Advances in fetal and neonatal neuroimaging and everyday exposures.

The complex, tightly regulated process of prenatal brain development may be adversely affected by "everyday exposures" such as stress and environmental pollutants. Researchers are only just beginning to understand the neural sequelae of such exposures, with advances in fetal and neonatal neuroimaging elucidating structural, microstructural, and functional correlates in the developing brain. This narrative review discusses the wide-ranging literature investigating the influence of parental stress on fetal and neonatal brain development as well as emerging literature assessing the impact of exposure to environmental toxicants such as lead and air pollution. These 'everyday exposures' can co-occur with other stressors such as social and financial deprivation, and therefore we include a brief discussion of neuroimaging studies assessing the effect of social disadvantage. Increased exposure to prenatal stressors is associated with alterations in the brain structure, microstructure and function, with some evidence these associations are moderated by factors such as infant sex. However, most studies examine only single exposures and the literature on the relationship between in utero exposure to pollutants and fetal or neonatal brain development is sparse. Large cohort studies are required that include evaluation of multiple co-occurring exposures in order to fully characterize their impact on early brain development. IMPACT: Increased prenatal exposure to parental stress and is associated with altered functional, macro and microstructural fetal and neonatal brain development. Exposure to air pollution and lead may also alter brain development in the fetal and neonatal period. Further research is needed to investigate the effect of multiple co-occurring exposures, including stress, environmental toxicants, and socioeconomic deprivation on early brain development.

Post-acute sequelae of SARS-CoV-2 infection (Long COVID) in older adults.

Long COVID, also known as PASC (post-acute sequelae of SARS-CoV-2), is a complex infection-associated chronic condition affecting tens of millions of people worldwide. Many aspects of this condition are incompletely understood. Among them is how this condition may manifest itself in older adults and how it might impact the older population. Here, we briefly review the current understanding of PASC in the adult population and examine what is known on its features with aging. Finally, we outline the major gaps and areas for research most germane to older adults.

Exposure to urban particulate matter (UPM) impairs mitochondrial dynamics in BV2 cells, triggering a mitochondrial biogenesis response.

World Health Organisation data suggest that up to 99% of the global population are exposed to air pollutants above recommended levels. Impacts to health range from increased risk of stroke and cardiovascular disease to chronic respiratory conditions, and air pollution may contribute to over 7 million premature deaths a year. Additionally, mounting evidence suggests that in utero or early life exposure to particulate matter (PM) in ambient air pollution increases the risk of neurodevelopmental impairment with obvious lifelong consequences. Identifying brain-specific cellular targets of PM is vital for determining its long-term consequences. We previously established that microglial-like BV2 cells were particularly sensitive to urban (U)PM-induced damage including reactive oxygen species production, which was abrogated by a mitochondrially targeted antioxidant. Here we extend those studies to find that UPM treatment causes a rapid impairment of mitochondrial function and increased mitochondrial fragmentation. However, there is a subsequent restoration of mitochondrial and therefore cell health occurring concomitantly with upregulated measures of mitochondrial biogenesis and mitochondrial load. Our data highlight that protecting mitochondrial function may represent a valuable mechanism to offset the effects of UPM exposure in the neonatal brain. KEY POINTS: Air pollution represents a growing risk to long-term health especially in early life, and the CNS is emerging a target for airborne particulate matter (PM). We previously showed that microglial-like BV2 cells were vulnerable to urban (U)PM exposure, which impaired cell survival and promoted reactive oxygen species production. Here we find that, following UPM exposure, BV2 mitochondrial membrane potential is rapidly reduced, concomitant with decreased cellular bioenergetics and increased mitochondrial fission. However, markers of mitochondrial biogenesis and mitochondrial mass are subsequently induced, which may represent a cellular mitigation strategy. As mitochondria are more vulnerable in the developing brain, exposure to air pollution may represent a greater risk to lifelong health in this cohort; conversely, promoting mitochondrial integrity may offset these risks.

Advanced magnetic resonance imaging detects altered placental development in pregnancies affected by congenital heart disease.

Congenital heart disease (CHD) is the most common congenital malformation and is associated with adverse neurodevelopmental outcomes. The placenta is crucial for healthy fetal development and placental development is altered in pregnancy when the fetus has CHD. This study utilized advanced combined diffusion-relaxation MRI and a data-driven analysis technique to test the hypothesis that placental microstructure and perfusion are altered in CHD-affected pregnancies. 48 participants (36 controls, 12 CHD) underwent 67 MRI scans (50 control, 17 CHD). Significant differences in the weighting of two independent placental and uterine-wall tissue components were identified between the CHD and control groups (both pFDR < 0.001), with changes most evident after 30 weeks gestation. A significant trend over gestation in weighting for a third independent tissue component was also observed in the CHD cohort (R = 0.50, pFDR = 0.04), but not in controls. These findings add to existing evidence that placental development is altered in CHD. The results may reflect alterations in placental perfusion or the changes in fetal-placental flow, villous structure and maturation that occur in CHD. Further research is needed to validate and better understand these findings and to understand the relationship between placental development, CHD, and its neurodevelopmental implications.

Autoantibodies to type I interferons in patients with systemic mastocytosis.

Background: Autoantibodies to type I interferons have been identified in association with a variety of inflammatory and autoimmune diseases. Type I interferons have demonstrated inhibitory effects on mast cell proliferation and degranulation. Systemic mastocytosis (SM) is a disease characterized by increased mast cell burden and mediator release. Whether autoantibodies to type I interferon are present in the sera of patients with SM, and if so, whether they correlate with characteristics of disease, is unknown. Objective: The purpose of this study was to determine whether autoantibodies to type I interferons are observed in the sera of patients with SM, and if so, whether they correlate with biomarkers of disease severity. Methods: We analyzed sera from 89 patients with SM for concentrations of autoantibodies to type I interferon by using a multiplex particle-based assay and signal neutralization capacity by using a STAT1 activity assay and then compared these measurements with those in a database of information on 1284 healthy controls. Results: Our cohort was predominantly female (57.3%), with a median age of 56 years. Of the cohort members, 13 produced autoantibodies to IFN-ß, 3 to IFN-ω, and 0 to IFN-α. None of the 13 sera demonstrated signal neutralization. Neither autoantibody concentration nor signaling inhibition measurements correlated with tryptase concentrations or D816V allele burden. Conclusion: Although a small subpopulation of patients with SM have autoantibodies to type I interferons, there was no correlation between autoantibody production and signaling inhibition. These data are consistent with the conclusion that autoantibodies to type I interferon do not play a significant role in the pathogenesis or severity of SM.

Self-referential processing in anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) is a serious psychiatric illness associated with significant medical and psychiatric comorbidity and impairment. Theoretical models of AN and self-report studies suggest that negative self-evaluation (i.e., low self-esteem) is related to the development and maintenance of AN. The goal of this study was to extend findings from self-report methodology using a neurocognitive task that probes self-evaluation implicitly and explicitly. METHOD: We compared female adolescent and adult patients with AN (n = 35) and healthy controls (HC, n = 38) on explicit (i.e., endorsement of words as self-relevant), implicit (recall, recognition, reaction time), and composite (i.e., valence index, bias score, drift rates) indices of self-evaluation. We applied a drift-diffusion model to compute the drift rates, reflecting participants' decision-making process as to whether words were self-relevant. The association between self-evaluation indices and eating disorder severity was examined. RESULTS: There were significant Group × Condition interaction effects for all explicit and implicit measures (all p's ≤ .01), where the AN group endorsed, recalled, and recognized more negative relative to positive words than HC. The AN group had more negative valence index and bias scores, and slower drift rate away from negative words, reflecting more negative self-evaluation. The finding for recall was attenuated when individuals with depression were excluded. Measures of self-evaluation bias were not related to eating disorder severity. DISCUSSION: Using a neurocognitive approach that includes explicit and implicit indices of bias, results suggest that patients with AN have more negative self-evaluation. Due to the cross-sectional design, additional studies are needed to further evaluate directionality. PUBLIC SIGNIFICANCE: Negative self-evaluation/low self-esteem is thought to contribute to eating disorder symptoms. Findings of this study using a neurocognitive task to probe self-evaluation suggested that individuals with anorexia nervosa have more negative self-evaluation, reflected by endorsing and remembering more negative (than positive) words compared to healthy controls, and doing so faster. Targeting the construct of negative self-evaluation in treatment of AN may be warranted.

Neonatal brain dynamic functional connectivity in term and preterm infants and its association with early childhood neurodevelopment.

Brain dynamic functional connectivity characterises transient connections between brain regions. Features of brain dynamics have been linked to emotion and cognition in adult individuals, and atypical patterns have been associated with neurodevelopmental conditions such as autism. Although reliable functional brain networks have been consistently identified in neonates, little is known about the early development of dynamic functional connectivity. In this study we characterise dynamic functional connectivity with functional magnetic resonance imaging (fMRI) in the first few weeks of postnatal life in term-born (n = 324) and preterm-born (n = 66) individuals. We show that a dynamic landscape of brain connectivity is already established by the time of birth in the human brain, characterised by six transient states of neonatal functional connectivity with changing dynamics through the neonatal period. The pattern of dynamic connectivity is atypical in preterm-born infants, and associated with atypical social, sensory, and repetitive behaviours measured by the Quantitative Checklist for Autism in Toddlers (Q-CHAT) scores at 18 months of age.

Improving Vaccine Equity: How Community Engagement and Informatics Facilitate Health System Outreach to Underrepresented Groups.

BACKGROUND: Given the inequities in access to health care resources like COVID-19 vaccination, health systems should carefully consider how to reach underrepresented groups. Reflecting on vaccine rollout efforts holds insight on the role of community engagement and informatics support in promoting health equity. OBJECTIVES: This study aimed to assess the effectiveness of four outreach strategies deployed by University of Washington (UW) Medicine in improving vaccine equity over traditional vaccine scheduling online or by phone, we report on appointment scheduling and completion of appointments (i.e., vaccine administration) through (1) automated outreach to individuals from underrepresented groups, (2) temporary "pop-up" clinics in neighborhoods highly impacted by COVID-19, (3) vulnerable population clinics, and (4) mobile vaccine vans. METHODS: We conducted a 6-month retrospective analysis of electronic health records (EHR) to describe the sociodemographic characteristics of individuals who scheduled appointments using the outreach strategies and characteristics associated with a greater likelihood of vaccine administration based on appointment completion. To help explain trends in the EHR data, we engaged 10 health system leaders and staff who spearheaded the outreach strategies in follow-up conversations to identify qualitative insights into what worked and why. RESULTS: Compared with traditional scheduling, all outreach strategies except vulnerable population clinics had higher vaccine appointment completion rates, including automated outreach (N = 3,734 [94.7%], p < 0.001), pop-up clinics (N = 4,391 [96.0%], p < 0.001), and mobile vans (N = 4,198 [99.1%], p < 0.001); and lower cancellation rates, including automated outreach (N = 166 [1.1%], p < 0.001), pop-up clinics (N = 155 [0.6%], p < 0.001), and mobile vans (N = 0 [0%], p < 0.001). Qualitative insights emphasized ongoing community partnerships and information resources in successful outreach. CONCLUSION: Vaccine equity outreach strategies improved the proportion of patients who scheduled and completed vaccination appointments among populations disproportionately impacted by COVID-19. Engaging community partners and equity-focused informatics tools can facilitate outreach. Lessons from these outreach strategies carry practical implications for health systems to amplify their health equity efforts.

Executive Function in Preschool Children with Congenital Heart Disease and Controls: The Role of a Cognitively Stimulating Home Environment.

OBJECTIVE: To assess the relationships between (1) environmental and demographic factors and executive function (EF) in preschool children with congenital heart disease (CHD) and controls and (2) clinical and surgical risk factors and EF in preschool children with CHD. STUDY DESIGN: At 4-6 years of age, parents of children with CHD (n = 51) and controls (n = 124) completed the Behavior Rating Inventory of Executive Function, Preschool Version questionnaire and the Cognitively Stimulating Parenting Scale (CSPS). Multivariable general linear modeling assessed the relationship between Behavior Rating Inventory of Executive Function, Preschool Version composite scores (Inhibitory Self-Control Index [ISCI], Flexibility Index [FI], and Emergent Metacognition Index [EMI]) and group (CHD/control), sex, age at assessment, gestational age, Index of Multiple Deprivation, and CSPS scores. The relationships between CHD type, surgical factors, and brain magnetic resonance imaging injury rating and ISCI, FI, and EMI scores were assessed. RESULTS: The presence of CHD, age at assessment, sex, and Index of Multiple Deprivation were not associated with EF scores. Lower gestational age was associated with greater ISCI and FI scores, and age at assessment was associated with lower FI scores. Group significantly moderated the relationship between CSPS and EF, such that CSPS significantly predicted EF in children with CHD (ISCI: P = .0004; FI: P = .0015; EMI: P = .0004) but not controls (ISCI: P = .2727; FI: P = .6185; EMI: P = .3332). There were no significant relationships between EF scores and surgical factors, CHD type, or brain magnetic resonance imaging injury rating. CONCLUSIONS: Supporting parents to provide a cognitively stimulating home environment may improve EF in children with CHD. The home and parenting environment should be considered when designing intervention studies aimed at improving EF in this patient group.

Intra-tumoral T cells in pediatric brain tumors display clonal expansion and effector properties.

Brain tumors in children are a devastating disease in a high proportion of patients. Owing to inconsistent results in clinical trials in unstratified patients, the role of immunotherapy remains unclear. We performed an in-depth survey of the single-cell transcriptomes and clonal relationship of intra-tumoral T cells from children with brain tumors. Our results demonstrate that a large fraction of T cells in the tumor tissue are clonally expanded with the potential to recognize tumor antigens. Such clonally expanded T cells display enrichment of transcripts linked to effector function, tissue residency, immune checkpoints and signatures of neoantigen-specific T cells and immunotherapy response. We identify neoantigens in pediatric brain tumors and show that neoantigen-specific T cell gene signatures are linked to better survival outcomes. Notably, among the patients in our cohort, we observe substantial heterogeneity in the degree of clonal expansion and magnitude of T cell response. Our findings suggest that characterization of intra-tumoral T cell responses may enable selection of patients for immunotherapy, an approach that requires prospective validation in clinical trials.

Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

Development of neonatal-specific sequences for portable ultralow field magnetic resonance brain imaging: a prospective, single-centre, cohort study.

Background: Magnetic Resonance (MR) imaging is key for investigation of suspected newborn brain abnormalities. Access is limited in low-resource settings and challenging in infants needing intensive care. Portable ultralow field (ULF) MRI is showing promise in bedside adult brain imaging. Use in infants and children has been limited as brain-tissue composition differences necessitate sequence modification. The aim of this study was to develop neonatal-specific ULF structural sequences and test these across a range of gestational maturities and pathologies to inform future validation studies. Methods: Prospective cohort study within a UK neonatal specialist referral centre. Infants undergoing 3T MRI were recruited for paired ULF (64mT) portable MRI by convenience sampling from the neonatal unit and post-natal ward. Key inclusion criteria: 1) Infants with risk or suspicion of brain abnormality, or 2) preterm and term infants without suspicion of major genetic, chromosomal or neurological abnormality. Exclusions: presence of contra-indication for MR scanning. ULF sequence parameters were optimised for neonatal brain-tissues by iterative and explorative design. Neuroanatomic and pathologic features were compared by unblinded review, informing optimisation of subsequent sequence generations in a step-wise manner. Main outcome: visual identification of healthy and abnormal brain tissues/structures. ULF MR spectroscopy, diffusion, susceptibility weighted imaging, arteriography, and venography require pre-clinical technical development and have not been tested. Findings: Between September 23, 2021 and October 25, 2022, 102 paired scans were acquired in 87 infants; 1.17 paired scans per infant. Median age 9 days, median postmenstrual age 40+2 weeks (range: 31+3-53+4). Infants had a range of intensive care requirements. No adverse events observed. Optimised ULF sequences can visualise key neuroanatomy and brain abnormalities. In finalised neonatal sequences: T2w imaging distinguished grey and white matter (7/7 infants), ventricles (7/7), pituitary tissue (5/7), corpus callosum (7/7) and optic nerves (7/7). Signal congruence was seen within the posterior limb of the internal capsule in 10/11 infants on finalised T1w scans. In addition, brain abnormalities visualised on ULF optimised sequences have similar MR signal patterns to 3T imaging, including injury secondary to infarction (6/6 infants on T2w scans), hypoxia-ischaemia (abnormal signal in basal ganglia, thalami and white matter 2/2 infants on T2w scans, cortical highlighting 1/1 infant on T1w scan), and congenital malformations: polymicrogyria 3/3, absent corpus callosum 2/2, and vermian hypoplasia 3/3 infants on T2w scans. Sequences are susceptible to motion corruption, noise, and ULF artefact. Non-identified pathologies were small or subtle. Interpretation: On unblinded review, optimised portable MR can provide sufficient contrast, signal, and resolution for neuroanatomical identification and detection of a range of clinically important abnormalities. Blinded validation studies are now warranted. Funding: The Bill and Melinda Gates Foundation, the MRC, the Wellcome/EPSRC Centre for Medical Engineering, the MRC Centre for Neurodevelopmental Disorders, and the National Institute for Health Research (NIHR) Biomedical Research Centres based at Guy's and St Thomas' and South London & Maudsley NHS Foundation Trusts and King's College London.

FOXO inhibition rescues α-defensin expression in human intestinal organoids.

To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring DEFA5 and DEFA6 to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.

Non-invasive mapping of human placenta microenvironments throughout pregnancy with diffusion-relaxation MRI.

INTRODUCTION: In-vivo measurements of placental structure and function have the potential to improve prediction, diagnosis, and treatment planning for a wide range of pregnancy complications, such as fetal growth restriction and pre-eclampsia, and hence inform clinical decision making, ultimately improving patient outcomes. MRI is emerging as a technique with increased sensitivity to placental structure and function compared to the current clinical standard, ultrasound. METHODS: We demonstrate and evaluate a combined diffusion-relaxation MRI acquisition and analysis pipeline on a sizable cohort of 78 normal pregnancies with gestational ages ranging from 15 + 5 to 38 + 4 weeks. Our acquisition comprises a combined T2*-diffusion MRI acquisition sequence - which is simultaneously sensitive to oxygenation, microstructure and microcirculation. We analyse our scans with a data-driven unsupervised machine learning technique, InSpect, that parsimoniously identifies distinct components in the data. RESULTS: We identify and map seven potential placental microenvironments and reveal detailed insights into multiple microstructural and microcirculatory features of the placenta, and assess their trends across gestation. DISCUSSION: By demonstrating direct observation of micro-scale placental structure and function, and revealing clear trends across pregnancy, our work contributes towards the development of robust imaging biomarkers for pregnancy complications and the ultimate goal of a normative model of placental development.

Total and Regional Brain Volumes in Fetuses With Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) is common and is associated with impaired early brain development and neurodevelopmental outcomes, yet the exact mechanisms underlying these associations are unclear. PURPOSE: To utilize MRI data from a cohort of fetuses with CHD as well as typically developing fetuses to test the hypothesis that expected cerebral substrate delivery is associated with total and regional fetal brain volumes. STUDY TYPE: Retrospective case-control study. POPULATION: Three hundred eighty fetuses (188 male), comprising 45 healthy controls and 335 with isolated CHD, scanned between 29 and 37 weeks gestation. Fetuses with CHD were assigned into one of four groups based on expected cerebral substrate delivery. FIELD STRENGTH/SEQUENCE: T2-weighted single-shot fast-spin-echo sequences and a balanced steady-state free precession gradient echo sequence were obtained on a 1.5 T scanner. ASSESSMENT: Images were motion-corrected and reconstructed using an automated slice-to-volume registration reconstruction technique, before undergoing segmentation using an automated pipeline and convolutional neural network that had undergone semi-supervised training. Differences in total, regional brain (cortical gray matter, white matter, deep gray matter, cerebellum, and brainstem) and brain:body volumes were compared between groups. STATISTICAL TESTS: ANOVA was used to test for differences in brain volumes between groups, after accounting for sex and gestational age at scan. PFDR -values <0.05 were considered statistically significant. RESULTS: Total and regional brain volumes were smaller in fetuses where cerebral substrate delivery is reduced. No significant differences were observed in total or regional brain volumes between control fetuses and fetuses with CHD but normal cerebral substrate delivery (all PFDR > 0.12). Severely reduced cerebral substrate delivery is associated with lower brain:body volume ratios. DATA CONCLUSION: Total and regional brain volumes are smaller in fetuses with CHD where there is a reduction in cerebral substrate delivery, but not in those where cerebral substrate delivery is expected to be normal. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Individual Assessment of Perioperative Brain Growth Trajectories in Infants With Congenital Heart Disease: Correlation With Clinical and Surgical Risk Factors.

Background Infants with congenital heart disease (CHD) are at risk of neurodevelopmental impairments, which may be associated with impaired brain growth. We characterized how perioperative brain growth in infants with CHD deviates from typical trajectories and assessed the relationship between individualized perioperative brain growth and clinical risk factors. Methods and Results A total of 36 infants with CHD underwent preoperative and postoperative brain magnetic resonance imaging. Regional brain volumes were extracted. Normative volumetric development curves were generated using data from 219 healthy infants. Z-scores, representing the degree of positive or negative deviation from the normative mean for age and sex, were calculated for regional brain volumes from each infant with CHD before and after surgery. The degree of Z-score change was correlated with clinical risk factors. Perioperative growth was impaired across the brain, and it was associated with longer postoperative intensive care stay (false discovery rate P<0.05). Higher preoperative creatinine levels were associated with impaired brainstem, caudate nuclei, and right thalamus growth (all false discovery rate P=0.033). Older postnatal age at surgery was associated with impaired brainstem and right lentiform growth (both false discovery rate P=0.042). Longer cardiopulmonary bypass duration was associated with impaired brainstem and right caudate growth (false discovery rate P<0.027). Conclusions Infants with CHD can have impaired brain growth in the immediate postoperative period, the degree of which associates with postoperative intensive care duration. Brainstem growth appears particularly vulnerable to perioperative clinical course, whereas impaired deep gray matter growth was associated with multiple clinical risk factors, possibly reflecting vulnerability of these regions to short- and long-term hypoxic injury.

Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome.

Down syndrome (DS) is the most common genetic cause of intellectual disability with a wide range of neurodevelopmental outcomes. To date, there have been very few in vivo neuroimaging studies of the neonatal brain in DS. In this study we used a cross-sectional sample of 493 preterm- to term-born control neonates from the developing Human Connectome Project to perform normative modeling of regional brain tissue volumes from 32 to 46 weeks postmenstrual age, accounting for sex and age variables. Deviation from the normative mean was quantified in 25 neonates with DS with postnatally confirmed karyotypes from the Early Brain Imaging in DS study. Here, we provide the first comprehensive volumetric phenotyping of the neonatal brain in DS, which is characterized by significantly reduced whole brain, cerebral white matter, and cerebellar volumes; reduced relative frontal and occipital lobar volumes, in contrast with enlarged relative temporal and parietal lobar volumes; enlarged relative deep gray matter volume (particularly the lentiform nuclei); and enlargement of the lateral ventricles, amongst other features. In future, the ability to assess phenotypic severity at the neonatal stage may help guide early interventions and, ultimately, help improve neurodevelopmental outcomes in children with DS.

Exploring cognitive, behavioral and autistic trait network topology in very preterm and term-born children.

Introduction: Compared to full-term (FT) born peers, children who were born very preterm (VPT; <32 weeks' gestation) are likely to display more cognitive and behavioral difficulties, including inattention, anxiety and socio-communication problems. In the published literature, such difficulties tend to be studied independently, thus failing to account for how different aspects of child development interact. The current study aimed to investigate children's cognitive and behavioral outcomes as interconnected, dynamically related facets of development that influence one another. Methods: Participants were 93 VPT and 55 FT children (median age 8.79 years). IQ was evaluated with the Wechsler Intelligence Scale for Children-4th edition (WISC-IV), autism spectrum condition (ASC) traits with the social responsiveness scale-2nd edition (SRS-2), behavioral and emotional problems with the strengths and difficulties questionnaire (SDQ), temperament with the temperament in middle childhood questionnaire (TMCQ) and executive function with the behavior rating inventory of executive functioning (BRIEF-2). Outcome measures were studied in VPT and FT children using Network Analysis, a method that graphically represents partial correlations between variables and yields information on each variable's propensity to form a bridge between other variables. Results: VPT and FT children exhibited marked topological differences. Bridges (i.e., the variables most connected to others) in the VPT group network were: conduct problems and difficulties with organizing and ordering their environment. In the FT group network, the most important bridges were: difficulties with initiating a task or activity and prosocial behaviors, and greater emotional problems, such as lower mood. Discussion: These findings highlight the importance of targeting different aspects of development to support VPT and FT children in person-based interventions.

Assessing within-subject rates of change of placental MRI diffusion metrics in normal pregnancy.

PURPOSE: Studying placental development informs when development is abnormal. Most placental MRI studies are cross-sectional and do not study the extent of individual variability throughout pregnancy. We aimed to explore how diffusion MRI measures of placental function and microstructure vary in individual healthy pregnancies throughout gestation. METHODS: Seventy-nine pregnant, low-risk participants (17 scanned twice and 62 scanned once) were included. T2 -weighted anatomical imaging and a combined multi-echo spin-echo diffusion-weighted sequence were acquired at 3 T. Combined diffusion-relaxometry models were performed using both a T 2 * $$ {\mathrm{T}}_2^{\ast } $$ -ADC and a bicompartmental T 2 * $$ {\mathrm{T}}_2^{\ast } $$ -intravoxel-incoherent-motion ( T 2 * IVIM $$ {\mathrm{T}}_2^{\ast}\;\mathrm{IVIM} $$ ) model fit. RESULTS: There was a significant decline in placental T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and ADC (both P < 0.01) over gestation. These declines are consistent in individuals for T 2 * $$ {\mathrm{T}}_2^{\ast } $$ (covariance = -0.47), but not ADC (covariance = -1.04). The T 2 * IVIM $$ {\mathrm{T}}_2^{\ast}\;\mathrm{IVIM} $$ model identified a consistent decline in individuals over gestation in T 2 * $$ {\mathrm{T}}_2^{\ast } $$ from both the perfusing and diffusing placental compartments, but not in ADC values from either. The placental perfusing compartment fraction increased over gestation (P = 0.0017), but this increase was not consistent in individuals (covariance = 2.57). CONCLUSION: Whole placental T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and ADC values decrease over gestation, although only T 2 * $$ {\mathrm{T}}_2^{\ast } $$ values showed consistent trends within subjects. There was minimal individual variation in rates of change of T 2 * $$ {\mathrm{T}}_2^{\ast } $$ values from perfusing and diffusing placental compartments, whereas trends in ADC values from these compartments were less consistent. These findings probably relate to the increased complexity of the bicompartmental T 2 * IVIM $$ {\mathrm{T}}_2^{\ast}\;\mathrm{IVIM} $$ model, and differences in how different placental regions evolve at a microstructural level. These placental MRI metrics from low-risk pregnancies provide a useful benchmark for clinical cohorts.