Faculty Bibliography

Aberrant reward processing is common in psychiatric disorders that begin during development. However, our understanding of the early reward system is limited, due to few studies assessing reward engagement across development. Moreover, the interpretation of these findings is based primarily on our understanding of the adult reward system. Here, we argue that approaches to early reward processing must be re-framed within the context of developmental transitions. This alternate perspective takes into account unique, age-specific brain network functions that promote adaptive behaviors as environmental demands change from infancy through childhood. We survey the literature on developing reward systems and ask the following critical questions: (1) how are rewarding stimuli defined for infants and children? (2) do adult-defined neural reward circuits also support early reward behavior? and (3) how can early circuit perturbation impact infant and adult circuit function? Altogether, we argue that this developmental niche-centered framework is needed for conceptually and theoretically approaching developmental research questions, including but also extending beyond the scope of reward. Finally, this framework can help us understand how disturbance in developmental processes may ultimately manifest as pathology.

Monosodium glutamate (MSG) has become one of the most widely used food additives in the global food supply. Although it has been classified for decades as a food ingredient that is generally recognized as safe, concerns about the health impacts of chronic MSG use, especially its potential effect on weight, are still ongoing. This comprehensive review summarizes the available human and animal evidence, highlighting potential mechanisms linking MSG use to weight gain or obesity, and discusses challenges and future research directions. Because of MSG intake worldwide as well as hidden MSG in food labeling, there is a pressing need for a mechanistic understanding of the health impacts of MSG use especially on weight. To generate robust scientific evidence and to clarify public concerns, rigorous mechanistic studies and randomized controlled clinical trials are warranted.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.

IMPORTANCE/UNASSIGNED:General trauma is the leading cause of nonobstetric maternal morbidity and mortality, affecting approximately 8% of all pregnancies. Pregnant women with traumatic brain injury (TBI) face high morbidity and mortality rates, requiring complex management due to physiological changes, teratogenic risks of treatments, and the need for fetal monitoring. OBJECTIVES/UNASSIGNED:To assess the consequences of TBI during pregnancy on maternal and fetal outcomes and to evaluate management strategies to inform clinical decision-making. EVIDENCE REVIEW/UNASSIGNED:A systematic literature search was conducted on January 12, 2024, in PubMed, Web of Science, and PsycInfo to identify articles published in English, German, or Spanish between January 1, 1990, and December 31, 2023, that included at least 1 pregnant individual with TBI. Peer-reviewed, human-based studies with original data on maternal and fetal outcomes were included. Reviews, meta-analyses, and nonhuman studies were excluded. Two independent reviewers screened abstracts and full-text articles. Study characteristics, pregnancy outcomes (maternal and fetal), management methods, and authors' conclusions were extracted. Risk of bias was assessed by 2 reviewers, with interrater agreement measured using Cohen κ. Disagreements were resolved through discussion. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. FINDINGS/UNASSIGNED:This systematic review included 16 articles involving a total of 4112 individuals (mean maternal age, 26.9 years; range, 16-47 years) who experienced TBI during pregnancy (mean gestational age at injury, 24 weeks; range, 3-38 weeks). The articles comprised 10 case reports, 2 case series, and 4 cohort studies. Motor vehicle crashes were the most common cause of injury, reported in 12 articles. The average Glasgow Coma Scale score ranged from 3 to 15 across all individuals. Conservative management was reported in 7 case patients, whereas surgery was performed in 6 case patients. Maternal outcomes ranged from functional recovery to severe cognitive impairment, and fetal outcomes varied from stable to severe adverse outcomes, including stillbirth and death. Risk of bias assessment indicated moderate to good methodological validity overall, but most articles demonstrated poor quality of evidence. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this review, no definitive association between TBI during pregnancy and maternal or fetal outcomes was found owing to conflicting findings, poor to moderate study quality, and limited evidence. Although some articles suggested increased risks such as placental abruption and cesarean delivery, the findings remained inconclusive. The findings of this review underscore the need for high-quality research, standardized reporting, and rigorous methodology to improve data reliability. Future research should focus on developing consensus-driven, multidisciplinary management strategies to improve maternal and fetal outcomes.

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.

Iron in the brain is essential to neurodevelopmental processes, as it supports neural functions, including processes of oxygen delivery, electron transport, and enzymatic activity. However, the development of brain iron before birth is scarcely understood. By estimating R2* (1/T2*) relaxometry from a sizable sample of fetal multiecho echo-planar imaging (EPI) scans, which is the standard sequence for functional magnetic resonance imaging (fMRI), across gestation, this study investigates age and sex-related changes in iron, across regions and tissue segments. Our findings reveal that brain R2* levels significantly increase throughout gestation spanning many different regions, except the frontal lobe. Furthermore, females exhibit a faster rate of R2* increase compared to males, in both gray matter and white matter. This sex effect is particularly notable within the left insula. This work represents the first MRI examination of iron accumulation and sex differences in developing fetal brains. This is also the first study to establish R2* estimation methodology in fetal multiecho functional MRI.

Parental depression is a risk factor for children's cognitive and psychological development. Literature has found reciprocal relations between parental depression and child psychopathology and effects of parental depression on children's cognition. The present study is the first to examine reciprocity among parental depression and child cognition, and pathways to child psychopathology. Structural equation models were conducted using data from the Early Head Start Research and Evaluation Project, a nationally representative sample of 3,001 economically marginalized families. Measures were collected in four waves from 14 months to 10-11 years. Reciprocal associations emerged between maternal and paternal depression at from 14 months to 5 years. Reciprocal parental depression was associated with greater psychopathology at age 10-11. Maternal depression predicted poorer child cognition, which indirectly predicted increased depression in mothers of children aged 3-5 through paternal depression, and in fathers at age 3, through earlier paternal depression. This study was unable to parse within- and between-person effects. Additionally, data for paternal depression was limited to ages 2 and 3. Findings emphasize the transactional nature of child cognition and child and parent psychopathology, supporting family focused intervention and prevention efforts that target parent psychopathology and child cognition.

Although parenting interventions are recommended by major clinical guidelines for managing children's behavioral challenges, including ADHD, their uptake in clinical practice remains limited. Building on the contributions of Hodson et al. and Nijboer et al. in the current issue of this journal, we here explore solutions to enhance this uptake. We first summarize the usual suspects: solutions that could be implemented in our current mental healthcare systems. Digital and brief interventions could remove obstacles that are often experienced with traditional parenting interventions, and nudges inspired by behavioral economic theories can help remove dynamic, time-varying barriers experienced by parents that may arise during the course of the intervention. We then zoom out and present a paradigmatic challenge. The current narrative surrounding behavioral problems like ADHD is predominantly biomedical, which tends to elevate expectations for treatments such as medication while simultaneously diminishing confidence in parenting interventions. From this perspective, it is unsurprising that engagement issues arise when a context-focused intervention such as parent training is proposed as a solution to a decontextualized problem like ADHD. Adopting a truly balanced biopsychosocial-societal perspective on behavioral problems like ADHD would better reflect their complex and heterogeneous etiology, and would broaden the scope for interventions, such as parenting programs, that focus on optimizing children's contextual environments.