Faculty Bibliography

Evidence suggests that maternal health in pregnancy is associated with autism in the offspring. However, most diagnoses in pregnant women have not been examined, and the role of familial confounding remains unknown. Our cohort included all children born in Denmark between 1998 and 2015 (n = 1,131,899) and their parents. We fitted Cox proportional hazard regression models to estimate the likelihood of autism associated with each maternal prenatal ICD-10 diagnosis, accounting for disease chronicity and comorbidity, familial correlations and sociodemographic factors. We examined the evidence for familial confounding using discordant sibling and paternal negative control designs. Among the 1,131,899 individuals in our sample, 18,374 (1.6%) were diagnosed with autism by the end of follow-up. Across 236 maternal diagnoses we tested (prevalence ≥0.1%), 30 were significantly associated with autism after accounting for sociodemographic factors, disorder chronicity and comorbidity, and correction for multiple testing. This included obstetric, cardiometabolic and psychiatric disorders (for example, diabetes in pregnancy (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.08-1.31) and depression (HR 1.49, 95% CI 1.27-1.75)), previously shown to be associated with autism. Family-based analyses provided strong evidence for familial confounding in most of the observed associations. Our findings indicate pervasive associations between maternal health in pregnancy and offspring autism and underscore that these associations are largely attributable to familial confounding.

We read with interest the paper "Meta-analysis: The Effectiveness of Youth Psychotherapy Interventions in Low- and Middle-Income Countries" by Venturo-Conerly et al. (2023).¹ The paper presents results on the effectiveness of youth psychotherapies in low- and middle-income countries (LMICs) from a systematic review and meta-analysis using rigorous, highly regarded methods. The authors should be commended for taking on this important subject. However, we feel that the paper needs to be situated in the backdrop of a few concerns that we believe are important for LMIC geographies. In our reply, we mainly focus on the finding that interventions developed in high-income countries (HIC) were more effective if not adapted to local conditions, suggesting that non-culturally adapted interventions had better outcomes than culturally adapted ones. This, as the authors note, seems counterintuitive.

IMPORTANCE/UNASSIGNED:Down syndrome, resulting from trisomy 21, is the most prevalent chromosomal disorder and a leading cause of intellectual disability. Despite its significant impact on brain development, research on the white matter microstructure in infants with Down syndrome remains limited. OBJECTIVE/UNASSIGNED:To investigate early white matter microstructure in infants with Down syndrome using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). DESIGN/UNASSIGNED:Infants were recruited and scanned between March 2019 and May 2024 as participants in prospective studies conducted by the Infant Brain Imaging Study (IBIS) Network. Data were analyzed in October 2024. SETTING/UNASSIGNED:Data collection occurred at five research centers in Minnesota, Missouri, North Carolina, Pennsylvania, and Washington. PARTICIPANTS/UNASSIGNED:Down syndrome and control infants were scanned at 6 months of age. Control infants had no Down syndrome diagnosis and either had a typically developing older sibling or, if they had an older sibling with autism, were confirmed not to meet clinical best estimate criteria for an autism diagnosis. EXPOSURE/UNASSIGNED:Diagnosis of Down syndrome. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The outcome of interest was white matter microstructure quantified using DTI and NODDI measures. RESULTS/UNASSIGNED:A total of 49 Down syndrome (28 [57.14%] female) and 37 control (18 [48.65%] female) infants were included. Infants with Down syndrome showed significant reductions in fractional anisotropy and neurite density index across multiple association tracts, particularly in the inferior fronto-occipital fasciculus and superior longitudinal fasciculus II, consistent with reduced structural integrity and neurite density. These tracts also demonstrated increased radial diffusivity, suggesting delayed myelination. The inferior fronto-occipital fasciculus and uncinate fasciculus exhibited increased neurite dispersion and fanning in Down syndrome infants, reflected by elevated orientation dispersion index. Notably, the optic tracts in Down syndrome infants exhibited a distinct pattern of elevated fractional anisotropy and axial diffusivity, and lower radial diffusivity and orientation dispersion index, suggesting an early maturation of these pathways. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This first characterization of white matter microstructure in Down syndrome infants reveals widespread white matter developmental delays. These findings provide new insights into the early neurodevelopment of Down syndrome and may inform early therapeutic interventions.

Active avoidance is a core behavior for human coping, and its excess is common across psychiatric diseases. The decision to actively avoid a threat is influenced by cost and reward. Yet, threat, avoidance, and reward have been studied in silos. We discuss behavioral and brain circuits of active avoidance and the interactions with fear and threat. In addition, we present a neural toggle switch model enabling fear-to-anxiety transition and approaching reward vs. avoiding harm decision. To fully comprehend how threat, active avoidance, and reward intersect, it is paramount to develop one shared experimental approach across phenomena and behaviors, which will ultimately allow us to better understand human behavior and pathology.

UNLABELLED:restored food intake, suppressed cachexia and rescued lethality of autophagy-deficient mice. To test if appetite suppression by CCL2 was responsible for lethal cachexia we performed single nucleus RNA sequencing of the hypothalamus, the center of appetite control in the brain. Notably, we found that autophagy deficiency was specifically toxic to PMCH and HCRT neurons that produce orexigenic neuropeptides that promote food intake, which was rescued by deficiency in CCL2. Finally, the restoration of food intake via leptin deficiency prevented lethal cachexia in autophagy-deficient mice. Our findings demonstrate a novel mechanism where autophagy prevents induction of a cachexia factor, CCL2, which damages neurons that maintain appetite, the destruction of which may be central to degenerative wasting conditions. KEY POINTS OF PAPER/UNASSIGNED:1) Autophagy-deficient mice have reduced food intake, systemic inflammation, and cachexia2) CCL2, but not GDF15 or CXCL10, induces lethal cachexia caused by autophagy defect3) Autophagy-deficient mice have CCL2-dependent destruction of appetite-promoting neurons in the hypothalamus4) Leptin deficiency restores appetite and rescues lethal cachexia in autophagy-deficient mice5) Autophagy-deficient mice die from cachexia mediated by appetite loss6) Degenerative conditions due to impaired autophagy are caused by the inflammatory response to the damage7) Targeting CCL2 may be a viable approach to prevent degenerative wasting disorders.

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.