Child maltreatment increases the risk for psychiatric disorders throughout childhood and into adulthood. One negative outcome of child maltreatment can be a disorder of emotional functioning, reactive attachment disorder (RAD), where the child displays wary, watchful, and emotionally withdrawn behaviours. Despite its clinical importance, little is known about the potential neurobiological consequences of RAD. The aim of this study was to elucidate whether RAD was associated with alterations in grey matter volume (GMV). High-resolution magnetic resonance imaging datasets were obtained for children and adolescents with RAD (n = 21; mean age = 12.76 years) and typically developing (TD) control subjects (n = 22; mean age = 12.95 years). Using a whole-brain voxel-based morphometry approach, structural images were analysed controlling for age, gender, full scale intelligence quotient, and total brain volume. The GMV was significantly reduced by 20.6% in the left primary visual cortex (Brodmann area 17) of the RAD group compared to the TD group (p = .038, family-wise error-corrected cluster level). This GMV reduction was related to an internalising problem measure of the Strength and Difficulties Questionnaire. The visual cortex has been viewed as part of the neurocircuit regulating the stress response to emotional visual images. Combined with previous studies of adults with childhood maltreatment, early adverse experience (e.g. sensory deprivation) may affect the development of the primary visual system, reflecting in the size of the visual cortex in children and adolescents with RAD. These visual cortex GMV abnormalities may also be associated with the visual emotion regulation impairments of RAD, leading to an increased risk for later psychopathology.

Reactive attachment disorder (RAD) is a severe social functioning disorder associated with early childhood maltreatment where the child displays emotionally withdrawn/inhibited behaviors toward caregivers. Brain regions develop at different rates and regions undergoing rapid change may be particularly vulnerable during these times to stressors or adverse experiences. The aim of this study was to investigate the effect of type and timing of childhood adversities on structural alterations in regional gray matter (GM) volume in maltreated children with RAD. High-resolution magnetic resonance imaging datasets were obtained for children and adolescents with RAD (n = 21; mean age = 12.76 years) and typically developing (TD) control subjects (n = 22; mean age = 12.95 years). Structural images were analyzed using a whole-brain voxel-based morphometry approach and the type and timing of maltreatment, which may be more strongly associated with structural alterations, was assessed using random forest regression with conditional inference trees. Our findings revealed that there is a potential sensitive period between 5 and 7 years of age for GM volume reduction of the left primary visual cortex (BA17) due to maltreatment. We also found that the number of types of maltreatment had the most significant effect on GM volume reduction and that the second most significant variable was exposure to neglect. The present study provides the first evidence showing that type and timing of maltreatment have an important role in inducing structural abnormalities in children and adolescents with RAD.

Child maltreatment is a major risk factor for psychopathology, including reactive attachment disorder (RAD).

The scale-free dynamics of human brain activity, characterized by an elaborate temporal structure with scale-free properties, can be quantified using the power-law exponent (PLE) as an index. Power laws are well documented in nature in general, particularly in the brain. Some previous fMRI studies have demonstrated a lower PLE during cognitive-task-evoked activity than during resting state activity. However, PLE modulation during cognitive-task-evoked activity and its relationship with an associated behavior remain unclear. In this functional fMRI study in the resting state and face processing + control task, we investigated PLE during both the resting state and task-evoked activities, as well as its relationship with behavior measured using mean reaction time (mRT) during the task. We found that (1) face discrimination-induced BOLD signal changes in the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), amygdala, and fusiform face area; (2) PLE significantly decreased during task-evoked activity specifically in mPFC compared with resting state activity; (3) most importantly, in mPFC, mRT significantly negatively correlated with both resting state PLE and the resting-task PLE difference. These results may lead to a better understanding of the associations between task performance parameters (e.g., mRT) and the scale-free dynamics of spontaneous and task-evoked brain activities.

Autism spectrum disorders (ASD) are characterized by impaired social cognition and communication. In addition to social impairment, individuals with ASD often have intellectual disability. Intelligence is known to influence the phenotypic presentation of ASD. Nevertheless, the relation between intelligence and social reciprocity in people with ASD remains unclear, especially in childhood. To elucidate this relation, we analyzed 56 typically developing children (35 male, 21 female, aged 60-91 months) and 46 children with ASD (35 male, 11 female, aged 60-98 months) from university and affiliated hospitals. Their cognitive function was evaluated using the Kaufman Assessment Battery for Children. Their social cognition was assessed using the Social Responsiveness Scale. We used linear regression models to ascertain whether the associations between intelligence and social cognition of typically developing children and children with ASD are significantly different. Among the children with ASD, scores on the Kaufman Assessment Battery for Children correlated significantly with social cognition, indicating that higher intelligence is associated with better social cognition. For typically developing children, however, no significant correlation was found. One explanation might be that children with ASD fully use general intelligence for successful learning in social cognition, although extensive use of intelligence might not be necessary for TD children. Alternatively, autistic impairment in social cognition can be compensated by intelligence despite a persistent deficit in social cognition. In either case, when using the SRS as a quantitative phenotype measure for ASD, the influence of intelligence must be considered.

Many neuroimaging studies on morality focus on functional brain areas that relate to moral judgment specifically in morally negative situations. To date, there have been few studies on differences in brain activity under conditions of being morally good and bad along a continuum. To explore not only the brain regions involved but also their functional connections during moral judgments, we used magnetoencephalography (MEG), which is superior to other imaging modalities for analyzing time-dependent brain activities; only men were recruited because sex differences might be a confounding factor. While analyses showed that general patterns of brain activation and connectivity were similar between morally good judgments (MGJs) and morally bad judgments (MBJs), activation in brain areas that subserve emotion and "theory of mind" on the right hemisphere was larger in MGJ than MBJ conditions. In the left local temporal region, the connectivity between brain areas related to emotion and reward/punishment was stronger in MBJ than MGJ conditions. The time-frequency analysis showed distinct laterality (left hemisphere dominant) occurring during early moral information processing in MBJ conditions compared to MGJ conditions and phase-dependent differences in the appearance of theta waves between MBJ and MGJ conditions. During MBJs, connections within the hemispheric regions were more robust than those between hemispheric regions. These results suggested that the local temporal region on the left hemisphere is more important in the execution of MBJs during early moral valence processing than in that with MGJs. Shorter neuronal connections within the hemisphere may allow to make MBJs punctual.

The social motivation hypothesis posits that people with autism spectrum disorder (ASD) find social stimuli less rewarding and are therefore less motivated towards social interaction than people with neuro-typical development (TD). However, the less rewarding social stimuli characteristics during social interaction for people with ASD are largely unknown. The contingent positive responsiveness of others relevant to self-action motivates the early development of social interaction, thus representing a social reward. As individuals with ASD often exhibit atypical responses to self-relevant stimuli in their early life, we hypothesized that the self-relevant responses of others are less rewarding for individuals with ASD. To test this hypothesis, we conducted a functional magnetic resonance imaging study using a social contingency task. During the task, the participants attempted to make the audience laugh by telling funny jokes and thus activating the anterior rostral medial prefrontal cortex (arMPFC) of TD individuals (Sumiya et al., 2017). We explicitly predicted that the atypical activation of the arMPFC is related to the reduced reward value of self-relevant responses to others in individuals with ASD. Thirty-one adults with ASD and 24 age- and intelligence quotient-matched TD adults participated in the study. Participants with ASD reported significantly lower pleasure after the audience's responses to their own actions than those in the TD group. Correspondingly, the self-related activation of the arMPFC, defined by the results of our previous study, was attenuated in the ASD group compared to the TD group. The present findings indicate that weak self-relevant outcome processing mediated by the arMPFC of individuals with ASD dampens the rewarding nature of social interaction.

Many individuals with autism spectrum disorders have comorbid epilepsy. Even in the absence of observable seizures, interictal epileptiform discharges are common in individuals with autism spectrum disorders. However, how these interictal epileptiform discharges are related to autistic symptomatology remains unclear. This study used magnetoencephalography to investigate the relation between interictal epileptiform discharges and altered functional brain networks in children with autism spectrum disorders. Instead of particularly addressing individual brain regions, we specifically examine network properties. For this case-control study, we analysed 70 children with autism spectrum disorders (52 boys, 18 girls, 38-92 months old) and 19 typically developing children (16 boys, 3 girls, 48-88 months old). After assessing the participants' social reciprocity using the Social Responsiveness Scale, we constructed graphs of functional brain networks from frequency band separated task-free magnetoencephalography recordings. Nodes corresponded to Desikan-Killiany atlas-based 68 brain regions. Edges corresponded to phase lag index values between pairs of brain regions. To elucidate the effects of the existence of interictal epileptiform discharges on graph metrics, we matched each of three pairs from three groups (typically developing children, children with autism spectrum disorders who had interictal epileptiform discharges and those who did not) in terms of age and sex. We used a coarsened exact matching algorithm and applied adjusted regression analysis. We also investigated the relation between social reciprocity and the graph metric. Results show that, in children with autism spectrum disorders, the average clustering coefficient in the theta band was significantly higher in children who had interictal epileptiform discharges. Moreover, children with autism spectrum disorders who had no interictal epileptiform discharges had a significantly lower average clustering coefficient in the theta band than typically developing children had. However, the difference between typically developing children and children with autism spectrum disorder who had interictal epileptiform discharges was not significant. Furthermore, the higher average clustering coefficient in the theta band corresponded to severe autistic symptoms in children with autism spectrum disorder who had interictal epileptiform discharges. However, the association was not significant in children with autism spectrum disorders who had no interictal epileptiform discharge. In conclusion, results demonstrate that alteration of functional brain networks in children with autism spectrum disorders depends on the existence of interictal epileptiform discharges. Interictal epileptiform discharges might 'normalize' the deviation of altered brain networks in autism spectrum disorders, increasing the clustering coefficient. However, when the effect exceeds tolerance, it actually exacerbates autistic symptoms.

In children with autism spectrum disorder (ASD), joint attention is regarded as a predictor of language function, social skills, communication, adaptive function, and intelligence. However, existing information about the association between joint attention and intelligence is limited. Most such studies have examined children with low intelligence. For this study, we investigated whether joint attention is related to intelligence in young children with autism spectrum disorder (ASD) without severe intellectual disability. We analyzed 113 children with ASD aged 40-98 months. Their Kaufman Assessment Battery (K-ABC) Mental Processing Index (MPI) scores are 60 and more (mean 93.4). We evaluated their intelligence using K-ABC and evaluated their joint attention using ADOS-2. After we performed simple regression analyses using K-ABC MPI and its nine subscales as dependent variables, using joint attention as the independent variable, we identified joint attention as a positive predictor of the MPI and its two subscales. From this result, we conclude that joint attention is related to intelligence in young children with ASD without severe intellectual disability. This result suggests a beneficial effect of early intervention targeting joint attention for children with ASD. LAY SUMMARY: Joint attention is the ability to coordinate visual attention with another person and then shift one's gaze toward an object or event. Impairment of joint attention is regarded as an early marker of autism spectrum disorder (ASD). This study revealed impairment of joint attention as associated with lower intelligence in ASD children. These results are expected to constitute a rationale for future studies, particularly addressing beneficial effects of early intervention targeting joint attention for children with ASD.

Individuals with autism spectrum disorder (ASD) often lack cognitive empathy, so they experience difficulty in empathizing with others. Although deficits in social abilities, such as empathy, have been demonstrated in previous studies, most stimuli used in previous studies were developed for typically developing (TD) individuals. Previous studies have demonstrated that adults with and without ASD display empathetic responses toward similar others. Adults with ASD (n = 22, 7 women and 15 men, mean age = 26.8 years) and intelligence- and age-matched TD adults (n = 20, 8 women and 12 men, mean age = 24.0 years) participated in the study. They were instructed to read 24 stories (12 stories featured protagonists with characteristics of ASD, and the other 12 featured TD protagonists) and respond to the following questions: "How did the protagonist feel?" and "Would you help if the protagonist were in trouble?" After controlling for alexithymia and AQ based on multiple regression analyses, individuals with ASD empathize with other people who have ASD and are motivated to help other people with ASD. Additionally, social skills and attention to detail were associated with decreased helping motivation for story characters with ASD. Social skills among AQ subscales (social skills, attention switching, attention to detail, communication, and imagination) were the most potent predictor of decreased helping motivation. These findings suggest that the reason why individuals with ASD are considered to have limited cognitive empathy and helping motivation could be related to alexithymia and the lack of social skills and attention to detail, which are related to atypical perception.

Although rapid cycling (RC), a course specifier of bipolar I or II disorder, is particularly common among bipolar II patients compared with bipolar I patients, the pathophysiological lines of evidence regarding bipolar II with RC are still limited. In this preliminary study with a cross-sectional design, we examined the regional gray matter (GM) volume in 14 bipolar II patients with RC, 17 patients without RC and 84 healthy controls by whole-brain and region-of-interest (ROI) analysis methods, using magnetic resonance imaging with voxel-based morphometry. Whole-brain analysis in this study revealed that the bipolar II patients with RC showed GM volume reductions in the bilateral hemispheres of the medial orbital prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate, insula and parahippocampus, in the left hemisphere of the inferior temporal cortex and cerebellum, and in the brainstem, compared with the healthy controls. Moreover, ROI analysis focusing on the ventral prefrontal cortex, i.e., Brodmann areas 10, 11 and 47, revealed that the bipolar II patients with RC showed GM volume reduction in the ventromedial prefrontal cortex, compared with the patients without RC. The findings of our pilot study suggest that the ventromedial prefrontal cortex is associated with the generation of RC in bipolar II disorder.

Individuals with autism spectrum disorder (ASD) are thought to lack self-awareness and to experience difficulty empathizing with others. Although these deficits have been demonstrated in previous studies, most of the target stimuli were constructed for typically developing (TD) individuals. We employed judgment tasks capable of indexing self-relevant processing in individuals with and without ASD. Fourteen Japanese men and 1 Japanese women with high-functioning ASD (17-41 years of age) and 13 Japanese men and 2 TD Japanese women (22-40 years of age), all of whom were matched for age and full and verbal intelligence quotient scores with the ASD participants, were enrolled in this study. The results demonstrated that the ventromedial prefrontal cortex was significantly activated in individuals with ASD in response to autistic characters and in TD individuals in response to non-autistic characters. Although the frontal-posterior network between the ventromedial prefrontal cortex and superior temporal gyrus participated in the processing of non-autistic characters in TD individuals, an alternative network was involved when individuals with ASD processed autistic characters. This suggests an atypical form of empathy in individuals with ASD toward others with ASD.

Autism is hypothesized to result in a cortical excitatory and inhibitory imbalance driven by inhibitory interneuron dysfunction, which is associated with the generation of gamma oscillations. On the other hand, impaired motor control has been widely reported in autism. However, no study has focused on the gamma oscillations during motor control in autism. In the present study, we investigated the motor-related gamma oscillations in autism using magnetoencephalography. Magnetoencephalographic signals were recorded from 14 right-handed human children with autism (5 female), aged 5-7 years, and age- and IQ-matched 15 typically developing children during a motor task using their right index finger. Consistent with previous studies, the autism group showed a significantly longer button response time and reduced amplitude of motor-evoked magnetic fields. We observed that the autism group exhibited a low peak frequency of motor-related gamma oscillations from the contralateral primary motor cortex, and these were associated with the severity of autism symptoms. The autism group showed a reduced power of motor-related gamma oscillations in the bilateral primary motor cortex. A linear discriminant analysis using the button response time and gamma oscillations showed a high classification performance (86.2% accuracy). The alterations of the gamma oscillations in autism might reflect the cortical excitatory and inhibitory imbalance. Our findings provide an important clue into the behavioral and neurophysiological alterations in autism and a potential biomarker for autism.SIGNIFICANCE STATEMENT Currently, the diagnosis of autism has been based on behavioral assessments, and a crucial issue in the diagnosis of autism is to identify objective and quantifiable clinical biomarkers. A key hypothesis of the neurophysiology of autism is an excitatory and inhibitory imbalance in the brain, which is associated with the generation of gamma oscillations. On the other hand, motor deficits have also been widely reported in autism. This is the first study to demonstrate low motor performance and altered motor-related gamma oscillations in autism, reflecting a brain excitatory and inhibitory imbalance. Using these behavioral and neurophysiological parameters, we classified autism and control group with good accuracy. This work provides important information on behavioral and neurophysiological alterations in patients with autism.

Multifractal analysis based on generalized concepts of fractals has been applied to evaluate biological tissues composed of complex structures. This type of analysis can provide a precise quantitative description of a broad range of heterogeneous phenomena. Previously, we applied multifractal analysis to describe heterogeneity in white matter signal fluctuation on T2-weighted MR images as a new method of texture analysis and established Deltaalpha as the most suitable index for evaluating white matter structural complexity (Takahashi et al. J. Neurol. Sci., 2004; 225: 33-37). Considerable evidence suggests that pathophysiological processes occurring in deep white matter regions may be partly responsible for cognitive deterioration and dementia in elderly subjects. We carried out a multifractal analysis in a group of 36 healthy elderly subjects who showed no evidence of atherosclerotic risk factors to examine the microstructural changes of the deep white matter on T2-weighted MR images. We also performed conventional texture analysis, i.e., determined the standard deviation of signal intensity divided by mean signal intensity (SD/MSI) for comparison with multifractal analysis. Next, we examined the association between the findings of these two types of texture analysis and the ultrasonographically measured intima-media thickness (IMT) of the carotid arteries, a reliable indicator of early carotid atherosclerosis. The severity of carotid IMT was positively associated with Deltaalpha in the deep white matter region. In addition, this association remained significant after excluding 12 subjects with visually detectable deep white matter hyperintensities on MR images. However, there was no significant association between the severity of carotid IMT and SD/MSI. These results indicate the potential usefulness of applying multifractal analysis to conventional MR images as a new approach to detect the microstructural changes of apparently normal white matter during the early stages of atherosclerosis.

Attention ability is one of the most important cognitive functions. It develops mainly during school age. However, the neural basis for the typical development of attentional functions has not been fully investigated. To clarify the development of the aforementioned function and its neural basis, this study examined brain function in children and adolescents during the performance of an attention network test (ANT) using functional magnetic resonance imaging. One hundred and sixty-three volunteers (8-23 years, 80 female) participated in this study. Using a modified version of ANT, we assessed the efficiency of two attentional functions-orienting and executive attention-by measuring how reaction time is affected by spatial cue location and flanker congruency and examined the functional brain areas-attentional networks-associated with two attentional functions. Consistent with the findings of previous studies, the superior parietal lobule, visual association cortex, left precentral gyrus, and supplementary motor area were activated during the orienting attention, while the anterior cingulate cortex, visual association cortex, lateral prefrontal cortex, thalamus, and caudate were activated during the executive attention. Moreover, negative correlations with age were found for activations in the inferior frontal gyrus, dorsomedial prefrontal cortex, and caudate nucleus in the orienting attention, while no correlations with age related to executive attention were found. In conclusion, this study revealed common and distinct features in the neural basis of the attentional functions in children and adolescents compared with that of adults and their developmental changes with age.

Individuals with autism spectrum disorders (ASDs) exhibit atypical sensory characteristics, impaired social skills, deficits in verbal and nonverbal communication, and restricted and repetitive behaviors. The relationship between sensory characteristics and brain morphological changes in ASD remains unclear. In this study, we investigated the association between brain morphological changes and sensory characteristics in individuals with ASD using brain image analysis and a sensory profile test. Forty-three adults with ASD and 84 adults with typical development underwent brain image analysis using FreeSurfer. The brain cortex was divided into 64 regions, and the cortical thickness and volume of the limbic system were calculated. The sensory characteristics of the participants were evaluated using the Adolescent/Adult Sensory Profile (AASP). Correlation analysis was performed for cortical thickness, limbic area volume, and AASP scores. In the ASD group, there was a significant positive correlation between visual sensory sensitivity scores and the right lingual cortical thickness (r = 0.500). There were also significant negative correlations between visual sensation avoiding scores and the right lateral orbitofrontal cortical thickness (r = -0.513), taste/smell sensation avoiding scores and the right hippocampal volume (r = -0.510), and taste/smell sensation avoiding scores and the left hippocampal volume (r = -0.540). The study identified associations among the lingual cortical thickness, lateral orbitofrontal cortical thickness, and hippocampal volume and sensory characteristics. These findings suggest that brain morphological changes may trigger sensory symptoms in adults with ASD.

The lateral occipitotemporal cortex (LOTC) that responds to human bodies and body parts has been implicated in social development and neurodevelopmental disorders like autism spectrum disorder (ASD). Neuroimaging studies using a representational similarity analysis (RSA) revealed that body representation in the LOTC of typically developing (TD) adults is categorized into 3 clusters: action effector body parts, noneffector body parts, and face parts. However, its organization of younger people (i.e., children and adolescents) and its association with individual traits remain unclear. In this functional MRI study, TD adults and children/adolescents observed photographs of hands, feet, arms, legs, chests, waists, upper/lower faces, the whole body, and chairs. The univariate analysis showed that fewer child/adolescent participants showed left LOTC activation in response to whole-body images (relative to those of chairs) than adult participants. Contrastingly, the RSA on both age groups revealed a comparable body representation with 3 clusters of body parts in the bilateral LOTC. Hence, this result indicates that, although response to whole-body images can differ, LOTC body part representations for children/ adolescents and adults are highly similar. Furthermore, sensory atypicality is associated with spatial LOTC organization, suggesting the importance of this region for understanding individual difference, which is frequently observed in ASD.

A growing body of anecdotal evidence indicates that the use of robots may provide unique opportunities for assisting children with autism spectrum disorders (ASD). However, previous studies investigating the effects of interventions using robots on joint attention (JA) in children with ASD have shown insufficient results. The robots used in these studies could not turn their eyes, which was a limitation preventing the robot from resembling a human agent.

Autism spectrum disorder (ASD) has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical interhemispheric circuitry. In the context of ASD, alterations in both peripheral and central auditory processes have also attracted a great deal of interest because these changes appear to represent pathophysiological processes; therefore, many prior studies have focused on atypical auditory responses in ASD. The auditory evoked field (AEF), recorded by magnetoencephalography, and the synchronization of these processes between right and left hemispheres was recently suggested to reflect various cognitive abilities in children. However, to date, no previous study has focused on AEF synchronization in ASD subjects. To assess global coordination across spatially distributed brain regions, the analysis of Omega complexity from multichannel neurophysiological data was proposed. Using Omega complexity analysis, we investigated the global coordination of AEFs in 3-8-year-old typically developing (TD) children (n = 50) and children with ASD (n = 50) in 50-ms time-windows. Children with ASD displayed significantly higher Omega complexities compared with TD children in the time-window of 0-50 ms, suggesting lower whole brain synchronization in the early stage of the P1m component. When we analyzed the left and right hemispheres separately, no significant differences in any time-windows were observed. These results suggest lower right-left hemispheric synchronization in children with ASD compared with TD children. Our study provides new evidence of aberrant neural synchronization in young children with ASD by investigating auditory evoked neural responses to the human voice.

Eye contact provides a communicative link between humans, prompting joint attention. As spontaneous brain activity might have an important role in the coordination of neuronal processing within the brain, their inter-subject synchronization might occur during eye contact. To test this, we conducted simultaneous functional MRI in pairs of adults. Eye contact was maintained at baseline while the subjects engaged in real-time gaze exchange in a joint attention task. Averted gaze activated the bilateral occipital pole extending to the right posterior superior temporal sulcus, the dorso-medial prefrontal cortex, and the bilateral inferior frontal gyrus. Following a partner's gaze toward an object activated the left intraparietal sulcus. After all the task-related effects were modeled out, inter-individual correlation analysis of residual time-courses was performed. Paired subjects showed more prominent correlations than non-paired subjects in the right inferior frontal gyrus, suggesting that this region is involved in sharing intention during eye contact that provides the context for joint attention.