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.

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.

Increased resting-state activity in the cerebellum with mothers having less adaptive sensory processing and trait anxiety.

Child-rearing mothers with high levels of trait anxiety have a tendency for less adaptive sensory processing, which causes parenting stress. However, the neural mechanisms underlying this sensory processing and trait anxiety remain unclear. We aimed to determine the whole-brain spontaneous neural activity and sensory processing characteristics in mothers with varying parenting stress levels. Using resting-state functional magnetic resonance imaging, we assessed mothers caring for more than one preschool aged (2-5 years) child and presenting with varying levels of sensory processing, trait anxiety, and parenting stress. Spontaneous neural activities in select brain regions were evaluated by whole-brain correlation analyses based on the fractional amplitude of low-frequency fluctuations (fALFF). We found significant positive correlations between levels of sensory processing with trait anxiety and parenting stress. Mothers having less adaptive sensory processing had significantly increased resting-state network activities in the left lobule VI of the cerebellum. Increased fALFF values in the left lobule VI confirmed the mediation effect on the relationship between trait anxiety and sensory processing. A tendency for less adaptive sensory processing involving increased brain activity in lobule VI could be an indicator of maternal trait anxiety and the risk of parenting stress.

The Effects of COMT Polymorphism on Cortical Thickness and Surface Area Abnormalities in Children with ADHD.

The catechol-O-methyltransferase (COMT) gene is associated with frontal cortex development and the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, how the COMT gene impacts brain structure and behavior in ADHD remains unknown. In the present study, we identify the effect of COMT on cortical thickness and surface area in children with ADHD and children with typically developing (TD) using a machine learning approach. In a sample of 39 children with ADHD and 34 age- and IQ-matched TD children, we found that cortical thickness and surface area differences were predominantly observed in the frontal cortex. Furthermore, a path analysis revealed that a COMT genotype affected abnormal development of the frontal cortex in terms of both cortical thickness and surface area and was associated with working memory changes in children with ADHD. Our study confirms that the role of COMT in ADHD is not restricted to the development of behavior but may also affect the cortical thickness and surface area. Thus, our findings may help to improve the understanding of the neuroanatomic basis for the relationship between the COMT genotype and ADHD pathogenesis.

Association between parental visitation and depressive symptoms among institutionalized children in Japan: a cross-sectional study.

BACKGROUND: Mental health problems are an important issue among institutionalized children. Although positive communication with parents is essential for children's well-being, it has not been sufficiently verified how interactions with parents affect mental health among institutionalized children, who have experienced childhood adversity and likely lack secure attachment formation with their parents. The objectives of this study were to investigate the association between parental visitation and depressive symptoms among institutionalized children in Japan, and to explore whether the established security of attachment interacts with that association. METHODS: A cross-sectional data from 399 institutionalized children aged 9 to 18 in Japan was used for the analysis. A mixed effects regression analysis was conducted to investigate the associations. RESULTS: Institutionalized children who had parental visitation showed higher depressive symptoms than those who did not. In particular, father's visitations were significantly associated with higher depressive symptoms. There was a significant interaction with score of secure attachment; children with low scores on secure attachment showed higher levels of depression with their father's visitation, whereas children with high scores on secure attachment did not. CONCLUSIONS: Findings suggested that parental visitation and the frequency of visitation were not actually associated with better psychological status, but that instead, father's visitations were associated with higher depressive symptoms among institutionalized children. It should be noted that our cross-sectional results cannot infer any causal relationship and do not emphasize that parental visitation should be avoided. However, it may be important to conduct careful assessment before starting parental visitation, especially when children seem to have problems with attachment formation.

Association of estrogen receptor alpha polymorphisms with symptoms of autism among Chinese Han children.

OBJECTIVES: Autism has a significant sex difference. This implies that the sex hormones might have effect on autism. Estrogens play an important role in early nervous system development and sex differentiation through estrogen receptors in brain. Thus, we tested the hypothesis that estrogen receptor alpha (ESR1) gene affects the pathogenesis of autism and related symptoms. METHODS: Genotypes of rs11155819 and rs2234693 were determined in boys with autism and normal boys from Chinese Han population. A case-control study was performed to explore the association between polymorphisms in ESR1 gene and autism susceptibility. Assessment tool was used to evaluate the neuropsychological developmental level of autistic children. Finally, we analyzed the association of these single nucleotide polymorphisms (SNPs) with specific symptoms. RESULTS: The results showed no significant differences between cases and controls in the distribution of genotypes and allele frequencies of the two SNPs. However, rs11155819 TT genotype showed a lower neuropsychological development level among autistic children, especially in the aspects of fine motor and adaptation ability (p=0.028; p=0.042). CONCLUSION: Polymorphisms of ESR1 are relevant to autism symptoms in Chinese Han children.

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.

Corrigendum: Effect of the nature of subsequent environment on oxytocin and cortisol secretion in maltreated children.

[This corrects the article DOI: 10.3389/fpsyt.2015.00173.].

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.

Subclinical structural atypicality of retinal thickness and its association with gray matter volume in the visual cortex of maltreated children.

Childhood maltreatment is reportedly associated with atypical gray matter structures in the primary visual cortex (V1). This study explores the hypothesis that retinal structures, the sensory organs of vision, are associated with brain atypicality and child maltreatment and examines their interrelation. General ophthalmologic examinations, visual cognitive tasks, retinal imaging, and structural magnetic resonance imaging (MRI) were conducted in children and adolescents aged 9-18 years with maltreatment experiences (CM) and typically developing (TD) children. The retinal nerve fiber layer (RNFL), the most superficial of the ten distinct retinal layers, was found to be significantly thinner in both eyes in CM. While whole-brain analysis using Voxel-based morphometry revealed a significantly larger gray matter volume (GMV) in the thalamus in CM, no significant correlation with RNFL thickness was observed. However, based on region-of-interest analysis, a thinner RNFL was associated with a larger GMV in the right V1. Although it cannot be ruled out that this outcome resulted from maltreatment alone, CM demonstrated subclinical structural atypicality in the retina, which may also correlate with the immaturity of V1 development. Examination of retinal thickness offers a novel clinical approach to capturing characteristics associated with childhood maltreatment.

No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents.

BACKGROUND: Identification of gene × environment interactions (G × E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin-regulating genes. METHODS: This study was designed to ascertain the G × E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother's history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients' depression symptoms. RESULTS: Binary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression. CONCLUSIONS: To assess G × E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects.

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.

What daily factors affect the sleep habits of Japanese toddlers?

STUDY OBJECTIVES: Good sleep, especially during early childhood, is important for development. In Japan, the mean nocturnal sleep duration of toddlers is < 10 hours, and even if toddlers slept for > 11 hours/day, as recommended by the National Sleep Foundation, some of them showed late bedtime and late wake-up time or took long naps. Therefore, we provisionally assumed the minimal sleep conditions for Japanese toddlers, named Nenne-criteria, such as bedtime before 10:00 pm, nocturnal sleep duration of ≥ 9 hours, and < 1 average time of awakening after sleep onset, and investigated the important factors for good sleep. METHODS: We analyzed cross-sectional data from online surveys describing the sleep-related behaviors of 2,124 toddlers and their caregivers. We compared the daily schedules that affect sleep between the Nenne-criteria-meet group and the not-meet group. RESULTS: The Nenne-criteria-meet group showed better daytime behaviors than the not-meet group. Structural equation modeling on daily schedules revealed that, to increase sleep pressure at the appropriate time, it is important to restrict media viewing, play outdoors in the morning, have an early nap ending time, avoid hyperarousal-inducing behaviors before bedtime, maintain daily schedules regularly, and decrease social jetlag. CONCLUSIONS: The Nenne-criteria are useful for screening Japanese toddlers who require intervention for sleep hygiene. To improve toddlers' sleep, it is important not only to guide the ideal bedtime but also to provide tips for improving daily schedules and to avoid suboptimal sleep-related behaviors. CITATION: Murata E, Yoshizaki A, Fujisawa TX, Tachibana M, Taniike M, Mohri I. What daily factors affect the sleep habits of Japanese toddlers? J Clin Sleep Med. 2023;19(6):1089-1101.

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.

Improving Children's Sleep Habits Using an Interactive Smartphone App: Community-Based Intervention Study.

BACKGROUND: Sleep problems are quite common among young children and are often a challenge for parents and a hinderance to children's development. Although behavioral therapy has proven effective in reducing sleep problems in children, a lack of access to professionals who can provide effective support is a major barrier for many caregivers. Therefore, pediatric sleep experts have begun developing apps and web-based services for caregivers. Despite the substantial influence of cultural and familial factors on children's sleep, little effort has gone into developing cultural or family-tailored interventions. OBJECTIVE: This study aimed to examine the effectiveness of the interactive smartphone app "Nenne Navi," which provides culturally and family-tailored suggestions for improving sleep habits in young Japanese children through community-based long-term trials. The study also aimed to investigate the association between app-driven improvements in sleep and mental development in children. METHODS: This study adopted a community-based approach to recruit individuals from the Higashi-Osaka city (Japan) who met ≥1 of the following eligibility criteria for sleep problems: sleeping after 10 PM, getting <9 hours of nighttime sleep, and experiencing frequent nighttime awakenings. A total of 87 Japanese caregivers with young children (mean 19.50, SD 0.70 months) were recruited and assigned to the app use group (intervention group) or the video-only group (control group). Both groups received educational video content regarding sleep health literacy. The caregivers in the intervention group used the app, which provides family-tailored suggestions, once per month for 1 year. RESULTS: A total of 92% (33/36) of the caregivers in the app use group completed 1 year of the intervention. The participants' overall evaluation of the app was positive. The wake-up time was advanced (base mean 8:06 AM; post mean 7:48 AM; F1,65=6.769; P=.01 and sleep onset latency was decreased (base mean 34.45 minutes; post mean 20.05 minutes; F1,65=23.219; P<.001) significantly in the app use group at the 13th month compared with the video-only group. Moreover, multiple regression analysis showed that decreased social jetlag (ß=-0.302; P=.03) and increased sleep onset latency SD (ß=.426; P=.02) in children predicted a significant enhancement in the development of social relationships with adults. At 6 months after the completion of the app use, all the caregivers reported continuation of the new lifestyle. CONCLUSIONS: The present findings suggest that the app "Nenne Navi" has high continuity in community use and can improve sleep habits in young Japanese children and that interventions for sleep habits of young children may lead to the enhancement of children's social development. Future studies must focus on the effectiveness of the app in other regions with different regional characteristics and neuroscientific investigations on how changes in sleep impact brain development.

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.

Loneliness depends on salivary estradiol levels in adolescent females.

OBJECTIVE: Loneliness is one of the psychological characteristics in adolescence, during which sex hormones are elevated. The elevation of sex steroid hormones is known to sculpture and remodel neuronal circuits, which cause behavioral characteristics in adolescence. The aim of the present study is to investigate the relationship between loneliness and sex steroid hormones, testosterone (T) and 17ß-estradiol (E2). METHODS: Fifty-eight adolescents (28 boys and 30 girls) participated in this study. The salivary levels of T and E2 were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Loneliness was assessed by the UCLA loneliness scale, which is widely used as a self-administered questionnaire. RESULTS: The results showed that Salivary E2 levels had positive relevance to loneliness in females, whereas there was no relationship in males. Salivary T level was not shown to be relevant with loneliness in either sex group. CONCLUSIONS: These findings suggest that E2 has gender specific effects on loneliness in adolescent females.

Epigenetic Clock Deceleration and Maternal Reproductive Efforts: Associations With Increasing Gray Matter Volume of the Precuneus.

Reproductive efforts, such as pregnancy, delivery, and interaction with children, make maternal brains optimized for child-rearing. However, extensive studies in non-human species revealed a tradeoff between reproductive effort and life expectancy. In humans, large demographic studies have shown that this is the case for the most part; however, molecular marker studies regarding aging remain controversial. There are no studies simultaneously evaluating the relationship between reproductive effort, aging, and brain structures. We therefore examined the associations between reproductive efforts (parity status, number of deliveries, motherhood period, and cumulative motherhood period), DNA methylation age (mAge) acceleration (based on Horvath's multi-tissue clock and the skin & blood clock), and the regional gray matter volumes (obtained through brain magnetic resonance imaging (MRI) using voxel-based morphometry) in 51 mothers aged 27-46 years of children in early childhood. We found that increasing reproductive efforts were significantly associated with decelerated aging in mothers with one to four children, even after adjusting for the confounding effects in the multiple linear regression models. We also found that the left precuneus gray matter volume was larger as deceleration of aging occurred; increasing left precuneus gray matter volume, on the other hand, mediates the relationship between parity status and mAge deceleration. Our findings suggest that mothers of children in early childhood, who have had less than four children, may benefit from deceleration of aging mediated via structural changes in the precuneus.

The influence of intelligence and cognitive abilities on the reading ability of Japanese students with developmental disorders.

OBJECTIVE: We examined the differences in reading skills between Japanese students with developmental dyslexia (DD) having developmental disorders who had borderline IQ (BIQ) and those who had normal IQ (NIQ), and the influence of cognitive factors through subscale scores of the Wechsler Intelligence Scale for Children - Fourth Edition on the reading skills of all students with DD having developmental disorders. METHODS: One-way analysis of variance revealed differences in reading scores among the four groups (DD with NIQ, DD with BIQ, as well as non-DD with NIQ and non-DD with BIQ as control groups). To examine the influence of cognitive factors, we used multiple regression analysis for all participants, and then for participants with DD. RESULTS: Regarding hiragana nonword fluency reading, no difference was observed between the two DD groups, and cognitive factors did not affect the performance of all participants with DD. Concerning hiragana word fluency reading, DD with NIQ group performed better than DD group with BIQ, and working memory index affected reading skills of participants with DD. Regarding kanji accuracy reading, DD with NIQ group performed better than DD with BIQ group, and processing speed index affected performance of participants with DD. CONCLUSIONS: The results of hiragana reading suggest that the two DD groups shared similar weak sub-lexical route processing, while the acquisition of lexical route processing was hindered by lower IQ and weak phonological working memory in transparent phonographic hiragana reading. For kanji reading, lower IQ and weak visuomotor processing ability hampered the learning of visually complex logographic kanji characters.