Brain structures and functional connectivity in neglected children with no other types of maltreatment.

Child maltreatment can adversely affect brain development, leading to vulnerabilities in brain structure and function and various psychiatric disorders. Among the various types of child maltreatment, neglect has the highest incidence rate (76.0%); however, data on its sole adverse influence on the brain remain limited. This case-control brain magnetic resonance imaging (MRI) study identified the changes in gray matter structure and function that distinguish neglected children with no other type of maltreatment (Neglect group, n = 23) from typically developing children (TD group, n = 140), and investigated the association between these structural and functional differences and specific psychosocial phenotypes observed in neglected children. Our results showed that the Neglect group had a larger right and left anterior cingulate cortex (R/L.ACC) and smaller left angular gyrus (L.AG) gray matter volume. The larger R/L.ACC was associated with hyperactivity and inattention. Resting-state functional analysis showed increased functional connectivity (FC) between the left supramarginal gyrus (L.SMG) in the salience network (SN) and the right middle frontal gyrus (R.MFG) simultaneously with a decrease in FC with the L.ACC for the same seed. The increased FC for the R.MFG was associated with difficulty in peer problems and depressive symptoms; a mediating effect was evident for depressive symptoms. These results suggest that the structural atypicality of the R/L.ACC indirectly contributes to the disturbed FCs within the SN, thereby exacerbating depressive symptoms in neglected children. In conclusion, exposure to neglect in childhood may lead to maladaptive brain development, particularly neural changes associated with depressive symptoms.

Diffusion tensor imaging of white-matter structural features of maltreating mothers and their associations with intergenerational chain of childhood abuse.

Child abuse causes lifelong adverse outcomes for both physical and mental health, although many are resilient. Efforts to prevent this issue from the parental side require an understanding of the neurobiological basis that leads abusive parents to perpetrate abuse and the influence of the intergenerational chain of childhood abuse. Therefore, this study was conducted to compare the brain white-matter fiber structures between 11 maltreating mothers who had been recognized as having conducted child abuse prior to the intervention and 40 age-matched control mothers using tract-based spatial statistics. There was a significantly reduced axial diffusivity (AD) and a similar trend in fractional anisotropy (FA) in the right corticospinal tract in maltreating mothers compared to control mothers. Therefore, maltreating mothers may have excessive control over the forcefulness of voluntary movements. These features also decreased as the number of childhood abuse experiences increased, suggesting that an intergenerational chain of child abuse may also be involved. Other aspects observed were that the higher the current depressive symptoms, the lower the AD and FA values; however, they were not related to parental practice or empathy. These results corroborate the neurobiological features that perpetrate behaviors in abusive mothers.

The neurobiological effects of childhood maltreatment on brain structure, function, and attachment.

Childhood maltreatment is a risk factor for psychopathologies, and influences brain development at specific periods, particularly during early childhood and adolescence. This narrative review addresses phenotypic alterations in sensory systems associated with specific types of childhood maltreatment exposure, periods of vulnerability to the neurobiological effects of maltreatment, and the relationships between childhood maltreatment and brain structure, function, connectivity, and network architecture; psychopathology; and resilience. It also addresses neurobiological alterations associated with maternal communication and attachment disturbances, and uses laboratory-based measures during infancy and case-control studies to elucidate neurobiological alterations in reactive attachment disorders in children with maltreatment histories. Moreover, we review studies on the acute effects of oxytocin on reactive attachment disorder and maltreatment and methylation of oxytocin regulatory genes. Epigenetic changes may play a critical role in initiating or producing the atypical structural and functional brain alterations associated with childhood maltreatment. However, these changes could be reversed through psychological and pharmacological interventions, and by anticipating or preventing the emergence of brain alterations and subsequent psychopathological risks.

Data science using the human epigenome for predicting multifactorial diseases and symptoms.

Tweetable abstract This article reviews machine learning models that leverages epigenomic data for predicting multifactorial diseases and symptoms as well as how such models can be utilized to explore new research questions.

Longitudinal changes in attention bias to infant crying in primiparous mothers.

Introduction: Infant stimuli attract caregiver attention and motivate parenting behavior. Studies have confirmed the existence of attentional bias toward infant face stimuli; however, relatively little is known about whether attentional bias exists for infant cry stimuli, which are as important as faces in child-rearing situations. Furthermore, scarce longitudinal evidence exists on how attentional bias toward infant crying changes through the postpartum period. Methods: In the present study, we conducted an experiment to assess bias toward infant crying at two postpartum time points: at Time 1 (Mean = 75.24 days), 45 first-time mothers participated and at Time 2 (Mean = 274.33 days), 30 mothers participated. At both time points, the mothers participated in a Stroop task with infant crying and white noise as the stimuli. They were instructed to answer the color out loud as quickly and accurately as possible, while ignoring the sound. Four types of audio stimuli were used in this task (the cry of the mother's own infant, the cry of an unfamiliar infant, white noise matched to the cry of the mother's own infant, and white noise matched to the cry of an unfamiliar infant), one of which was presented randomly before each trial. Response time and the correct response rate for each condition were the dependent variables. Results: For response time, the main effect of familiarity was significant, with longer response times when the participant's infant's cry was presented. In addition, response times were lower at Time 2 than at Time 1 in some conditions in which crying was presented. Discussion: The results suggest that mothers may be less disturbed by infant crying as they gain more experience. Elucidating the characteristics of postpartum mothers' changes in cognitive performance related to infants' cries would be useful in fundamental and applied research to understand the process of parents' adaptation to parenting.

Evaluation of the pooled sample method in Infinium MethylationEPIC BeadChip array by comparison with individual samples.

BACKGROUND: The pooled sample method is used in epigenomic research and expression analysis and is a cost-effective screening approach for small amounts of DNA. Evaluation of the pooled sample method in epigenomic studies is performed using the Illumina Infinium Methylation 450K BeadChip array; however, subsequent reports on the updated 850K array are lacking. A previous study demonstrated that the methylation levels obtained from individual samples were accurately replicated using pooled samples but did not address epigenome-wide association study (EWAS) statistics. The DNA quantification method, which is important for the homogeneous mixing of DNA in the pooled sample method, has since become fluorescence-based, and additional factors need to be considered including the resolution of batch effects of microarray chips and the heterogeneity of the cellular proportions from which the DNA samples are derived. In this study, four pooled samples were created from 44 individual samples, and EWAS statistics for differentially methylated positions (DMPs) and regions (DMRs) were conducted for individual samples and compared with the statistics obtained from the pooled samples. RESULTS: The methylation levels could be reproduced fairly well in the pooled samples. This was the case for the entire dataset and when limited to the top 100 CpG sites, consistent with a previous study using the 450K BeadChip array. However, the statistical results of the EWAS for the DMP by individual samples were not replicated in pooled samples. Qualitative analyses highlighting methylation within an arbitrary candidate gene were replicable. Focusing on chr 20, the statistical results of EWAS for DMR from individual samples showed replicability in the pooled samples as long as they were limited to regions with a sufficient effect size. CONCLUSIONS: The pooled sample method replicated the methylation values well and can be used for EWAS in DMR. This method is sample amount-effective and cost-effective and can be utilized for screening by carefully understanding the effective features and disadvantages of the pooled sample method and combining it with candidate gene analyses.

Bayesian dynamical system analysis of the effects of methylphenidate in children with attention-deficit/hyperactivity disorder: a randomized trial.

Methylphenidate is a widely used and effective treatment for attention-deficit/hyperactivity disorder (ADHD), yet the underlying neural mechanisms and their relationship to changes in behavior are not fully understood. Specifically, it remains unclear how methylphenidate affects brain and behavioral dynamics, and the interplay between these dynamics, in individuals with ADHD. To address this gap, we used a novel Bayesian dynamical system model to investigate the effects of methylphenidate on latent brain states in 27 children with ADHD and 49 typically developing children using a double-blind, placebo-controlled crossover design. Methylphenidate remediated greater behavioral variability on a continuous performance task in children with ADHD. Children with ADHD exhibited aberrant latent brain state dynamics compared to typically developing children, with a single latent state showing particularly abnormal dynamics, which was remediated by methylphenidate. Additionally, children with ADHD showed brain state-dependent hyper-connectivity in the default mode network, which was also remediated by methylphenidate. Finally, we found that methylphenidate-induced changes in latent brain state dynamics, as well as brain state-related functional connectivity between salience and default mode networks, were correlated with improvements in behavioral variability. Taken together, our findings reveal a novel latent brain state dynamical process and circuit mechanism underlying the therapeutic effects of methylphenidate in childhood ADHD. We suggest that Bayesian dynamical system models may be particularly useful for capturing complex nonlinear changes in neural activity and behavioral variability associated with ADHD. Our approach may be of value to clinicians and researchers investigating the neural mechanisms underlying pharmacological treatment of psychiatric disorders.

Child Developmental MRI (CDM) project: protocol for a multi-centre, cross-sectional study on elucidating the pathophysiology of attention-deficit/hyperactivity disorder and autism spectrum disorder through a multi-dimensional approach.

INTRODUCTION: Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have demonstrated differences in extensive brain structure, activity and network. However, there remains heterogeneity and inconsistency across these findings, presumably because of the diversity of the disorders themselves, small sample sizes, and site and parameter differences in MRI scanners, and their overall pathogenesis remains unclear. To address these gaps in the literature, we will apply the travelling-subject approach to correct site differences in MRI scanners and clarify brain structure and network characteristics of children with ADHD and ASD using large samples collected in a multi-centre collaboration. In addition, we will investigate the relationship between these characteristics and genetic, epigenetic, biochemical markers, and behavioural and psychological measures. METHODS AND ANALYSIS: We will collect resting-state functional MRI (fMRI) and T1-weighted and diffusion-weighted MRI data from 15 healthy adults as travelling subjects and 300 children (ADHD, n=100; ASD, n=100; and typical development, n=100) with multi-dimensional assessments. We will also apply data from more than 1000 samples acquired in our previous neuroimaging studies on ADHD and ASD. ETHICS AND DISSEMINATION: The study protocol has been approved by the Research Ethics Committee of the University of Fukui Hospital (approval no: 20220601). Our study findings will be submitted to scientific peer-reviewed journals and conferences.

Neural and behavioral effects of parent training on emotion recognition in mothers rearing children with attention-deficit/hyperactivity disorder.

This randomized controlled study examined neurological changes in socioemotional processing skills through parent training in caregivers of children with attention-deficit/hyperactivity disorder. Thirty mothers of children with attention-deficit/hyperactivity disorder were stratified into parent training and non-parent training groups. Functional magnetic resonance imaging was performed during the "Reading the Mind in the Eyes" test, and parenting difficulties were evaluated using the Parenting Stress Index and the Parenting Scale, twice (before and after parent training). Only mothers in the parent training group showed a significant decrease in Parenting Stress Index and Parenting Scale scores. They also demonstrated increased activity in the left occipital fusiform gyrus during the task of estimating emotions from facial pictures. We presumed that these changes might reflect the potential impact of enrollment in parent training in reducing stress, which might have increased activation of the fusiform gyrus.

Effects of prenatal cannabis exposure on developmental trajectory of cognitive ability and brain volumes in the adolescent brain cognitive development (ABCD) study.

Although cannabis use during pregnancy is increasing widely, the effects of cannabis on developmental trajectories, such as whether its effects during pregnancy remain the same between time points or gradually increase, are unclear. This study aimed to examine whether cannabis use during pregnancy affects the process of change in cognition and brain volume. Data from two-time points measured longitudinally were analyzed. We used data from the Adolescent Brain and Cognitive Development Study. Participants included 11,876 children aged 9-11 years participated at baseline, and 10,414 participated at 2-year follow-up from 22 sites across the United States. We explored the associations between prenatal cannabis exposure and cognitive abilities and brain volumes developmental trajectories. Among 11,530 children with valid data for prenatal cannabis exposure, 10,833 had no prenatal cannabis use, and 697 had cannabis use during their pregnancy. There was a significant interaction between time points and cannabis use during pregnancy on visuo-perceptual processing ability (b = -0.019, p = .009) and intracranial volumes (b = -6338.309, p = .009). We found that the effects of exposure to cannabis during pregnancy are not uniform at all times and may gradually become more apparent and magnified as development progresses.

Cross-tissue correlations of genome-wide DNA methylation in Japanese live human brain and blood, saliva, and buccal epithelial tissues.

Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13-73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva-brain correlation (r = 0.90) was higher than that for blood-brain (r = 0.87) and buccal-brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, cross-database correlations of the correlation coefficients revealed a relatively low (brain vs. blood: r = 0.27, saliva: r = 0.18, and buccal: r = 0.24). To the best of our knowledge, this is the fifth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.

Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Methylphenidate, a first-line treatment for attention-deficit/hyperactivity disorder (ADHD), is thought to influence dopaminergic neurotransmission in the nucleus accumbens (NAc) and its associated brain circuitry, but this hypothesis has yet to be systematically tested. METHODS: We conducted a randomized, placebo-controlled, double-blind crossover trial including 27 children with ADHD. Children with ADHD were scanned twice with resting-state functional magnetic resonance imaging under methylphenidate and placebo conditions, along with assessment of sustained attention. We examined spontaneous neural activity in the NAc and the salience, frontoparietal, and default mode networks and their links to behavioral changes. Replicability of methylphenidate effects on spontaneous neural activity was examined in a second independent cohort. RESULTS: Methylphenidate increased spontaneous neural activity in the NAc and the salience and default mode networks. Methylphenidate-induced changes in spontaneous activity patterns in the default mode network were associated with improvements in intraindividual response variability during a sustained attention task. Critically, despite differences in clinical trial protocols and data acquisition parameters, the NAc and the salience and default mode networks showed replicable patterns of methylphenidate-induced changes in spontaneous activity across two independent cohorts. CONCLUSIONS: We provide reproducible evidence demonstrating that methylphenidate enhances spontaneous neural activity in NAc and cognitive control networks in children with ADHD, resulting in more stable sustained attention. Our findings identified a novel neural mechanism underlying methylphenidate treatment in ADHD to inform the development of clinically useful biomarkers for evaluating treatment outcomes.

Impact of stable environments on maltreated children.

BACKGROUND: The development of the ability to understand others' facial expressions is thought to be dependent on the environment in which one has been reared. METHODS: This study compared the ability to understand others' facial expressions between 15 children who were in an unstable environment, 11 children who had been maltreated before and were in a stable environment, like a foster family, and 33 children who had never been maltreated. We used the Reading the Mind in the Eyes Test (RMET) as measure. RESULTS: Children who were in an unstable environment scored higher on the RMET than children who had never been maltreated. CONCLUSIONS: The results suggested that hypersensitivity to others' facial expressions might be an adaptive response to a harmful environment and that it might decline when in a stable environment because such sensitivity is no longer needed.

Longitudinal impact of COVID-19 pandemic on mental health of children in the ABCD study cohort.

A large longitudinal study on the impact of the COVID-19 pandemic on mental health in children is limited. This large-scale longitudinal observational study examines the pandemic's effects on children's mental health while considering the effects of parental care styles. The Adolescent Brain Cognitive Development Study is a large-scale, longitudinal multicenter study in the United States. Of the 11,875 children aged 9-12 years in its database, 4702 subjects were selected for this study. The child behavior checklist and parental monitoring questionnaire (PMQ) were used to assess children's mental health and parental support styles, respectively. Data collected before and during the pandemic were compared. Withdrawn/depressed and attention problems significantly worsened during compared to before the COVID-19 pandemic (p < 0.001, withdrawn/depressed; 53.4 ± 5.7 to 53.7 ± 5.9, attention problems; 53.4 ± 5.4 to 53.6 ± 5.6). However, the T scores are in the normal range both before and during the crisis. Simple slope analysis found withdrawn/depressed problems and aggressive behavior worsened when the PMQ was 1 SD below the mean, and rule-breaking behavior was improved when the PMQ was 1 SD above the mean. While the COVID-19 pandemic exacerbated children's depressive symptoms and attention issues, the effects may be minor. Additionally, parental involvement serve as a protective factor for the child's mental health even during the pandemic.

Methylphenidate remediates aberrant brain network dynamics in children with attention-deficit/hyperactivity disorder: A randomized controlled trial.

Methylphenidate is a widely used first-line treatment for attention deficit/hyperactivity disorder (ADHD), but the underlying circuit mechanisms are poorly understood. Here we investigate whether a single dose of osmotic release oral system methylphenidate can remediate attention deficits and aberrancies in functional circuit dynamics in cognitive control networks, which have been implicated in ADHD. In a randomized placebo-controlled double-blind crossover design, 27 children with ADHD were scanned twice with resting-state functional MRI and sustained attention was examined using a continuous performance task under methylphenidate and placebo conditions; 49 matched typically-developing (TD) children were scanned once for comparison. Dynamic time-varying cross-network interactions between the salience (SN), frontoparietal (FPN), and default mode (DMN) networks were examined in children with ADHD under both administration conditions and compared with TD children. Methylphenidate improved sustained attention on a continuous performance task in children with ADHD, when compared to the placebo condition. Children with ADHD under placebo showed aberrancies in dynamic time-varying cross-network interactions between the SN, FPN and DMN, which were remediated by methylphenidate. Multivariate classification analysis confirmed that methylphenidate remediates aberrant dynamic brain network interactions. Furthermore, dynamic time-varying network interactions under placebo conditions predicted individual differences in methylphenidate-induced improvements in sustained attention in children with ADHD. These findings suggest that a single dose of methylphenidate can remediate deficits in sustained attention and aberrant brain circuit dynamics in cognitive control circuits in children with ADHD. Findings identify a novel brain circuit mechanism underlying a first-line pharmacological treatment for ADHD, and may inform clinically useful biomarkers for evaluating treatment outcomes.

Beneficial Effects of Behavioral Parent Training on Inhibitory Control in Children With Attention-Deficit/Hyperactivity Disorder: A Small-Scale Randomized Controlled Trial.

The purpose of this study was to examine whether the beneficial effects of behavioral parent training (BPT), as an indirect type of psychosocial treatment, are extended to cognitive manifestations beyond behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Although previous studies of community families have shown an association between parenting quality and a child's cognitive functions, little is known about the effects of BPT on cognitive manifestations in children with ADHD. In this study, we focused on inhibitory control among cognitive domains, which is considered to be the most malleable to direct types of psychosocial treatment for ADHD. We hypothesized that inhibitory control is affected by BPT, which uses parents as the primary agents of change to help their children. Thirty school-age children (6-12 years old) with ADHD and their parents (mothers) participated and were randomly assigned to either the standard BPT or waitlist control group. Using two objective laboratory-based tasks of inhibitory control (i.e., go/no-go and single response selection tasks), we assessed baseline and post-treatment response inhibition to suppress task-irrelevant responses and response selection to select task-relevant responses. In addition to decreased ADHD symptoms and negative parenting, the BPT group exhibited significantly improved performance in the single response selection task, but not in the go/no-go task, compared with the waitlist control group. Although tentative, these findings partially support our hypothesis that BPT has beneficial effects on the cognitive inhibitory control of ADHD, highlighting the potential for supportive environmental modifications to advance cognitive development in children with ADHD.

The Effectiveness and Cost-effectiveness of Well Parent Japan for Japanese Mothers of Children With ADHD: Protocol for a Randomized Controlled Trial.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder associated with numerous functional deficits and poor long-term outcomes. Internationally, behavioral interventions are recommended as part of a multimodal treatment approach for children with ADHD. Currently, in Japan, there are limited interventions available to target ADHD. Well Parent Japan (WPJ), a new hybrid parent-training program, provides a culturally acceptable and effective way to help support Japanese children with ADHD and their parents. OBJECTIVE: This pragmatic multicenter randomized controlled trial aims to provide preliminary evidence about the effectiveness and cost-effectiveness of WPJ evaluated against treatment as usual (TAU) within routine Japanese mental health services. METHODS: Mothers of children (aged 6-12 years) diagnosed with ADHD were recruited from child and adolescent mental health care services at three hospital sites across Japan (Fukui, Fukuoka, and Okinawa). The mothers were randomized to receive immediate treatment or TAU. The effectiveness and cost-effectiveness of WPJ over TAU at the end of the intervention and at 3-month follow-up will be evaluated. The primary outcome is maternal parent domain stress in the parenting role. The following secondary outcomes will be explored: child behavior, including severity of ADHD symptoms; parenting practices; emotional well-being; and the parent-child relationship and maternal child domain parenting stress. Data analysis will follow intention-to-treat principles with treatment effects quantified through analysis of covariance using multilevel modeling. An incremental cost-effectiveness ratio will be used to analyze the cost-effectiveness of the WPJ intervention. RESULTS: Study funding was secured through a proof-of-concept grant in July 2018. Approval by the institutional review board for the data collection sites was obtained between 2017 and 2019. Data collection began in August 2019 and was completed in April 2022. Participant recruitment (N=124) was completed in May 2021. Effectiveness and cost-effectiveness analyses are expected to be completed by July 2022 and December 2022, respectively. These timelines are subject to change owing to the COVID-19 pandemic. CONCLUSIONS: This is the first multisite pragmatic trial of WPJ based on the recruitment of children referred directly to routine clinical services in Japan. This multisite randomized trial tests the effectiveness of WPJ in children and families by comparing WPJ directly with the usual clinical care offered for children diagnosed with ADHD in Japan. We also seek to assess and compare the cost-effectiveness of WPJ with TAU in Japan. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN66978270; https://www.isrctn.com/ISRCTN66978270. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32693.