ABSTRACT Recent studies have implicated oxidative stress in the pathophysiology of autism spectrum disorder (ASD). Postmortem brain studies have revealed decreased levels of the reduced form of glutathione (GSH), an important antioxidant, in some brain regions in individuals with ASD; however, in vivo evidence is lacking. Using proton magnetic resonance spectroscopy, T ₁ ‐weighted/T ₂ ‐weighted ratio‐derived myelin maps, resting‐state functional magnetic resonance imaging (MRI), and cognitive tasks, we examined whether brain GSH levels are lower in individuals with ASD than in those with typical development (TD) and explored ASD‐specific association patterns between brain GSH levels, myelination, functional connectivity, and behavioral characteristics. Data from 30 adults with ASD and 27 adults with TD were analyzed. Contrary to our hypothesis, GSH levels in the left temporoparietal junction (TPJ) were higher in the ASD group than in the TD group. Using individual myelin maps, we found a significant group difference in the correlation between left middle frontal gyrus (MFG) myelination and left TPJ GSH levels. Multivariate pattern analysis of resting‐state functional MRI revealed that whole‐brain functional connectivity patterns from the left MFG differed between the groups in their association with left MFG myelination. Finally, we found a significant group difference in the correlation between emotion recognition ability and the functional connectivity of the left MFG with the bilateral occipitoparietal junction. In conclusion, our findings demonstrate an ASD‐specific pattern of associations between left TPJ GSH levels, left MFG myelination, whole‐brain functional connectivity patterns of the left MFG, and cognitive phenotype, which suggests compensatory neural mechanisms in ASD.

Abstract Background Neurodevelopmental delay precedes attention‐deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) diagnoses. However, exactly when this emerges in association with these outcomes remains unclear. We investigated (1) the earliest representations of neurodevelopmental variation and (2) what neurodevelopmental variations at an early age (10 months to 3 years) are specifically associated with the emergence of parentally reported behavioral traits of ADHD, ASD, and related disorders at age 9. Methods Children from the Hamamatsu Birth Cohort of Mothers and Children (HBC Study) born between December 2007 and March 2012 were enrolled and followed from birth to age 9. Standardized scores of neurodevelopment across five domains (gross motor, visual reception, fine motor, receptive language, and expressive language) were calculated using the Mullen Scales of Early Learning at ages 10, 14, 18, 24, 32, and 40 months. ADHD and ASD traits were ascertained as Z‐scores using the ADHD‐Rating Scale and Social Responsiveness Scale‐2 at age 9. To explore the earliest recognition of neurodevelopmental variation with credibility, structural equation modeling (SEM) was used to estimate the total effects of the linear associations between exposures and outcomes. Results 836 children (405 females, 48%) were enrolled in the analysis. The ADHD trait was associated with visual reception score before age 1 and was concurrent with both fine motor and receptive language scores between ages 1–2. The ASD trait was associated with gross motor score before age 1 and expressive language score between ages 1.5 and 3. Conclusion Suboptimal visual‐motor coordination can be a prototype of the ADHD trait, while a cascading pattern of suboptimalities from gross motor to language domains can be a prototype of the ASD trait. The distinct neurodevelopmental variations related to ADHD and ASD traits running in the general population can be found before age 1.

Introduction Zika virus (ZIKV) infection during pregnancy has been associated with adverse birth outcomes, including congenital Zika syndrome, characterised by features such as microcephaly. However, the broader neurodevelopmental influence of prenatal ZIKV exposure, especially among offspring without congenital anomalies at birth, remains poorly understood. While previous studies, including a review, have explored neurodevelopment in ZIKV-exposed children, comparative pooled estimates between exposed and unexposed groups remain scarce. This systematic review and meta-analysis aims to evaluate the association between prenatal ZIKV exposure and neurodevelopmental outcomes in offspring without congenital anomalies at birth, using data from observational studies with defined control groups. Methods and analysis We will systematically search multiple databases, including PubMed, EMBASE, Scopus, CINAHL, PsycINFO, Cochrane Library and Web of Science, alongside grey literature sources such as Google Scholar and conference proceedings. Eligible studies will include observational designs (cohort and case-control) comparing neurodevelopmental outcomes between children with and without prenatal ZIKV exposure. Primary outcomes will include gross motor, fine motor, communication, problem-solving, social-emotional and cognitive development assessed with validated tools. Three reviewers will independently screen studies, extract data and assess methodological quality using the Newcastle-Ottawa Scale and the Grading of Recommendations, Assessment, Development and Evaluation approach. A meta-analysis will be conducted where appropriate, with heterogeneity assessed using the I² statistic and further explored through subgroup and meta-regression analyses. Ethics and dissemination Ethical approval is not required, as the study involves secondary analysis of publicly available data. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO registration number CRD420251011184.

Abstract Zinc regulates dopaminergic signaling, and reduced serum zinc levels have been reported in individuals with ADHD. However, genetic associations between zinc and ADHD remain unclear. We examined this link using large-scale GWAS and molecular analyses across three cohorts: iPSYCH (14,584 ADHD cases and 22,492 controls), FAMHES (n = 1798), and the Hamamatsu Birth Cohort (n = 726). Two-sample Mendelian randomization revealed bidirectional associations between low serum zinc levels and ADHD diagnosis. Genetic correlation and polygenic risk score analyses supported this association. In the birth cohort, lower cord blood zinc were associated with higher ADHD symptom scores at ages 8–9. Zinc levels negatively correlated with IL-6 and maternal depressive symptoms. Directed acyclic graph analysis indicated that maternal stress increased IL-6, which reduced fetal zinc levels, linking to ADHD symptoms. These findings suggest low prenatal zinc may contribute to ADHD pathophysiology in genetically vulnerable children, potentially mediated by maternal stress and inflammation.

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) can be traced back to specific early childhood temperament patterns. However, no unique pattern has been identified for their co-occurrence. Given that children with both traits often require more clinical attention, this study aimed to discover such patterns by examining three temperament domains measured during early childhood-Surgency/Extraversion (SE), Negative Affectivity (NA), and Effortful Control (EC)-and their association with group membership defined as being above the cut-off points for either ASD- or ADHD-trait scores or their co-occurrence at school age. We enrolled 814 children from a birth cohort, assessing temperament at 18 months using the Early Childhood Behavior Questionnaire, and ASD- and ADHD-trait scores at ages 8-9 using the Social Responsiveness Scale-2 and ADHD-Rating Scale. Group membership was determined by clinically significant symptoms, defined as + 1 SD after standardizing scores by age and sex. Multinomial regression analyses examined associations between temperament domain scores and group membership (ASD-dominant, ADHD-dominant, co-occurring, neither-ASD-nor-ADHD). The co-occurring group showed a unique temperament profile, with higher scores in both NA and EC (OR in NA = 1.48, 95% confidence interval (CI): 1.11 to 1.96 and OR in EC = 1.61, 95% CI: 1.18 to 2.20), distinct from the patterns shown by the ASD-dominant and ADHD-dominant groups. The combination of high NA and EC scores uniquely characterizes the co-occurring group, highlighting the need for early temperament assessments to identify children potentially requiring clinical attention for both ASD and ADHD traits.

Background/Objectives: Autistic people employ various social strategies to form and maintain interpersonal relationships in their daily environments. These strategies can help autistic people with social interactions (leading to self-perceived efficacy of using social strategies), but can also lead to cognitive fatigue (self-perceived effort of using social strategies). However, previous studies have focused primarily on self-perceived effort, overlooking the self-perceived efficacy of using social strategies, and the balance between self-perceived effort and efficacy. To address this gap, this study examined the impact of autistic people’s use of social strategies on their well-being, focusing on self-perceived effort, self-perceived efficacy, and their interaction effect. Methods: An online survey was conducted among self-reported autistic people in Japan aged 18–65 years, using a modified Compensation Checklist. Data from 104 self-reported autistic participants were analyzed using linear regression. Results: High self-perceived effort in using social strategies was negatively associated with well-being, whereas high self-perceived efficacy was positively associated with well-being. The interaction effect between effort and efficacy was not significant. These results were supported even when loneliness was used as an index of social well-being. Additionally, the number of strategies used by an autistic person was positively associated with well-being. Conclusions: This study highlights the double-edged effect of autistic people using social strategies, and that using a broader repertoire of social strategies may improve the well-being of autistic people. These findings call for a nuanced approach by researchers and clinicians considering both the positive and negative aspects of using social strategies.

Objective The implementation of school-based mental health screening offers promise for early detection of mental health issues in children; however, various barriers hinder its widespread adoption. This study aimed to investigate the predictive value of digital data obtained from an established daily health observation scheme in Japanese schools to identify later mental health issues in children. Methods Data for the analysis were obtained from 2,433 students enrolled in five public schools. The data acquisition period spanned 76 school days, from September 1, 2022, to December 23, 2022, and student absences were recorded during this period. Depressive and anxiety symptoms were assessed in January 2023. The students’ daily physical and emotional health status was recorded as “daily health issue” scores and group-based trajectory modeling was employed to classify the long-term trends in these scores. Additionally, rolling z-scores were utilized to capture variability in daily health issue scores, with z-scores above +1 considered unusual responses. Results After 4 months of daily health observations, students’ response trends were classified into five trajectory groups. The group experiencing the highest number of daily health issues (Group 5; 5.4% of the sample) exhibited more subsequent depressive and anxiety symptoms compared to the group with fewer issues (Group 1; 47.5%) (incident rate ratio [IRR] = 5.17; 95% confidence interval [CI]: 3.82, 6.99). Group 5 also demonstrated significantly more days of absence than Group 1 (IRR = 2.14, 95% CI: 1.19, 3.85). The average daily health issue scores for the entire period were associated with both depressive/anxiety symptoms and the number of days absent from school (IRR = 1.59, 95% CI: 1.45, 1.73; IRR = 1.18, 95% CI: 1.04, 1.35, respectively). Furthermore, a higher number of unusual responses during the entire period was also associated with more depressive/anxiety symptoms (IRR = 1.10, 95% CI: 1.07, 1.12). Conclusion The current study is the first to demonstrate the predictive capability of a traditional daily health observation scheme to identify mental health issues in children. This study highlights the scheme’s potential to screen and safeguard children’s mental health, emphasizing the importance of digitalization and collaboration with various stakeholders.

Abstract Many autistic people reportedly engage in camouflaging to navigate everyday social interactions; however, the function of this behavior remains largely unknown. We hypothesized that autistic people camouflage more toward neurotypical others than toward autistic others, employing it as a strategy to “fit in” within the neurotypical-majority community. This study aimed to empirically investigate this hypothesis for the first time. Autistic and neurotypical participants took part in a web-based survey. Data from 48 autistic and 137 neurotypical participants were analyzed. Camouflaging toward autistic and neurotypical others was separately measured using the modified Camouflaging Autistic Traits Questionnaire (CAT-Q). For each CAT-Q item, a sentence describing a hypothetical interaction partner with autistic or neurotypical characteristics was added, creating respective sentence conditions. The interaction effect of the participants’ characteristics and sentence conditions was analyzed using a multilevel regression analysis, accounting for differing individual baselines. The analysis revealed an interaction effect between participants’ characteristics and sentence conditions. The autistic group showed significantly more camouflaging in the autistic sentence condition than in the neurotypical sentence condition. Conversely, the neurotypical group did not differ significantly in camouflaging levels in the sentence conditions. Contrary to our hypothesis, autistic people demonstrated more camouflaging toward autistic others than toward neurotypical others. This finding questions the assumption that autistic people camouflage to assimilate into a neurotypical-majority society. Instead, it could be conceptualized as a more general social strategy used by autistic people aiming to improve their relationships with others.

ABSTRACT: Objectives: Motor planning is the cognitive process of planning necessary steps for achieving a purposeful movement and is specifically reflected through object manipulation. This study aimed to investigate whether fine motor skills, a surrogate of the motor planning ability of object manipulation, in early childhood are associated with later social skills, in a general-population birth cohort. Methods: A total of 913 children, participating in the Hamamatsu Birth Cohort for Mothers and Children, were enrolled. Social skills were measured using the Vineland Adaptive Behavior Scales-II, Socialization domain, at age 6 years. Fine motor skills were measured using the Mullen Scales of Early Learning at 14, 24, and 32 months. The associations between fine motor skills at ages 14, 24, and 32 months and social skills at age 6 years were tested separately through multivariable linear regression after adjusting for covariates, including gross motor and language skills at the contemporaneous age, autistic symptoms at age 6 years, and demographic factors. Results: Fine motor skills at 24 and 32 months were significantly associated with social skills at age 6 years (at 24 months: nonstandardized regression coefficient = 1.38 [95% CI, 0.50–2.26], p = 0.002; at 32 months: 1.47 [0.56–2.38], p = 0.001). Conclusion: Fine motor skills in early childhood predicted social skills at age 6 years, indicating an association between the complex motor planning ability of object manipulation and later social skills. Children who demonstrate fine motor delay at as early an age as 2 years should be closely monitored by child professionals.

IMPORTANCE: Whether the association between higher screen time in infancy and later suboptimal neurodevelopment can be mitigated by frequency of outdoor play is unknown. OBJECTIVE: To investigate whether higher screen time at age 2 years is associated with neurodevelopmental outcomes at age 4 years and whether this association is mediated by frequency of outdoor play at age 2 years 8 months. DESIGN, SETTING, AND PARTICIPANTS: Participants were a subsample of the Hamamatsu Birth Cohort Study for Mothers and Children (HBC Study, N = 1258). Children were born between December 2007 and March 2012 and followed up from 1 year 6 months to 4 years. The analysis was conducted from April 2021 to June 2022. EXPOSURES: Screen time longer than 1 hour a day at age 2 years was coded as higher screen time. MAIN OUTCOMES AND MEASURES: Standardized scores for communication, daily living skills, and socialization domains of the Vineland Adaptive Behavior Scale, second edition, at age 4 years were used (mean [SD], 100 [15]). The mediating factor was frequency of outdoor play at age 2 years 8 months, with 6 or 7 days per week coded as frequent outdoor play. RESULTS: Of 885 participants, 445 children (50%) were female; mean (SD) screen time per day was 2.6 (2.0) hours. Causal mediation analyses revealed that higher screen time at age 2 years was associated with lower scores in communication at age 4 years (nonstandardized coefficient b = -2.32; 95% CI, -4.03 to -0.60), but the association was not mediated by frequency of outdoor play. Higher screen time was also associated with lower scores in daily living skills (b = -1.76; 95% CI, -3.21 to -0.31); 18% of this association was mediated by frequency of outdoor play. Frequency of outdoor play was associated with socialization (b = 2.73; 95% CI, 1.06 to 4.39), whereas higher screen time was not (b = -1.34; 95% CI, -3.05 to 0.36). CONCLUSIONS AND RELEVANCE: Higher screen time at age 2 years was directly associated with poorer communication at age 4 years. It was also associated with daily living skills, but frequency of outdoor play at age 2 years 8 months alleviated it, suggesting outdoor play mitigated the association between higher screen time and suboptimal neurodevelopment. Future research should specify the nature of the associations and intervention measures, enabling targeted interventions that reduce the potential risk in screen time.

Subnational evidence on the level of inequality in receiving complementary feeding practice among Bangladeshi children is lacking. This study estimated inequality in the minimum acceptable diet (MAD) among Bangladeshi children aged 6–23 months, and identified risk factors for and developed projections of the MAD up to 2030. Data from the Bangladesh Demographic and Health Survey 2017–2018 were used in this cross-sectional study. Regression-based slope (SII) and relative index of inequality (RII) were used to quantify the level of absolute and relative inequality, respectively. A Bayesian logistic regression model was used to identify the potential determinants of a MAD and project prevalence up to 2030. About 38% of children aged 6–23 months received a MAD. The national prevalence of a MAD was 26.0 percentage points higher among children from the richest compared to the poorest households, and 32.1 percentage points higher among children of higher-educated over illiterate mothers. Socioeconomic inequality was found to be the highest in the Chattogram division (SII: 43.9), while education-based inequality was highest in the Sylhet division (SII: 47.7). Maternal employment and the number of ANC visits were also identified as significant determinants of a MAD, and the prevalence of a MAD was projected to increase from 42.5% in 2020 to 67.9% in 2030. Approximately two out of five children received a MAD in Bangladesh and significant socioeconomic and education-based inequalities in the MAD were observed. Subnational variation in socioeconomic and education-based inequalities in the MAD requires further public health attention, and poverty reduction programs need to be strengthened.

AIM: Little is known about early manifestations of autism spectrum disorders (ASD) in females, including those who may be overlooked by the current diagnostic criteria. We longitudinally explored sex differences in the trajectories of cognitive and motor functions and adaptive behaviors in children with different levels of autistic traits. METHODS: The participants were 824 children from the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), Japan, who were classified into three autistic trait groups-low, moderate, and high-based on the Social Responsiveness Scale-Second Edition. Cognitive and motor functions were measured at seven time-points from 0.5 to 3.5 years of age using the Mullen Scales of Early Learning. Adaptive behaviors were measured at five time-points from 2.7 to 9 years of age using the Vineland Adaptive Behavior Scales-Second Edition. Trajectories were depicted using latent growth curve modeling. RESULTS: Sex-specific trajectories were observed in the high-autistic-trait group, with only males showing a temporary decline in expressive language around the age of 2 years and a slight improvement thereafter. They also showed a slight improvement around 3 years in the adaptive behavior communication domain but a gradual downward trend later. Females in the high-autistic-trait group showed no distinct manifestation before the age of 3 years but showed a downward trend after 3.5 years in the adaptive behavior communication domain. CONCLUSION: Females and males with higher autistic traits than their same-sex peers, independent of clinical diagnosis, may have different phenotypes in certain neurodevelopmental domains during infancy and early childhood. This article is protected by copyright. All rights reserved.

Abstract The ability of humans to use rules for organizing action demands a high level of executive control. Situational complexity mediates rule selection, from the adoption of a given rule to the selection of complex rules to achieve an appropriate response. Several rules have been proposed to be superordinate to human behavior in a cognitive hierarchy and mediated by different brain regions. In the present study, using a novel rule-selection task based on pre-response evaluations that require several cognitive operations, we examined whether the task is mediated by a specific region of the prefrontal cortex using near-infrared spectroscopy. We showed that the selection of rules, including prior evaluation of a stimulus, activates broader areas of the prefrontal and premotor regions than response selection based on a given rule. The results are discussed in terms of hierarchical cognitive models, the functional specialization of multiple-cognitive operations in the prefrontal cortex, and their contribution to a novel cognitive task.

The social motivation hypothesis of autism proposes that social communication symptoms in autism-spectrum disorder (ASD) stem from atypical social attention and reward networks, where dopamine acts as a crucial mediator. However, despite evidence indicating that individuals with ASD show atypical activation in extrastriatal regions while processing reward and social stimuli, no previous studies have measured extrastriatal dopamine D2/3 receptor (D2/3R) availability in ASD. Here, we investigated extrastriatal D2/3R availability in individuals with ASD and its association with ASD social communication symptoms using positron emission tomography (PET). Moreover, we employed a whole-brain multivariate pattern analysis of resting-state functional magnetic resonance imaging (fMRI) to identify regions where functional connectivity atypically correlates with D2/3R availability depending on ASD diagnosis. Twenty-two psychotropic-free males with ASD and 24 age- and intelligence quotient-matched typically developing males underwent [11C]FLB457 PET, fMRI, and clinical symptom assessment. Participants with ASD showed lower D2/3R availability throughout the D2/3R-rich extrastriatal regions of the dopaminergic pathways. Among these, the posterior region of the thalamus, which primarily comprises the pulvinar, displayed the largest effect size for the lower D2/3R availability, which correlated with a higher score on the Social Affect domain of the Autism Diagnostic Observation Schedule-2 in participants with ASD. Moreover, lower D2/3R availability was correlated with lower functional connectivity of the thalamus-superior temporal sulcus and cerebellum-medial occipital cortex, specifically in individuals with ASD. The current findings provide novel molecular evidence for the social motivation theory of autism and offer a novel therapeutic target.

Little is known about the trajectory patterns and sex differences in adaptive behaviors in the general population. We examined the trajectory classes of adaptive behaviors using a representative sample and examined whether the class structure and trajectory patterns differed between females and males. We further explored sex differences in neurodevelopmental traits in each latent class. Participants (n = 994) were children in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study)—a prospective birth cohort study. Adaptive behaviors in each domain of communication, daily living skills, and socialization were evaluated at five time points when participants were 2.7, 3.5, 4.5, 6, and 9 years old using the Vineland Adaptive Behavior Scales–Second Edition. Parallel process multigroup latent class growth analysis extracted sex-specific trajectory classes. Neurodevelopmental traits of children at age 9, autistic traits, attention deficit hyperactivity disorder (ADHD) traits, and cognitive ability were examined for females and males in each identified class. A 4-class model demonstrated the best fit. Moreover, a 4-class model that allowed for differences in class probabilities and means of growth parameters between females and males provided a better fit than a model assuming no sex differences. In the communication domain, females scored higher than their male counterparts in all four classes. In the daily living skills and socialization domains, the two higher adaptive classes (Class 1: females, 18.6%; males, 17.8%; Class 2: females, 48.8%; males, 49.8%) had similar trajectories for males and females, whereas in the two lower adaptive behavior classes (Class 3: females, 27.5%; males, 29.4%; Class 4: females, 5.1%; males, 3.0%), females had higher adaptive scores than their male counterparts. In Class 4, females were more likely to have autistic and ADHD traits exceeding the cutoffs, while males were more likely to have below-average IQ. Different trajectories in females and males suggest that adaptive skills may require adjustment based on the sex of the child, when standardizing scores, in order to achieve better early detection of skill impairment.

<sec><title>Introduction</title>Accumulating evidence has shown that maternal metabolic conditions, such as pre-pregnancy overweight, diabetes mellitus, and hypertensive disorders of pregnancy (HDP) are potential risk factors of autism spectrum disorder (ASD). However, it remains unclear how these maternal conditions lead to neurodevelopmental outcomes in the offspring, including autistic symptoms. Leptin, an adipokine that has pro-inflammatory effects and affects fetal neurodevelopment, is a candidate mediator of the association between maternal metabolic factors and an increased risk of ASD. However, whether prenatal exposure to leptin mediates the association between maternal metabolic conditions and autistic symptoms in children has not been investigated yet. </sec><sec><title>Methods</title>This study investigated the associations between mothers' metabolic conditions (pre-pregnancy overweight, diabetes mellitus during or before pregnancy, and HDP), leptin concentrations in umbilical cord serum, and autistic symptoms among 762 children from an ongoing cohort study, using generalized structural equation modeling. We used the Social Responsive Scale, Second Edition (SRS-2) at 8–9 years old to calculate total T-scores. Additionally, we used the T-scores for two subdomains: Social Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB). </sec><sec><title>Results</title>Umbilical cord leptin levels were associated with pre-pregnancy overweight [coefficient = 1.297, 95% confidence interval (CI) 1.081–1.556, <italic>p</italic> = 0.005] and diabetes mellitus (coefficient = 1.574, 95% CI 1.206–2.055, <italic>p</italic> = 0.001). Furthermore, leptin levels were significantly associated with SRS-2 total T-scores (coefficient = 1.002, 95% CI 1.000–1.004, <italic>p</italic> = 0.023), SCI scores (coefficient = 1.002, 95% CI 1.000–1.004, <italic>p</italic> = 0.020), and RRB scores (coefficient = 1.001, 95% CI 1.000–1.003, <italic>p</italic> = 0.044) in children. Associations between maternal metabolic factors and autistic symptoms were not significant. </sec><sec><title>Discussion</title>The present study uncovered an association between cord leptin levels and autistic symptoms in children, while maternal metabolic conditions did not have an evident direct influence on the outcome. These results imply that prenatal pro-inflammatory environments affected by maternal metabolic conditions may contribute to the development of autistic symptoms in children. The findings warrant further investigation into the role of leptin in the development of autistic symptoms. </sec>

It is unclear whether neurodevelopmental progress from infancy to early childhood remains stable. Moreover, little is known about the risk factors, if any, affecting neurodevelopmental descending transition patterns and the relationship between these patterns and later childhood adaptive behaviours. We used data of 875 children from the Hamamatsu Birth Cohort Study in Japan. Children's neurodevelopment at 18 and 32 months and adaptive behaviours at 40 months were evaluated. Perinatal factors and infant overweight status at 18 months were investigated to identify descending-transition-associated risk factors. In the latent transition analysis, ultimately, three classes were identified for each time-point, resulting in nine transition patterns; among them, 10.4% of children showed descending class shifts (normal to delayed class). Such decelerated growth was predicted by maternal pre-pregnancy overweight status (odds ratio [OR] 2.49; 95% confidence interval [CI] 1.23, 5.02), low maternal educational history (OR 1.20; 95% CI 1.04, 1.36), and infant overweight status at 18 months (OR 5.89; 95% CI 1.26, 27.45). Children with descending transition showed poor functioning in adaptive behaviours at the age of 40 months. To prevent subsequent poor adaptive functioning, it may be necessary to consider that a certain percentage of children show decelerated growth.

<title>Abstract</title><sec> <title>Background</title> Mastering language involves the development of expressive and receptive skills among children. While it has been speculated that early temperament plays a role in the acquisition of language, the actual mechanism has not yet been explored. We investigated whether temperament at 18 months predicted expressive or receptive language skills at 40 months. </sec><sec> <title>Methods</title> A representative sample of 901 children and their mothers who were enrolled and followed-up longitudinally in the Hamamatsu Birth Cohort for Mothers and Children study was included in the analysis. Child temperament was measured at 18 months using the Japanese version of the Early Childhood Behavior Questionnaire. Expressive and receptive language skills were measured at 40 months using the Mullen Scales of Early Learning. </sec><sec> <title>Results</title> The multiple regression analysis, adjusting for potential confounders, suggested that higher motor activation (fidgeting) at 18 months was associated with lower expressive and receptive language skills at 40 months. Higher perceptual sensitivity was associated with higher expressive and receptive language skills at 40 months. </sec><sec> <title>Conclusions</title> Specific temperament at 18 months of age predicted the development of the child’s expressive and receptive language skills at 40 months. </sec>

This cohort study examines whether sleep problems and polygenic risk scores for attention-deficit/hyperactivity disorder are associated with hyperactivity/inattention symptoms in children aged 8 to 9 years from the general population in Japan.

<title>Abstract</title>Prenatal exposure to perfluoroalkyl substances (PFAS) has been reported to affect body weight from birth to childhood, but the results remain inconclusive. We investigated whether umbilical cord blood concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are associated with children’s risk trajectory for obesity. 600 children were randomly selected from the Hamamatsu Birth Cohort for Mothers and Children (HBC study) and their umbilical cord serum PFAS concentrations were quantified. Participants underwent BMI measurements at ages 1, 4, 10, 18, 24, 32, 40, 50, and 66 months. Growth curve modeling with random intercept was performed with standardized BMI as outcome variable. PFOS was negatively associated with standardized BMI (β =  − 0.34; <italic>p</italic> = 0.01), with a marginally significant interaction with the child’s age (β = 0.0038; <italic>p</italic> = 0.08). PFOA was negatively associated with standardized BMI (β =  − 0.26, 95% CI − 0.51, 0; <italic>p</italic> = 0.05), with a significant interaction with the child’s age (β = 0.005; <italic>p</italic> = 0.01). Stratified analysis by sex revealed that these effects were significant only among girls. Prenatal exposure to PFAS initially was associated with lower standardized BMI during infancy, but this effect dissipated over time and reversed in direction during later childhood. The effects of prenatal PFAS on higher standardized BMI is stronger in girls.

<title>Abstract</title><sec> <title>Background</title> Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. </sec><sec> <title>Methods</title> We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children<bold>,</bold> we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as &lt;2000 g, 2000–2499 g, and ≥2500 g. Polygenic risk score for ADHD was generated using the summary data of a large-scale genome-wide association study. The Rating Scale IV (ADHD-RS) assessed ADHD traits (inattention and hyperactivity/impulsivity) based on parental reports. Following previous studies, sex, birth order of the child, gestational age at birth, mother’s age at delivery, educational attainment, pre-pregnancy body mass index, pre-pregnancy or during pregnancy smoking status, alcohol consumption during pregnancy, father’s age, education, and annual family income were considered as covariates. Multivariable negative binomial regression was applied to evaluate the association between birth weight and ADHD traits, while adjusting for potential covariates. The interaction term between birth weight categories and binary polygenic risk was added to the model. </sec><sec> <title>Results</title> Birth weight of 2000–2499 g was not associated with ADHD traits. Birth weight under 2000 g was significantly associated with both inattention and hyperactivity. When accounting for higher and lower genetic risk for ADHD, only those with higher genetic risk and birth weight &lt; 2000 g were associated with inattention (rate ratio [RR] 1.56, 95% CI 1.07–2.27) and hyperactivity (RR 1.87, 95% CI 1.14–3.06)<bold>.</bold> </sec><sec> <title>Conclusions</title> Birth weight under 2000 g, together with the genetic risk of ADHD, contributes to higher levels of ADHD traits among Japanese children aged 8 to 9 years. The suggested association between low birth weight and ADHD is confined to children with a genetic susceptibility to ADHD, indicating the relevance of genetic-environmental interactions in the etiology. </sec>

<bold>Introduction:</bold> Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated. <bold>Methods:</bold> In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory. <bold>Results:</bold> A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (β[SE], −1.807 [0.668]; <italic>p</italic> = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (β[SE], −2.020 [6.39]; <italic>p</italic> = 0.002, corrected), negative regulation of GTPase activity (β[SE], 2.001 [0.630]; <italic>p</italic> = 0.002, corrected), and regulation of gene expression epigenetic (β[SE], −2.119 [0.664]; <italic>p</italic> = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children. <bold>Conclusion:</bold> Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.

<title>Abstract</title> To characterize the brain responses to traumatic memories in posttraumatic stress disorder (PTSD), we conducted task-employed functional magnetic resonance imaging and, in the process, devised a simple but innovative approach—correlation computation between task conditions. A script-driven imagery task was used to compare the responses to a script of the patients’ own traumatic memories and that of tooth brushing as a daily activity and to evaluate how eye movement desensitization and reprocessing (EMDR), an established therapy for PTSD, resolved the alterations in patients. Nine patients with PTSD (7 females, aged 27–50 years) and nine age- and gender-matched healthy controls participated in this study. Six patients underwent the second scan under the same paradigm after EMDR. We discovered intense negative correlations between daily and traumatic memory conditions in broad areas, including the hippocampus; patients who had an intense suppression of activation during daily recognition showed an intense activation while remembering a traumatic memory, whereas patients who had a hyperarousal in daily recognition showed an intense suppression while remembering a traumatic memory as a form of “shut-down.” Moreover, the magnitude of the discrepancy was reduced in patients who remitted after EMDR, which might predict an improved prognosis of PTSD.

Although the left anterior temporal lobe (ATL) has been associated with semantic processing, the role of this region in syntactic structure building of sentences remains a subject of debate. Functional neuroimaging studies contrasting well-formed sentences with word lists lacking syntactic structure have produced mixed results. The current functional magnetic resonance imaging study examined whether the left ATL is selectively involved in semantic processing or also plays a role in syntactic structure building by manipulating syntactic complexity and meaningfulness in a novel way. To deprive semantic/pragmatic information from a sentence, we replaced all content words with pronounceable meaningless placeholders. We conducted an experiment with a 2 × 2 factorial design with factors of SEMANTICS (natural sentences [NAT]; sentences with placeholders [SPH]) and SYNTAX (the basic Japanese Subject-Object-Verb [SOV] word order; a changed Object-Subject-Verb [OSV] word order). A main effect of SEMANTICS (NAT > SPH) was found in the left ATL, as well as in the ventral occipitotemporal regions. The opposite contrast (SPH > NAT) revealed activation in the dorsal regions encompassing Brodmann area 44, the premotor area, and the parietal cortex in the left hemisphere. We found no main effect of SYNTAX (OSV > SOV) in a subregion of the left ATL that was more responsive to natural sentences than meaningless sentences. These results indicate selective involvement of a subregion of the left ATL in semantic/pragmatic processing.

A growing body of evidence has indicated that individuals with autism spectrum disorder (ASD) exhibit abnormal reactions to sensory stimuli and impaired face processing. Although behavioral studies have reported that individual differences in sensory processing patterns are correlated with performance in face processing tasks, the neural substrates underlying the association between sensory processing patterns and face processing remain unknown. Using functional magnetic resonance imaging, the present study examined the relationships between sensory processing patterns assessed with the Adolescent/Adult Sensory Profile (AASP) and brain activity during a one-back task with two types of stimuli (face or house pictures). We enrolled 18 Japanese adults with ASD and 19 age- and IQ-matched controls. Sensation Avoiding scores, which were assessed using the AASP, were positively correlated with right fusiform activity during the presentation of pictures of faces in the ASD group, but not in the control group. This suggests that abnormal sensory processing patterns in ASD are associated with abnormal face-related brain activity, possibly resulting in impaired face processing. LAY SUMMARY: Sensory abnormalities are one of the most common symptoms in people with autism spectrum disorder (ASD). This study shows that individuals with ASD who react abnormally to sensory stimuli also exhibit atypical brain activity when recognizing faces. Abnormal sensory processing may partly explain the difficulty that people diagnosed with ASD have in identifying others' faces.

Importance: Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood. Objective: To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population. Design, Setting, and Participants: In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019. Main Outcomes and Measures: Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months. Results: Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; β, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; β, -1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; β, -1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; β, -5.28; SE, 1.40; P < .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; β, -5.30; SE 1.30; P < .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; β, -6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; β, -6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; β, 7.37; SE, 2.15; P = .001); glutamatergic signaling-associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; β, -5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; β, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; β, -5.38; SE, 1.74; P = .002). Conclusions and Relevance: In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills.

Using functional magnetic resonance imaging (fMRI), we show that the neural substrate of language does not overlap with that for verbal working memory when we carefully define verbal working memory in sentence processing. Object-Subject-Verb (OSV) sentences in Japanese were contrasted with canonical Subject-Object-Verb (SOV) sentences, which had less hierarchy in linguistic structure. This contrast revealed the posterior part of Broca's area and the left posterior middle temporal gyrus (pMTG) as the neural bases for hierarchical structure building. Furthermore, we changed verbal working memory load in OSV sentences by adding modifiers to the subject or object noun phrases; this resulted in the activation in the op9, which is situated in the frontal operculum and is adjacent to, but not situated in, Broca's area. The neuroanatomical segregation of language processing from verbal working memory suggests independence of the faculty of language from the verbal working memory system, providing evidence for the domain-specificity of language in human cognition.

Observing mouth movements has strikingly effects on the perception of speech. Any mismatch between sound and mouth movements will result in listeners perceiving illusory consonants (McGurk effect), whereas matching mouth movements assist with the correct recognition of speech sounds. Recent neuroimaging studies have yielded evidence that the motor areas are involved in speech processing, yet their contributions to multisensory illusion remain unclear. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in an event-related design, we aimed to identify the functional roles of the motor network in the occurrence of multisensory illusion in female and male brains. fMRI showed bilateral activation of the inferior frontal gyrus (IFG) in audiovisually incongruent trials. Activity in the left IFG was negatively correlated with occurrence of the McGurk effect. The effective connectivity between the left IFG and the bilateral precentral gyri was stronger in incongruent than in congruent trials. The McGurk effect was reduced in incongruent trials by applying single-pulse TMS to motor cortex (M1) lip areas, indicating that TMS facilitates the left IFG-precentral motor network to reduce the McGurk effect. TMS of the M1 lip areas was effective in reducing the McGurk effect within the specific temporal range from 100 ms before to 200 ms after the auditory onset, and TMS of the M1 foot area did not influence the McGurk effect, suggesting topographical specificity. These results provide direct evidence that the motor network makes specific temporal and topographical contributions to the processing of multisensory integration of speech to avoid illusion.SIGNIFICANCE STATEMENT The human motor network, including the inferior frontal gyrus and primary motor cortex lip area, appears to be involved in speech perception, but the functional contribution to the McGurk effect is unknown. Functional magnetic resonance imaging revealed that activity in these areas of the motor network increased when the audiovisual stimuli were incongruent, and that the increased activity was negatively correlated with perception of the McGurk effect. Furthermore, applying transcranial magnetic stimulation to the motor areas reduced the McGurk effect. These two observations provide evidence that the motor network contributes to the avoidance of multisensory illusory perception.