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.

Validity and reliability of the Japanese versions of the coronavirus anxiety scale for adolescents and obsession with COVID-19 scale for adolescents.

Background: The coronavirus disease 2019 (COVID-19) has caused mental health issues in both adults and adolescents. The Coronavirus Anxiety Scale (CAS) and Obsession with COVID-19 Scale (OCS) questionnaires measure anxiety and persistent and disturbed thoughts (also known as obsessions) related to COVID-19. We developed Japanese versions of the CAS (i.e., CAS-JA) and OCS (i.e., OCS-JA) questionnaires to make them suitable for adolescents and validated the characteristics of these scales. Methods: Two online surveys were administered to high school students aged 15-18 years. A total of 263 students participated in the first survey and almost half of them participated in the second survey. In the first survey, participants responded to the CAS-JA, OCS-JA, generalized anxiety and obsessive-compulsive subscales of the Spence Children's Anxiety Scale (SCAS), and Kessler 6 Scale (K6). The SCAS and K6 were used to verify discriminant validity and inter-scale correlations. In the second survey, the participants completed the CAS-JA and OCS-JA again to verify test-retest reliability. We performed a confirmatory factor analysis and calculated the model fit indices. Additionally, we examined the internal consistency reliability, convergent validity, and inter-item correlations of the CAS-JA and OCS-JA. Moreover, differences in CAS-JA and OCS-JA responses by gender and region of residence (state of emergency and non-emergency areas) were examined. Results: The results of the single-factor model confirmatory factor analysis of model fit indices were above the threshold. The required criteria for internal consistency reliability, test-retest reliability, and discriminant and convergent validity were met in both the CAS-JA and OCS-JA. No statistically significant differences attributed to residence and gender were found in both questionnaires. Conclusions: The results indicate that the CAS-JA and OCS-JA questionnaires are useful in measuring COVID-19-related anxiety, and persistent and disturbed thoughts in Japanese adolescents.

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.

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.

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.

Endogenous oxytocin levels in extracted saliva elevates during breastfeeding correlated with lower postpartum anxiety in primiparous mothers.

BACKGROUND: Breastfeeding in the early postpartum period is expected to have mental benefits for mothers; however, the underlying psychobiological mechanisms remain unclear. Previously, we hypothesized that the release of oxytocin in response to the suckling stimuli during breastfeeding would mediate a calming effect on primiparous mothers, and we examined salivary oxytocin measurements in primiparous mothers at postpartum day 4 using saliva samples without extraction, which was erroneous. Thus, further confirmation of this hypothesis with a precise methodology was needed. METHODS: We collected saliva samples at three time points (baseline, feeding, and post-feeding) to measure oxytocin in 24 primiparous mothers on postpartum day 2 (PD2) and 4 (PD4) across the breastfeeding cycle. Salivary oxytocin levels using both extracted and unextracted methods were measured and compared to determine the qualitative differences. State and trait anxiety and clinical demographics were evaluated to determine their association with oxytocin changes. RESULTS: Breastfeeding elevated salivary oxytocin levels; however, it was not detected to a significant increase in the extraction method at PD4. We found a weak but significant positive correlation between changes in extracted and unextracted oxytocin levels during breastfeeding (feeding minus baseline); there were no other significant positive correlations. Therefore, we used the extracted measurement index for subsequent analysis. We showed that the greater the increase in oxytocin during breastfeeding, the lower the state anxiety, but not trait anxiety. Mothers who exclusively breastfed at the 1-month follow-up tended to be associated with slightly higher oxytocin change at PD2 than those who did not. CONCLUSIONS: Breastfeeding in early postpartum days could be accompanied by the frequent release of oxytocin and lower state anxiety, potentially contributing to exclusive breastfeeding.

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 effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults.

DNA methylation age has been used in recent studies as an epigenetic marker of accelerated cellular aging, whose contribution to the brain structural changes was lately acknowledged. We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. Using the multi-tissue method (Horvath S. DNA methylation age of human tissues and cell types. 2013. Genome Biol 14), epigenetic age was computed with saliva sample. Epigenetic age acceleration was derived from residuals after adjusting epigenetic age for chronological age. Multiple regression models were computed for 148 brain regions for surface area, cortical thickness, and volume using epigenetic age or accelerated epigenetic age as a predictor and controlling for sex. Epigenetic age was associated with surface area reduction of the left insula. It was also associated with cortical thinning and volume reduction in multiple regions, with prominent changes of cortical thickness in the left temporal regions and of volume in the bilateral orbital gyri. Finally, accelerated epigenetic age was negatively associated with right cuneus gyrus volume. Our findings suggest that understanding the mechanisms of epigenetic age acceleration in young individuals may yield valuable insights into the relationship between epigenetic aging and the cortical change and on the early development of neurocognitive pathology among young adults.

A multi-modal MRI analysis of brain structure and function in relation to OXT methylation in maltreated children and adolescents.

Child maltreatment dysregulates the brain's oxytocinergic system, resulting in dysfunctional attachment patterns. However, how the oxytocinergic system in children who are maltreated (CM) is epigenetically affected remains unknown. We assessed differences in salivary DNA methylation of the gene encoding oxytocin (OXT) between CM (n = 24) and non-CM (n = 31), alongside its impact on brain structures and functions using multi-modal brain imaging (voxel-based morphometry, diffusion tensor imaging, and task and resting-state functional magnetic resonance imaging). We found that CM showed higher promoter methylation than non-CM, and nine CpG sites were observed to be correlated with each other and grouped into one index (OXTmi). OXTmi was significantly negatively correlated with gray matter volume (GMV) in the left superior parietal lobule (SPL), and with right putamen activation during a rewarding task, but not with white matter structures. Using a random forest regression model, we investigated the sensitive period and type of maltreatment that contributed the most to OXTmi in CM, revealing that they were 5-8 years of age and physical abuse (PA), respectively. However, the presence of PA (PA+) was meant to reflect more severe cases, such as prolonged exposure to multiple types of abuse, than the absence of PA. PA+ was associated with significantly greater functional connectivity between the right putamen set as the seed and the left SPL and the left cerebellum exterior. The results suggest that OXT promoter hypermethylation may lead to the atypical development of reward and visual association structures and functions, thereby potentially worsening clinical aspects raised by traumatic experiences.

Mismatch negativity of preschool children at risk of developing mental health problems.

This study examined the relationship between mismatch negativity (MMN) during the passive oddball task and clinical assessment using a behavioral scale in nonclinical preschool children to identify neurobiological endophenotypes associated with the risk of developing mental health problems. We assessed the risk of developing mental health problems in preschool children using the Strengths and Difficulties Questionnaire, which is used worldwide as a behavior-based screening tool for assessing mental health risks, and examined its relevance to amplitude and latency MMN. As a result, we found that children at a higher risk of mental health problems had smaller MMN amplitudes than those at lower risk. It was also found that MMN amplitude was negatively correlated with the assessed higher risk of mental health problems. Although it is not clear what neural mechanisms underlie the functional association between MMN and risk of mental health problems in preschool children, the findings of this study indicate that there is an involvement of individual differences in auditory processing in childhood mental health problems. The findings suggest that such neurological changes may be prodromal symptoms of the onset of psychiatric disorders and applicable as endophenotypic markers for the early detection of various psychiatric disorders.

RETRACTED: Epigenetic modification of the oxytocin gene is associated with gray matter volume and trait empathy in mothers.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). The Editor has concluded that the acceptance of this article was partly based upon the positive advice of an unreliable reviewer report. The report was provided to the journal by a reviewer suggested by the authors, and there were inappropriate communications between the authors and reviewer during the peer-review process. The Editor has therefore concluded that the review was not appropriate or independent. This manipulation of the peer-review process represents a clear violation of the fundamentals of peer review, our publishing policies, and publishing ethics standards. Apologies are offered to the readers of the journal that this deception was not detected during the submission process.

Epigenetic prediction of 17ß-estradiol and relationship to trauma-related outcomes in women.

17ß-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r â€‹= â€‹0.75, p â€‹= â€‹1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (ߠ​= â€‹-0.38, p â€‹= â€‹0.01) and major depressive disorder (MDD) diagnoses (ߠ​= â€‹-0.45, p â€‹= â€‹0.02), as well as a continuous measure of PTSD symptom severity (ߠ​= â€‹-2.3, p â€‹= â€‹0.007) in females. Finally, we tested our predictor in an independent data set (n â€‹= â€‹85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r â€‹= â€‹0.48, p â€‹= â€‹3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured.

Influence of the COVID-19 Pandemic on Parenting Stress Across Asian Countries: A Cross-National Study.

Background: In a previous study, we demonstrated that the accumulation of parenting stress during prolonged school closures and restrictions on daily activities due to the COVID-19 pandemic in Japan indicates the need for mental health intervention for parents at higher risk of parenting stress. However, few studies have focused on parenting stress in other Asian countries, although they have experienced higher numbers of infections. The aim of the present study was to investigate whether parenting stress among caregivers increased across Asia due to school closures and restrictions on activities during the COVID-19 pandemic and to examine whether there were any country-specific, cross-country, or cross-regional risk factors for increased parenting stress. Methods: We conducted an online survey immediately after the number of new cases in India significantly increased (September-November 2020). We measured parenting stress, anxiety, and fear associated with the COVID-19 crisis, as evaluated by the Parenting Stress Index, Short-Form (PSI-SF), and the Coronavirus Anxiety Scale (CAS), across three Asian countries-India (n = 142), Malaysia (n = 69), and Japan (n = 182)-in addition to the United States (n = 203). We also investigated whether respondents had adverse childhood experiences (ACE) as a risk factor for parenting stress. Results: For all countries, we found significant increases in participants' current parenting stress levels, compared to what they recalled regarding their lives before COVID-19-related restrictions and school closures were enacted. Textual analysis qualitatively identified common terms related to parenting stress across all countries. We also found a statistical model that indicated ACE in parents was a critical risk factor for higher parenting stress via increasing anxiety and fear related to the pandemic. Conclusion: These results indicate the need to improve the mental health of caregivers who are at risk for higher levels of parenting stress during the COVID-19 pandemic in Asian countries as well as Western countries. These results indicate that there is a need to improve the mental health of caregivers who are at risk for higher levels of parenting stress during the COVID-19 pandemic globally.

Association of Epigenetic Differences Screened in a Few Cases of Monozygotic Twins Discordant for Attention-Deficit Hyperactivity Disorder With Brain Structures.

The present study examined the relationship between DNA methylation differences and variations in brain structures involved in the development of attention-deficit hyperactivity disorder (ADHD). First, we used monozygotic (MZ) twins discordant (2 pairs of 4 individuals, 2 boys, mean age 12.5 years) for ADHD to identify candidate DNA methylation sites involved in the development of ADHD. Next, we tried to replicate these candidates in a case-control study (ADHD: N = 18, 15 boys, mean age 10.0 years; Controls: N = 62, 40 boys, mean age 13.9 years). Finally, we examined how methylation rates at those sites relate to the degree of local structural alterations where significant differences were observed between cases and controls. As a result, we identified 61 candidate DNA methylation sites involved in ADHD development in two pairs of discordant MZ twins, among which elevated methylation at a site in the sortilin-related Vps10p domain containing receptor 2 (SorCS2) gene was replicated in the case-control study. We also observed that the ADHD group had significantly reduced gray matter volume (GMV) in the precentral and posterior orbital gyri compared to the control group and that this volume reduction was positively associated with SorCS2 methylation. Furthermore, the reduced GMV regions in children with ADHD are involved in language processing and emotional control, while SorCS2 methylation is also negatively associated with emotional behavioral problems in children. These results indicate that SorCS2 methylation might mediate a reduced GMV in the precentral and posterior orbital gyri and therefore influence the pathology of children with ADHD.

Pathways linking adverse environments to emerging adults' substance abuse and depressive symptoms: A prospective analysis of rural African American men.

For African American emerging adult men, developmental challenges are evident in their escalating substance abuse and depressive symptoms; this is particularly true for men from low-resource communities. The present study tests a developmental model linking childhood adversity and contemporaneous contextual stressors to increases in emerging adults' substance use and depressive symptoms, indirectly, via increases in defensive/hostile relational schemas and social developmental risk factors (e.g., risky peers and romantic partners, lack of involvement in school or work). We also advance exploratory hypotheses regarding DNA methylation in the oxytocin receptor gene (OXTR) as a moderator of the effects of stress on relational schemas. Hypotheses were tested with three waves of data from 505 rural African American men aged 19-25 years. Adverse childhood experiences predicted exposure to emerging adult contextual stressors. Contextual stressors forecast increases in defensive/hostile relational schemas, which increased social developmental risk factors. Social developmental risk factors proximally predicted increases in substance abuse and depressive symptoms. OXTR DNA methylation moderated the effects of contextual stressors on defensive/hostile relational schemas. Findings suggest that early exposures to stress carry forward to affect the development of social developmental risk factors in emerging adulthood, which place rural African American men at risk for increased substance abuse and depressive symptoms during the emerging adult years.