Epigenetic scores derived in saliva are associated with gestational age at birth.

BACKGROUND: Epigenetic scores (EpiScores), reflecting DNA methylation (DNAm)-based surrogates for complex traits, have been developed for multiple circulating proteins. EpiScores for pro-inflammatory proteins, such as C-reactive protein (DNAm CRP), are associated with brain health and cognition in adults and with inflammatory comorbidities of preterm birth in neonates. Social disadvantage can become embedded in child development through inflammation, and deprivation is overrepresented in preterm infants. We tested the hypotheses that preterm birth and socioeconomic status (SES) are associated with alterations in a set of EpiScores enriched for inflammation-associated proteins. RESULTS: In total, 104 protein EpiScores were derived from saliva samples of 332 neonates born at gestational age (GA) 22.14 to 42.14 weeks. Saliva sampling was between 36.57 and 47.14 weeks. Forty-three (41%) EpiScores were associated with low GA at birth (standardised estimates |0.14 to 0.88|, Bonferroni-adjusted p-value < 8.3 × 10-3). These included EpiScores for chemokines, growth factors, proteins involved in neurogenesis and vascular development, cell membrane proteins and receptors, and other immune proteins. Three EpiScores were associated with SES, or the interaction between birth GA and SES: afamin, intercellular adhesion molecule 5, and hepatocyte growth factor-like protein (standardised estimates |0.06 to 0.13|, Bonferroni-adjusted p-value < 8.3 × 10-3). In a preterm subgroup (n = 217, median [range] GA 29.29 weeks [22.14 to 33.0 weeks]), SES-EpiScore associations did not remain statistically significant after adjustment for sepsis, bronchopulmonary dysplasia, necrotising enterocolitis, and histological chorioamnionitis. CONCLUSIONS: Low birth GA is substantially associated with a set of EpiScores. The set was enriched for inflammatory proteins, providing new insights into immune dysregulation in preterm infants. SES had fewer associations with EpiScores; these tended to have small effect sizes and were not statistically significant after adjusting for inflammatory comorbidities. This suggests that inflammation is unlikely to be the primary axis through which SES becomes embedded in the development of preterm infants in the neonatal period.

Precision fMRI reveals that the language network exhibits adult-like left-hemispheric lateralization by 4 years of age.

Left hemisphere damage in adulthood often leads to linguistic deficits, but many cases of early damage leave linguistic processing preserved, and a functional language system can develop in the right hemisphere. To explain this early apparent equipotentiality of the two hemispheres for language, some have proposed that the language system is bilateral during early development and only becomes left-lateralized with age. We examined language lateralization using functional magnetic resonance imaging with two large pediatric cohorts (total n=273 children ages 4-16; n=107 adults). Strong, adult-level left-hemispheric lateralization (in activation volume and response magnitude) was evident by age 4. Thus, although the right hemisphere can take over language function in some cases of early brain damage, and although some features of the language system do show protracted development (magnitude of language response and strength of inter-regional correlations in the language network), the left-hemisphere bias for language is robustly present by 4 years of age. These results call for alternative accounts of early equipotentiality of the two hemispheres for language.

Feature similarity gradients detect alterations in the neonatal cortex associated with preterm birth.

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multimodal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey index to provide a fine-grained description of regional homogeneities and sharp variations in cortical microstructure based on feature gradients, and we investigate the impact of being born preterm on cortical development at term-equivalent age. Compared with term-born controls, preterm infants have a homogeneous microstructure in temporal and occipital lobes, and the medial parietal, cingulate, and frontal cortices, compared with term infants. These observations replicated across two independent datasets and were robust to differences that remain in the data after matching samples and alignment of processing and quality control strategies. We conclude that cortical microstructural architecture is altered in preterm infants in a spatially distributed rather than localised fashion.

An unexpected ferromagnetic foreign body in a paediatric research participant undergoing 3T MRI.

Metallic foreign bodies (FBs) are a safety risk during MRI. Here, we describe a boy in early childhood with an unexpected ferromagnetic FB discovered during a research brain MRI. Safety precautions included written and oral safety screening checklists and visual check during a structured safety pause. During introduction to the scanner, he was lifted to look at the bore. Staff became aware of an object flying into the bore. The child reached for his ear, and a 5 mm diameter ball bearing was found in the bore. The child had no external injury. We have introduced a 0.1 T handheld magnet to check for metallic FBs not known to the parent. FBs are a common paediatric emergency department presentation, particularly in younger children or those with cognitive or behavioural problems. This case highlights the importance of safety screening in paediatric MRI scanning, along with its fallibility.

Open dataset of theory of mind reasoning in early to middle childhood.

Theory of mind (ToM) reasoning refers to the process by which we reason about the mental states (beliefs, desires, emotions) of others. Here, we describe an open dataset of responses from children who completed a story booklet task for assessing ToM reasoning (n = 321 3-12-year-old children, including 64 (neurotypical) children assessed longitudinally and 68 autistic children). Children completed one of two versions of the story booklet task (Booklet 1 or 2). Both versions include two-alternative forced choice and free response questions that tap ToM concepts ranging in difficulty from reasoning about desires and beliefs to reasoning about moral blameworthiness and mistaken referents. Booklet 2 additionally includes items that assess understanding of sarcasm, lies, and second-order belief-desire reasoning. Compared to other ToM tasks, the booklet task provides relatively dense sampling of ToM reasoning within each child (Booklet 1: 41 items; Booklet 2: 65 items). Experimental sessions were video recorded and data were coded offline; the open dataset consists of children's accuracy (binary) on each item and, for many children (n = 171), transcriptions of free responses. The dataset also includes children's scores on standardized tests of receptive language and non-verbal IQ, as well as other demographic information. As such, this dataset is a valuable resource for investigating the development of ToM reasoning in early and middle childhood.

Association of Preterm Birth and Socioeconomic Status With Neonatal Brain Structure.

Importance: Preterm birth and socioeconomic status (SES) are associated with brain structure in childhood, but the relative contributions of each during the neonatal period are unknown. Objective: To investigate associations of birth gestational age (GA) and SES with neonatal brain morphology by testing 3 hypotheses: GA and SES are associated with brain morphology; associations between SES and brain morphology vary with GA; and associations between SES and brain structure and morphology depend on how SES is operationalized. Design, Setting, and Participants: This cohort study recruited participants from November 2016 to September 2021 at a single center in the United Kingdom. Participants were 170 extremely and very preterm infants and 91 full-term or near-term infants. Exclusion criteria were major congenital malformation, chromosomal abnormality, congenital infection, cystic periventricular leukomalacia, hemorrhagic parenchymal infarction, and posthemorrhagic ventricular dilatation. Exposures: Birth GA and SES, operationalized at the neighborhood level (using the Scottish Index of Multiple Deprivation), the family level (using parental education and occupation), and subjectively (World Health Organization Quality of Life measure). Main Outcomes and Measures: Brain volume (85 parcels) and 5 whole-brain cortical morphology measures (gyrification index, thickness, sulcal depth, curvature, surface area) at term-equivalent age (median [range] age, 40 weeks, 5 days [36 weeks, 2 days to 45 weeks, 6 days] and 42 weeks [38 weeks, 2 days to 46 weeks, 1 day] for preterm and full-term infants, respectively). Results: Participants were 170 extremely and very preterm infants (95 [55.9%] male; 4 of 166 [2.4%] Asian, 145 of 166 [87.3%] White) and 91 full-term or near-term infants (50 [54.9%] male; 3 of 86 [3.5%] Asian, 78 of 86 [90.7%] White infants) with median (range) birth GAs of 30 weeks, 0 days (22 weeks, 1 day, to 32 weeks, 6 days) and 39 weeks, 4 days (36 weeks, 3 days, to 42 weeks, 1 day), respectively. In fully adjusted models, birth GA was associated with a higher proportion of brain volumes (27 of 85 parcels [31.8%]; ß range, -0.20 to 0.24) than neighborhood-level SES (1 of 85 parcels [1.2%]; ß = 0.17 [95% CI, -0.16 to 0.50]) or family-level SES (maternal education: 4 of 85 parcels [4.7%]; ß range, 0.09 to 0.15; maternal occupation: 1 of 85 parcels [1.2%]; ß = 0.06 [95% CI, 0.02 to 0.11] respectively). There were interactions between GA and both family-level and subjective SES measures on regional brain volumes. Birth GA was associated with cortical surface area (ß = 0.10 [95% CI, 0.02 to 0.18]) and gyrification index (ß = 0.16 [95% CI, 0.07 to 0.25]); no SES measure was associated with cortical measures. Conclusions and Relevance: In this cohort study of UK infants, birth GA and SES were associated with neonatal brain morphology, but low GA had more widely distributed associations with neonatal brain structure than SES. Further work is warranted to elucidate the mechanisms underlying the association of both GA and SES with early brain development.

Review and comparison of retinal vessel calibre and geometry software and their application to diabetes, cardiovascular disease, and dementia.

Developments in retinal imaging technologies have enabled the quantitative evaluation of the retinal vasculature. Changes in retinal calibre and/or geometry have been reported in systemic vascular diseases, including diabetes mellitus (DM), cardiovascular disease (CVD), and more recently in neurodegenerative diseases, such as dementia. Several retinal vessel analysis softwares exist, some being disease-specific, others for a broader context. In the research setting, retinal vasculature analysis using semi-automated software has identified associations between retinal vessel calibre and geometry and the presence of or risk of DM and its chronic complications, and of CVD and dementia, including in the general population. In this article, we review and compare the most widely used semi-automated retinal vessel analysis softwares and their associations with ocular imaging findings in common systemic diseases, including DM and its chronic complications, CVD, and dementia. We also provide original data comparing retinal calibre grading in people with Type 1 DM using two softwares, with good concordance.

Early stressful experiences are associated with reduced neural responses to naturalistic emotional and social content in children.

How do children's experiences relate to their naturalistic emotional and social processing? Because children can struggle with tasks in the scanner, we collected fMRI data while 4-to-11-year-olds watched a short film with positive and negative emotional events, and rich parent-child interactions (n = 70). We captured broad, normative stressful experiences by examining socioeconomic status (SES) and stressful life events, as well as children's more proximal experiences with their parents. For a sub-sample (n = 30), parenting behaviors were measured during a parent-child interaction, consisting of a picture book, a challenging puzzle, and free play with novel toys. We characterized positive parenting behaviors (e.g., warmth, praise) and negative parenting behaviors (e.g., harsh tone, physical control). We found that higher SES was related to greater activity in medial orbitofrontal cortex during parent-child interaction movie events. Negative parenting behaviors were associated with less activation of the ventral tegmental area and cerebellum during positive emotional events. In a region-of-interest analysis, we found that stressful life events and negative parenting behaviors were associated with less activation of the amygdala during positive emotional events. These exploratory results demonstrate the promise of using movie fMRI to study how early experiences may shape emotional, social, and motivational processes.

Using child-friendly movie stimuli to study the development of face, place, and object regions from age 3 to 12 years.

Scanning young children while they watch short, engaging, commercially-produced movies has emerged as a promising approach for increasing data retention and quality. Movie stimuli also evoke a richer variety of cognitive processes than traditional experiments, allowing the study of multiple aspects of brain development simultaneously. However, because these stimuli are uncontrolled, it is unclear how effectively distinct profiles of brain activity can be distinguished from the resulting data. Here we develop an approach for identifying multiple distinct subject-specific Regions of Interest (ssROIs) using fMRI data collected during movie-viewing. We focused on the test case of higher-level visual regions selective for faces, scenes, and objects. Adults (N = 13) were scanned while viewing a 5.6-min child-friendly movie, as well as a traditional localizer experiment with blocks of faces, scenes, and objects. We found that just 2.7 min of movie data could identify subject-specific face, scene, and object regions. While successful, movie-defined ssROIS still showed weaker domain selectivity than traditional ssROIs. Having validated our approach in adults, we then used the same methods on movie data collected from 3 to 12-year-old children (N = 122). Movie response timecourses in 3-year-old children's face, scene, and object regions were already significantly and specifically predicted by timecourses from the corresponding regions in adults. We also found evidence of continued developmental change, particularly in the face-selective posterior superior temporal sulcus. Taken together, our results reveal both early maturity and functional change in face, scene, and object regions, and more broadly highlight the promise of short, child-friendly movies for developmental cognitive neuroscience.

Examining the Use of a Brief Online Intervention in Primary Care for Changing Low-Income Caregivers' Attitudes Toward Spanking.

There is a robust and growing literature base indicating that spanking is a common, but potentially problematic, discipline strategy. Goals: Using a randomized controlled trial design, this study examined whether participation in a brief online program, Play Nicely, would result in favorable changes in caregivers' attitudes toward spanking. The study also examined whether the intervention was equally effective for participants of color (POC) and White participants, and it assessed caregivers' perceptions of the program's cultural sensitivity. Methods: Participants were 52 caregivers from 1- to 5-year-old children who were visiting a pediatric clinic. Participants were enrolled and randomly assigned to either engage in the Play Nicely online program (n = 21) or view a control condition website (n = 31) in a clinic exam room. Results: There was not a statistically significant difference between the treatment and control groups' scores on attitudes toward spanking (ATS) at post-test (F (1, 49) = 1.515, p = 0.224), but a small between-group effect size was detected (d = 0.20). Within the treatment condition, desired changes in ATS scores were significantly higher among White participants than POC (t (17) = -2.125, p = 0.049), but there was not a significant difference in reported perceptions of Play Nicely's cultural acceptability between White participants and POC (t (19) = 0.469, p = 0.644). Conclusions: Findings suggest a need for further investigation of Play Nicely's impact on caregivers' ATS with a larger sample to clarify the program's utility as a potential population-based tool for parent education and violence prevention. Additional research is needed to identify sociocultural factors that may moderate the effects of spanking interventions for families across diverse racial backgrounds.

Beliefs for human-unique social learning.

Phillips et al. argue that understanding what others know is central to social cognition across species and that this understanding underlies human-unique accumulation and transmission of cultural knowledge. Knowledge representations can't be both what we have in common with our evolutionary ancestors and what sets us apart from them. Belief representations are necessary for human-unique social learning.

An engaged approach to exploring issues around poverty and mental health: A reflective evaluation of the research process from researchers and community partners involved in the DeStress study.

BACKGROUND: Involving patients, service users, carers and members of the public in research has been part of health policy and practice in the UK for the last 15 years. However, low-income communities tend to remain marginalized from the co-design and delivery of mental health research, perpetuating the potential for health inequalities. Greater understanding is therefore needed on how to meaningfully engage low-income communities in mental health research. OBJECTIVES: To explore and articulate whether and how an engaged research approach facilitated knowledge coproduction relating to poverty and mental distress. SETTING: A reflective evaluation of community and researcher engagement in the DeStress study that took place in two low-income areas of South-west England. DESIGN: Reflective evaluation by the authors through on-going feedback, a focus group and first-person writing and discussion on experiences of working with the DeStress project, and how knowledge coproduction was influenced by an engaged research approach. RESULTS: An engaged research approach influenced the process and delivery of the DeStress project, creating a space where community partners felt empowered to coproduce knowledge relating to poverty-related mental distress, treatment and the training of health professionals that would otherwise have been missed. We examine motivations for involvement, factors sustaining engagement, how coproduction influenced research analysis, findings and dissemination of outputs, and what involvement meant for different stakeholders. CONCLUSION: Engaged research supported the coproduction of knowledge in mental health research with low-income communities which led to multiple impacts.

Reduced neural selectivity for mental states in deaf children with delayed exposure to sign language.

Language provides a rich source of information about other people's thoughts and feelings. Consequently, delayed access to language may influence conceptual development in Theory of Mind (ToM). We use functional magnetic resonance imaging and behavioral tasks to study ToM development in child (n = 33, 4-12 years old) and adult (n = 36) fluent signers of American Sign Language (ASL), and characterize neural ToM responses during ASL and movie-viewing tasks. Participants include deaf children whose first exposure to ASL was delayed up to 7 years (n = 12). Neural responses to ToM stories (specifically, selectivity of the right temporo-parietal junction) in these children resembles responses previously observed in young children, who have similar linguistic experience, rather than those in age-matched native-signing children, who have similar biological maturation. Early linguistic experience may facilitate ToM development, via the development of a selective brain region for ToM.

Response patterns in the developing social brain are organized by social and emotion features and disrupted in children diagnosed with autism spectrum disorder.

Adults and children recruit a specific network of brain regions when engaged in "Theory of Mind" (ToM) reasoning. Recently, fMRI studies of adults have used multivariate analyses to provide a deeper characterization of responses in these regions. These analyses characterize representational distinctions within the social domain, rather than comparing responses across preferred (social) and non-preferred stimuli. Here, we conducted opportunistic multivariate analyses in two previously collected datasets (Experiment 1: n = 20 5-11 year old children and n = 37 adults; Experiment 2: n = 76 neurotypical and n = 29 5-12 year old children diagnosed with Autism Spectrum Disorder (ASD)) in order to characterize the structure of representations in the developing social brain, and in order to discover if this structure is disrupted in ASD. Children listened to stories that described characters' mental states (Mental), non-mentalistic social information (Social), and causal events in the environment (Physical), while undergoing fMRI. We measured the extent to which neural responses in ToM brain regions were organized according to two ToM-relevant models: 1) a condition model, which reflected the experimenter-generated condition labels, and 2) a data-driven emotion model, which organized stimuli according to their emotion content. We additionally constructed two control models based on linguistic and narrative features of the stories. In both experiments, the two ToM-relevant models outperformed the control models. The fit of the condition model increased with age in neurotypical children. Moreover, the fit of the condition model to neural response patterns was reduced in the RTPJ in children diagnosed with ASD. These results provide a first glimpse into the conceptual structure of information in ToM brain regions in childhood, and suggest that there are real, stable features that predict responses in these regions in children. Multivariate analyses are a promising approach for sensitively measuring conceptual and neural developmental change and individual differences in ToM.

Sibling Child Protective Services Involvement Following a Child Maltreatment Fatality.

OBJECTIVE: This study examined CPS involvement of children surviving the CMF of a sibling as well as predictors of subsequent CPS reports. METHOD: Department of Human Services and Child Death Review Board data about children who died from a CMF during 1993-2003 (n = 416) and their siblings in the state of Oklahoma were used to examine CPS involvement and predictors of subsequent CPS reports for surviving siblings. RESULTS: Surviving siblings of a victim of a CMF experienced substantial CPS involvement; 81% of the original victims had siblings who were subsequently reported to CPS (n = 1,840). Original victim and family characteristics that predicted a greater rate of siblings' subsequent reports to CPS included younger original victim age, greater number of children in the original victim's home, and more previous reports of the original victim to CPS. DISCUSSION: A large portion of families with a CMF struggle to adequately care for their surviving children. Such families may need additional support after a CMF.

Development of predictive responses in theory of mind brain regions.

When we watch movies, we consider the characters' mental states in order to understand and predict the narrative. Recent work in functional magnetic resonance imaging (fMRI) uses movie-viewing paradigms to measure functional responses in brain regions recruited for such mental state reasoning (the theory of mind ["ToM"] network). Here, two groups of young children (n = 30 3-4 years old, n = 26 6-7 years old) viewed a short animated movie twice while undergoing fMRI. As children get older, ToM brain regions were recruited earlier in time during the second presentation of the movie. This "narrative anticipation" effect is specific: there was no such effect in a control network of brain regions that responds just as robustly to the movie (the "Pain Matrix"). These results complement prior studies in adults that suggest that ToM brain regions play a role not just in inferring, but in actively predicting, other people's thoughts and feelings, and provide novel evidence that as children get older, their ToM brain regions increasingly make such predictions.

Development of brain networks for social functions: Confirmatory analyses in a large open source dataset.

Human observers show robust activity in distinct brain networks during movie-viewing. For example, scenes that emphasize characters' thoughts evoke activity in the "Theory of Mind" (ToM) network, whereas scenes that emphasize characters' bodily sensations evoke activity in the "Pain Matrix." A prior exploratory fMRI study used a naturalistic movie-viewing stimulus to study the developmental origins of this functional dissociation, and the links between cortical and cognitive changes in children's social development (Richardson et al., 2018). To replicate and extend this work, the current study utilized a large publicly available dataset (n = 241, ages 5-20 years) (Alexander et al., 2017) who viewed "The Present" (Frey, 2014) and completed a resting state scan (n = 200) while undergoing fMRI. This study provides confirmatory evidence that 1) ToM and pain networks are functionally dissociated early in development, 2) selectivity increases with age, and in ToM regions, with a behavioral index of social reasoning. Additionally, while inter-region correlations are similar when measured during the movie and at rest, only inter-region correlations measured during movie-viewing correlated with functional maturity. This study demonstrates the scientific benefits of open source data in developmental cognitive neuroscience, and provides insight into the relationship between functional and intrinsic properties of the developing brain.

Development of the social brain from age three to twelve years.

Human adults recruit distinct networks of brain regions to think about the bodies and minds of others. This study characterizes the development of these networks, and tests for relationships between neural development and behavioral changes in reasoning about others' minds ('theory of mind', ToM). A large sample of children (n = 122, 3-12 years), and adults (n = 33), watched a short movie while undergoing fMRI. The movie highlights the characters' bodily sensations (often pain) and mental states (beliefs, desires, emotions), and is a feasible experiment for young children. Here we report three main findings: (1) ToM and pain networks are functionally distinct by age 3 years, (2) functional specialization increases throughout childhood, and (3) functional maturity of each network is related to increasingly anti-correlated responses between the networks. Furthermore, the most studied milestone in ToM development, passing explicit false-belief tasks, does not correspond to discontinuities in the development of the social brain.

Cortical responses to dynamic emotional facial expressions generalize across stimuli, and are sensitive to task-relevance, in adults with and without Autism.

Individuals with Autism Spectrum Disorders (ASD) report difficulties extracting meaningful information from dynamic and complex social cues, like facial expressions. The nature and mechanisms of these difficulties remain unclear. Here we tested whether that difficulty can be traced to the pattern of activity in "social brain" regions, when viewing dynamic facial expressions. In two studies, adult participants (male and female) watched brief videos of a range of positive and negative facial expressions, while undergoing functional magnetic resonance imaging (Study 1: ASD n = 16, control n = 21; Study 2: ASD n = 22, control n = 30). Patterns of hemodynamic activity differentiated among facial emotional expressions in left and right superior temporal sulcus, fusiform gyrus, and parts of medial prefrontal cortex. In both control participants and high-functioning individuals with ASD, we observed (i) similar responses to emotional valence that generalized across facial expressions and animated social events; (ii) similar flexibility of responses to emotional valence, when manipulating the task-relevance of perceived emotions; and (iii) similar responses to a range of emotions within valence. Altogether, the data indicate that there was little or no group difference in cortical responses to isolated dynamic emotional facial expressions, as measured with fMRI. Difficulties with real-world social communication and social interaction in ASD may instead reflect differences in initiating and maintaining contingent interactions, or in integrating social information over time or context.