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.

Development of attentional networks during childhood and adolescence: A functional MRI study.

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.

Corrigendum: Regional and Temporal Differences in Brain Activity With Morally Good or Bad Judgments in Men: A Magnetoencephalography Study.

[This corrects the article DOI: 10.3389/fnins.2021.596711.].

Effects of familiarity on child brain networks when listening to a storybook reading: A magneto-encephalographic study.

Parent-child book reading is important for fostering the development of various lifelong cognitive and social abilities in young children. Despite numerous reports describing the effects of familiarity on shared reading for children, the exact neural basis of the functional network architecture remains unclear. We conducted Magnet-Encephalographic (MEG) experiments using graph theory to elucidate the role of familiarity in shared reading in a child's brain network and to measure the connectivity dynamics of a child while Listening to Storybook Reading (LSBR), which represents the daily activity of shared book reading between the child and caregiver. The LSBR task was performed with normally developing preschool- and school-age children (N = 15) under two conditions: reading by their own mother (familiar condition) vs. an experimenter (unfamiliar condition). We used the phase lag index (PLI), which captures synchronization of MEG signals, to estimate functional connectivity. For the whole brain network topology, an undirected weighted graph was produced using 68 brain regions as nodes and interregional PLI values as edges for five frequency bands. Behavioral data (i.e., the degree of attention and facial expressions) were evaluated from video images of the child's face during the two conditions. Our results showed enhanced widespread functional connectivity in the alpha band during the mother condition. In the mother condition, the whole brain network in the alpha band exhibited topographically high local segregation with high global integration, indicating an increased small-world property. Results of the behavioral analysis revealed that children were more attentive and showed more positive facial expressions in the mother condition than in the experimenter condition. Behavioral data were significantly correlated with graph metrics in the mother condition but not in the experimenter condition. In this study, we identified the neural correlates of a familiarity effect in children's brain connectivity dynamics during LSBR. Furthermore, these familiarity-related brain dynamics were closely linked to the child's behavior. Graph theory applied to MEG data may provide useful insight into the familiarity-related child brain response in a naturalistic setting and its relevance to child attitudes.

Decreased grey matter volumes in unaffected mothers of individuals with autism spectrum disorder reflect the broader autism endophenotype.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an early onset and a strong genetic origin. Unaffected relatives may present similar but subthreshold characteristics of ASD. This broader autism phenotype is especially prevalent in the parents of individuals with ASD, suggesting that it has heritable factors. Although previous studies have demonstrated brain morphometry differences in ASD, they are poorly understood in parents of individuals with ASD. Here, we estimated grey matter volume in 45 mothers of children with ASD (mASD) and 46 age-, sex-, and handedness-matched controls using whole-brain voxel-based morphometry analysis. The mASD group had smaller grey matter volume in the right middle temporal gyrus, temporoparietal junction, cerebellum, and parahippocampal gyrus compared with the control group. Furthermore, we analysed the correlations of these brain volumes with ASD behavioural characteristics using autism spectrum quotient (AQ) and systemizing quotient (SQ) scores, which measure general autistic traits and the drive to systemize. Smaller volumes in the middle temporal gyrus and temporoparietal junction correlated with higher SQ scores, and smaller volumes in the cerebellum and parahippocampal gyrus correlated with higher AQ scores. Our findings suggest that atypical grey matter volumes in mASD may represent one of the neurostructural endophenotypes of ASD.

Shorter P1m Response in Children with Autism Spectrum Disorder without Intellectual Disabilities.

(1) Background: Atypical auditory perception has been reported in individuals with autism spectrum disorder (ASD). Altered auditory evoked brain responses are also associated with childhood ASD. They are likely to be associated with atypical brain maturation. (2) Methods: This study examined children aged 5-8 years old: 29 with ASD but no intellectual disability and 46 age-matched typically developed (TD) control participants. Using magnetoencephalography (MEG) data obtained while participants listened passively to sinusoidal pure tones, bilateral auditory cortical response (P1m) was examined. (3) Results: Significantly shorter P1m latency in the left hemisphere was found for children with ASD without intellectual disabilities than for children with TD. Significant correlation between P1m latency and language conceptual ability was found in children with ASD, but not in children with TD. (4) Conclusions: These findings demonstrated atypical brain maturation in the auditory processing area in children with ASD without intellectual disability. Findings also suggest that ASD has a common neural basis for pure-tone sound processing and language development. Development of brain networks involved in language concepts in early childhood ASD might differ from that in children with TD.

Regional and Temporal Differences in Brain Activity With Morally Good or Bad Judgments in Men: A Magnetoencephalography Study.

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.

Aberrant brain oscillatory coupling from the primary motor cortex in children with autism spectrum disorders.

Autism spectrum disorder (ASD) often involves dysfunction in general motor control and motor coordination, in addition to core symptoms. However, the neural mechanisms underlying motor dysfunction in ASD are poorly understood. To elucidate this issue, we focused on brain oscillations and their coupling in the primary motor cortex (M1). We recorded magnetoencephalography in 18 children with ASD, aged 5 to 7 years, and 19 age- and IQ-matched typically-developing children while they pressed a button during a video-game-like motor task. The motor-related gamma (70 to 90 Hz) and pre-movement beta oscillations (15 to 25 Hz) were analyzed in the primary motor cortex using an inverse method. To determine the coupling between beta and gamma oscillations, we applied phase-amplitude coupling to calculate the statistical dependence between the amplitude of fast oscillations and the phase of slow oscillations. We observed a motor-related gamma increase and a pre-movement beta decrease in both groups. The ASD group exhibited a reduced motor-related gamma increase and enhanced pre-movement beta decrease in the ipsilateral primary motor cortex. We found phase-amplitude coupling, in which high-gamma activity was modulated by the beta rhythm in the primary motor cortex. Phase-amplitude coupling in the ipsilateral primary motor cortex was reduced in the ASD group compared with the control group. Using oscillatory changes and their couplings, linear discriminant analysis classified the ASD and control groups with high accuracy (area under the receiver operating characteristic curve: 97.1%). The current findings revealed alterations in oscillations and oscillatory coupling, reflecting the dysregulation of motor gating mechanisms in ASD. These results may be helpful for elucidating the neural mechanisms underlying motor dysfunction in ASD, suggesting the possibility of developing a biomarker for ASD diagnosis.

Markers for the central serotonin system correlate to verbal ability and paralinguistic social voice processing in autism spectrum disorder.

Impairment in verbal communication abilities has been reported in autism spectrum disorder (ASD). Dysfunction of the serotonergic system has also been reported in ASD. However, it is still unknown how the brain serotonergic system relates to impairment in verbal communication abilities in individuals with ASD. In the present study, we investigated the correlation between brain serotonergic condition and brain sensitivity to paralinguistic stimuli (i.e., amplitude in the human voice prosodic change-evoked mismatch field) measured by magnetoencephalography (MEG) or verbal ability in 10 adults with ASD. To estimate the brain serotonergic condition, we measured the serotonin transporter nondisplaceable binding potential cerebrum-wide using positron emission tomography with [11C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([11C] DASB). The results demonstrated a significant positive correlation between brain activity to paralinguistic stimuli and brain serotonin transporter binding potential in the left lingual gyrus, left fusiform gyrus and left calcarine cortex. In addition, there were significant positive correlations between verbal ability and serotonergic condition in the right anterior insula, right putamen and right central operculum. These results suggested that the occipital cortex is implicated in recognition of the prosodic change in ASD, whereas the right insula-involved serotonergic system is important in nurturing verbal function in ASD.Trial registration: UMIN000011077.

The maturation of the P1m component in response to voice from infancy to 3 years of age: A longitudinal study in young children.

INTRODUCTION: In the early development of human infants and toddlers, remarkable changes in brain cortical function for auditory processing have been reported. Knowing the maturational trajectory of auditory cortex responses to human voice in typically developing young children is crucial for identifying voice processing abnormalities in children at risk for neurodevelopmental disorders and language impairment. An early prominent positive component in the cerebral auditory response in newborns has been reported in previous electroencephalography and magnetoencephalography (MEG) studies. However, it is not clear whether this prominent component in infants less than 1 year of age corresponds to the auditory P1m component that has been reported in young children over 2 years of age. METHODS: To test the hypothesis that the early prominent positive component in infants aged 0 years is an immature manifestation of P1m that we previously reported in children over 2 years of age, we performed a longitudinal MEG study that focused on this early component and examined the maturational changes over three years starting from age 0. Five infants participated in this 3-year longitudinal study. RESULTS: This research revealed that the early prominent component in infants aged 3 month corresponded to the auditory P1m component in young children over 2 years old, which we had previously reported to be related to language development and/or autism spectrum disorders. CONCLUSION: Our data revealed the development of the auditory-evoked field in the left and right hemispheres from 0- to 3-year-old children. These results contribute to the elucidation of the development of brain functions in infants.

Brain responses to human-voice processing predict child development and intelligence.

Children make rapid transitions in their neural and intellectual development. Compared to other brain regions, the auditory cortex slowly matures, and children show immature auditory brain activity. This auditory neural plasticity largely occurs as a response to human-voice stimuli, which are presented more often than other stimuli, and can even be observed in the brainstem. Early psychologists have proposed that sensory processing and intelligence are closely related to each other. In the present study, we identified brain activity related to human-voice processing and investigated a crucial neural correlate of child development and intelligence. We also examined the neurophysiological activity patterns during human-voice processing in young children aged 3 to 8 years. We investigated auditory evoked fields (AEFs) and oscillatory changes using child-customized magnetoencephalography within a short recording time (<6 min). We examined the P1m component of AEFs, which is a predominant component observed in young children. The amplitude of the left P1m was highly correlated with age, and the amplitude of the right P1m was highly correlated with the intelligence quotient. For auditory-related oscillatory changes, we found a positive correlation between the intelligence quotient and percent change of gamma increase relative to baseline in the right auditory cortex. We replicated the finding of age-related changes in auditory brain activity in young children, which is related to the slow maturation of the auditory cortex. In addition, these results suggest a close link between intelligence and auditory sensory processing, especially in the right hemisphere.

Brief Report: Odour Awareness in Young Children with Autism Spectrum Disorders.

The elucidation of odour awareness in children with autism spectrum disorders (ASD) is important. We compared the odour awareness of young children with ASD with those of typical development (TD) children using the Children's Olfactory Behavior in Everyday Life (COBEL) questionnaire, which is a self-report measure that mainly assesses odour awareness. Forty-five young boys (aged 5-6 years), including 20 children with ASD and 25 TD children, participated in this study. The total COBEL score of the young children with ASD was lower than that of the TD children (p < 0.01). Moreover, the total COBEL score was significantly correlated with the total VABS II score (p < 0.05). Our results improve understanding of the odour awareness in children with ASD.

Anodal Transcranial Direct Current Stimulation Induces High Gamma-Band Activity in the Left Dorsolateral Prefrontal Cortex During a Working Memory Task: A Double-Blind, Randomized, Crossover Study.

Transcranial direct current stimulation (tDCS) has been shown to have mixed effects on working memory (WM) capacity in healthy individuals. Different stimulation paradigms may account for these discrepancies, with certain features being favored. To determine the effect in the context of anodal tDCS, we investigated whether anodal tDCS induced cortical oscillatory changes during a WM task. Specifically, we tested whether anodal offline tDCS over the left prefrontal cortex (PFC) enhances WM capacity by modulating the oscillatory activity in the left dorsolateral PFC (DLPFC) using magnetoencephalography (MEG). This study employed a double-blind, randomized, crossover design, in which 24 healthy right-handed participants conducted MEG recordings during a 3-back task after administration of 2 mA tDCS or sham stimulation as a placebo. Our results showed that the effect of tDCS did not appear in the behavioral indices-WM accuracy (d') or reaction time (RT). From the results of the time-frequency analysis, significant event-related synchronization (ERS) in the high-gamma band (82-84 Hz) of the left DLPFC was found under the tDCS condition; however, ERS was not correlated with WM capacity. Furthermore, we calculated the modulation index (MI), which indicates the strength of phase-amplitude coupling (PAC). tDCS significantly decreased MI of the left DLPFC, representing the theta-gamma PAC during the n-back task using color names as verbal stimuli. Our results suggest that although tDCS increased the gamma-band oscillation indicating greater neural activity in the left DLPFC, it did not lead to an improvement of WM capacity; this may be due to the inability of gamma-band oscillation to couple with the task-induced theta wave. WM capacity might not increase unless theta-gamma PAC is not enhanced by tDCS.

Atypical body movements during night in young children with autism spectrum disorder: a pilot study.

Children with autism spectrum disorder (ASD) reportedly suffer from sleep problems at a higher rate than typically developing (TD) children. Several previous studies have reported differences in sleep indices (e.g., sleep latency) in children with ASD. However, no previous studies have focused specifically on the time course of body movements. In the present study, we investigated the time course of body movements in young TD children and young children with ASD as well as the relationship between body movements during night and social ability. Seventeen TD children and 17 children with ASD participated in this study (5 to 8 years old). We used an accelerometer attached to the waist to record movements during night and measured the average time course of body movements for 3 nights. Our results demonstrated that the rate of body movement 2 to 3 hours after the onset of body stillness was higher in children with ASD than in TD children. In addition, the higher rate of body movement at 0.5 to 1 hour after the onset of body stillness was associated with a lower social ability in the children with ASD. Our results suggested that the time course of body movements is an objective behavioural index for young children with ASD.

Local-to-distant development of the cerebrocerebellar sensorimotor network in the typically developing human brain: a functional and diffusion MRI study.

Sensorimotor function is a fundamental brain function in humans, and the cerebrocerebellar circuit is essential to this function. In this study, we demonstrate how the cerebrocerebellar circuit develops both functionally and anatomically from childhood to adulthood in the typically developing human brain. We measured brain activity using functional magnetic resonance imaging while a total of 57 right-handed, blindfolded, healthy children (aged 8-11 years), adolescents (aged 12-15 years), and young adults (aged 18-23 years) (n = 19 per group) performed alternating extension-flexion movements of their right wrists in precise synchronization with 1-Hz audio tones. We also collected their diffusion MR images to examine the extent of fiber maturity in cerebrocerebellar afferent and efferent tracts by evaluating the anisotropy-sensitive index of hindrance modulated orientational anisotropy (HMOA). During the motor task, although the ipsilateral cerebellum and the contralateral primary sensorimotor cortices were consistently activated across all age groups, the functional connectivity between these two distant regions was stronger in adults than in children and adolescents, whereas connectivity within the local cerebellum was stronger in children and adolescents than in adults. The HMOA values in cerebrocerebellar afferent and efferent tracts were higher in adults than in children (some were also higher than in adolescents). The results indicate that adult-like cerebrocerebellar functional coupling is not completely achieved during childhood and adolescence, even for fundamental sensorimotor brain function, probably due to anatomical immaturity of cerebrocerebellar tracts. This study clearly demonstrated the principle of "local-to-distant" development of functional brain networks in the human cerebrocerebellar sensorimotor network.

Brief Report: A Novel System to Evaluate Autism Spectrum Disorders Using Two Humanoid Robots.

We investigated the feasibility of our novel evaluation system for use with children with autism spectrum disorders (ASD). We prepared the experimental setting with two humanoid robots in reference to the birthday party scene in the Autism Diagnostic Observational Schedule (ADOS). We assessed the relationship between social communication ability measured in the ADOS condition (i.e., with a human clinician) and in a robotic condition for children with ASD. There were significant correlations between the social communication scores in the gold-standard ADOS condition and the robotic condition for children with ASD. The current work provides support for a unique application of a robotic system (i.e., two robot-mediated interaction) to evaluate the severity of autistic traits for children with ASD.

The impact of robotic intervention on joint attention in children with autism spectrum disorders.

Background: 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. Methods: We compared the behavior of children with ASD with that of children with typical development (TD) during a JA elicitation task while the children interacted with either a human or a robotic agent. We used the robot "CommU," which has clear eyes and can turn its eyes, for the robotic intervention. The age range of the participants was limited to 5-6 years. Results: Sixty-eight participants participated in this study, including 30 (10 females and 20 males) children with ASD and 38 (13 females and 25 males) children with TD. The participants were randomly assigned to one of the following two groups: the robotic intervention group or the control group. JA in the children with ASD was better during the robotic intervention than during the human agent intervention. These children exhibited improved performance in the JA task with human after interacting with the robot CommU. JA was differentially facilitated by the human and robotic agents between the ASD and TD children. Conclusions: The findings of this study significantly contribute to the literature on the impact of robots on JA and provide information regarding the suitability of specific robot types for therapeutic use.

Developmental Trajectory of Infant Brain Signal Variability: A Longitudinal Pilot Study.

The infant brain shows rapid neural network development that considerably influences cognitive and behavioral abilities in later life. Reportedly, this neural development process can be indexed by estimating neural signal complexity. However, the precise developmental trajectory of brain signal complexity during infancy remains elusive. This study was conducted to ascertain the trajectory of magnetoencephalography (MEG) signal complexity from 2 months to 3 years of age in five infants using multiscale entropy (MSE), which captures signal complexity at multiple temporal scales. Analyses revealed scale-dependent developmental trajectories. Specifically, signal complexity predominantly increased from 5 to 15 months of age at higher temporal scales, whereas the complexity at lower temporal scales was constant across age, except in one infant who showed decreased complexity. Despite a small sample size limiting this study's power, this is the first report of a longitudinal investigation of changes in brain signal complexity during early infancy and is unique in its application of MSE analysis of longitudinal MEG data during infancy. The results of this pilot study may serve to further our understanding of the longitudinal changes in the neural dynamics of the developing infant brain.

Altered Gamma Oscillations during Motor Control in Children with Autism Spectrum Disorder.

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.