up. Both programs yielded improvements in parenting skills and child problems at post-treatment. However, TE-HNC families evidenced greater maintenance of parent-reported and observed child behavior and observed positive parenting skills at the 6-month follow-up. CONCLUSIONS:Our findings contribute to an ongoing line of work suggesting that technology-enhanced treatment models hold promise for increasing markers of engagement in BPT and sustaining long-term outcomes among low-income families.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.¹ One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).² IT is a moderately heritable trait¹ that can be measured in multiple species.³ In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT¹ can be used later in life.

The COVID-19 pandemic has exacerbated some of the most pressing social problems and structural inequities, with a disproportionate impact on some of the most vulnerable youth. The goal of this article is to raise awareness among child mental health professionals of the ways in which the pandemic has likely exacerbated the commercial sexual exploitation of children in the United States. A second goal is to promote child mental health professionals' ability to identify and care for these resilient yet underresourced youth.

To identify the state-level policies and policy domains that state policymakers and advocates perceive as most important for positively impacting the use of children's mental health services (CMHS). We used a modified Delphi technique (i.e., two rounds of questionnaires and an interview) during Spring 2021 to elicit perceptions among state mental health agency officials and advocates (n = 28) from twelve states on state policies that impact the use of CMHS. Participants rated a list of pre-specified policies on a 7-point Likert scale (1 = not important, 7 = extremely important) in the following policy domains: insurance coverage and limits, mental health services, school and social. Participants added nine policies to the initial list of 24 policies. The "school" policy domain was perceived as the most important, while the "social" policy domain was perceived as the least important after the first questionnaire and the second most important policy domain after the second questionnaire. The individual policies perceived as most important were school-based mental health services, state mental health parity, and Medicaid reimbursement rates. Key stakeholders in CMHS should leverage this group of policies to understand the current policy landscape in their state and to identify gaps in policy domains and potential policy opportunities to create a more comprehensive system to address children's mental health from a holistic, evidence-based policymaking perspective.