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.

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.

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.

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.

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.

Guided internet-based cognitive behavioral therapy for obsessive-compulsive disorder: A multicenter randomized controlled trial in Japan.

Few studies have compared the effectiveness of internet-based cognitive behavior therapy (ICBT) for obsessive-compulsive disorder (OCD) with treatment as usual (TAU). We investigated the effectiveness of guided ICBT for patients with OCD. This prospective, randomized, controlled, assessor-blinded, multicenter clinical trial was conducted at three facilities in Japan from January 2020 to March 2021. Thirty-one patients with OCD as the primary diagnosis participated in the trial and were randomly assigned to either the intervention group or the control group. The primary outcome was the Yale-Brown obsessive-compulsive scale score; the assessors were blinded. Results of the analysis of covariance among the groups were significantly different between the groups (p < 0.01, effect size Cohen's d = 1.05), indicating the superiority of guided ICBT. The results suggest that guided ICBT is more effective than TAU for treating OCD. RCT REGISTRATION: UMIN Clinical Trials Registry (UMIN000039375).

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.

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.

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.

Low threshold to Vestibular and Oral Sensory stimuli might affect quality of sleep among children with autism spectrum disorder.

AIMS: The current study aimed to validate the relationship between sensory characteristics and sleep dynamics among children with autism spectrum disorder (ASD) using an actigraph, which is an objective assessment device used for sleep monitoring. METHODS: A total of 40 children (age range, 3-6 years) participated in this study (n = 20, with ASD and n = 20, age-matched children with typical development [TD]). We examined sleep dynamics using actigraph for 7 consecutive days, and the relationship between sleep parameters and sensory characteristics was analyzed using the Japanese Version of Sensory Profile (SP-J). RESULTS: Significant differences were observed in terms of activities per minute during sleep (p = 0.02), sleep efficiency (SE) (p = 0.005), and wake after sleep onset (WASO) (p = 0.02) between the two groups. In the ASD group, significant positive correlations were observed between activities per minute during sleep and low thresholds for Vestibular Sensory stimuli (p = 0.046) and Oral Sensory stimuli (p = 0.006) using the SP-J. Based on a multiple regression analysis, the activities per minute during sleep were associated with low thresholds for Oral Sensory stimuli (ß = 0.51, t = 2.29, p = 0.03), but not with other factors, in the ASD group. CONCLUSIONS: The current study showed that atypical Vestibular and Oral Sensory modulation may be a risk indicator for high activities during sleep among preschool children with ASD. Thus, whether the interventions for these sensory characteristics are effective in improving sleep quality, daytime activities, behaviors, and cognitive functions in this group of children must be considered.

White matter changes in children and adolescents with reactive attachment disorder: A diffusion tensor imaging study.

Childhood maltreatment is associated with altered brain structure and function and is a major risk factor for psychopathology, including reactive attachment disorder (RAD). However, whether changes to white matter microstructural integrity are associated with RAD is unclear. We used diffusion tensor imaging (DTI) to assess group differences in fractional anisotropy (FA) in patients with RAD (n = 25; mean age = 13.2) to typically developing (TD) controls (n = 33; mean age = 13.0). To further interpret differences in FA, additional parameters such as mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were assessed. We found that FA values in the body of corpus callosum (CC) and in the projection and thalamic pathways, including the posterior limb of the internal capsule and corona radiata (anterior, posterior, and superior), were significantly higher in the RAD than in the TD group. Additionally, RAD group showed significantly lower RD values in the body of the CC and abovementioned pathways than TD group. Our findings indicate that RAD is associated with altered structure of the CC and projection and thalamic pathways, which may play a role in emotion regulation. The aberrant development of these tracts in RAD may reflect stress-related psychophysiological responses.

Development of Social Attention and Oxytocin Levels in Maltreated Children.

Child maltreatment (CM) is a major risk factor for various psychopathologies but also adversely affects social development. Research on oxytocin (OT) is currently drawing attention as an endocrine basis for social development. In this study, we investigated the relationship between visual attention to social cues and salivary OT levels in children exposed to CM. The results revealed that the CM group had a significantly lower percentage of gaze fixation for the human face eye area and lower salivary OT levels compared to the typical development group. Moreover, a path analysis suggested that gaze fixation for the eye area was a mediator of the relationship between salivary OT levels and social-emotional problems in the CM group. These results suggest that lower endogenous OT levels in maltreated children may lead to atypical development of their visual attention to eyes as a social cue, resulting in social-emotional problems.

Developmental changes in attention to social information from childhood to adolescence in autism spectrum disorders: a comparative study.

BACKGROUND: Elucidating developmental changes in the symptoms of autism spectrum disorder (ASD) is important to support individuals with ASD. However, no report has clarified the developmental changes in attention to social information for a broad age range. The aim of this study was to investigate the developmental changes in attention to social information from early childhood to adolescence in individuals with ASD and typically developed (TD) children. METHODS: We recruited children with ASD (n = 83) and TD participants (n = 307) between 2 and 18 years of age. Using the all-in-one-eye-tracking system, Gazefinder, we measured the percentage fixation time allocated to areas of interest (AoIs) depicted in movies (the eyes and mouth in movies of a human face with/without mouth motion, upright and inverted biological motion in movies showing these stimuli simultaneously, people and geometry in preference paradigm movies showing these stimuli simultaneously, and objects with/without finger-pointing in a movie showing a woman pointing toward an object). We conducted a three-way analysis of variance, 2 (diagnosis: ASD and TD) by 2 (sex: male and female) by 3 (age group: 0-5, 6-11, and 12-18 years) and locally weighted the scatterplot smoothing (LOESS) regression curve on each AoI. RESULTS: In the face stimuli, the percentage fixation time to the eye region for the TD group increased with age, whereas the one for the ASD group did not. In the ASD group, the LOESS curves of the gaze ratios at the eye region increased up to approximately 10 years of age and thereafter tended to decrease. For the percentage fixation time to the people region in the preference paradigm, the ASD group gazed more briefly at people than did the TD group. LIMITATIONS: It is possible that due to the cross-sectional design, the degree of severity and of social interest might have differed according to the subjects' age. CONCLUSIONS: There may be qualitative differences in abnormal eye contact in ASD between individuals in early childhood and those older than 10 years.

Thalamic Volume Is Related to Increased Anterior Thalamic Radiations in Children with Reactive Attachment Disorder.

Reactive attachment disorder (RAD) is associated with childhood maltreatment and affects approximately 1% of the general population. Recent data suggest that childhood maltreatment is associated with brain alterations in white and gray matter. However, the neural mechanisms of RAD-related brain alterations remain unknown. Herein, we evaluated the white matter pathways and gray matter volumes in 31 and 41 age-matched children with RAD and typical development (TD), respectively, by analyzing T1- and diffusion-weighted images. An increased fractional anisotropy (FA) and axial diffusivity in the anterior thalamic radiations (ATR) and an increased volume in the bilateral pallidum and right thalamus were observed in children with RAD compared with those with TD. Moreover, the volume of the thalamus was associated with increased ATR FA in children with RAD. Our study confirmed the existence of atypical neurodevelopment processes in the thalamus, pallidum, and ATR in children with RAD and highlighted an interdependent relationship between the alterations in the thalamus and ATR. These findings may help to improve our understanding of the comprehensive neural mechanisms of RAD.

Structural brain abnormalities in children and adolescents with comorbid autism spectrum disorder and attention-deficit/hyperactivity disorder.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share high rates of comorbidity, with the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition now acknowledging the comorbid diagnosis of ASD and ADHD. Although structural abnormalities in the prefrontal cortex, cerebellum, and basal ganglia occur in both ASD and ADHD, no structural studies have focused exclusively on patients with comorbid ASD and ADHD. We thus aimed to clarify the structural features and developmental changes in patients with comorbid ASD and ADHD in a relatively large sample from two sites. Ninety-two patients were age-matched to 141 typically developing (TD) controls (age range: 5-16 years) and assessed for volumetric characteristics using structural magnetic resonance imaging (i.e. surface-based morphometry). While there were no significant differences in prefrontal cortex, cerebellum, and basal ganglia volumes, patients with ASD and ADHD exhibited significantly lower left postcentral gyrus volumes than TD controls. We observed significantly lower postcentral gyrus volumes exclusively in children and preadolescents, and not in adolescents. Our findings suggest that abnormal somatosensory, attributed to delayed maturation of the left postcentral gyrus, leads to the core symptoms experienced by patients with comorbid ASD and ADHD.

Oxytocin receptor DNA methylation and alterations of brain volumes in maltreated children.

Although oxytocin (OXT) plays an important role in secure attachment formation with a primary caregiver, which is impaired in many children with childhood maltreatment (CM), epigenetic regulation in response to CM is a key factor in brain development during childhood. To address this issue, we first investigated differences in salivary DNA methylation of the oxytocin receptor (OXTR) between CM and Non-CM groups of Japanese children (CM: n = 44; Non-CM: n = 41) and its impact on brain structures in subgroup analysis using brain imaging and full clinical data (CM: n = 24; Non-CM: n = 31). As a result, we observed that the CM group showed higher CpG 5,6 methylation than did the Non-CM group and confirmed negative correlations of gray matter volume (GMV) in the left orbitofrontal cortex (OFC) with CpG 5,6 methylation. In addition, the CM group showed significantly lower GMV in the left OFC than did the Non-CM group. Furthermore, as a result of examining the relationship between GMV in the left OFC and psychiatric symptoms in CM, we observed a negative association with insecure attachment style and also confirmed the mediation effect of left-OFC GMV reduction on the relationship between OXTR methylation and insecure attachment style. These results suggest that any modulation of the oxytocin signaling pathway induced by OXTR hypermethylation at CpG 5,6 leads to atypical development of the left OFC, resulting in distorted attachment formation in children with CM.