Language and sensory characteristics are reflected in voice-evoked responses in low birth weight children.

BACKGROUND: Children born with very low birth weight (VLBW) are at higher risk for cognitive impairment, including language deficits and sensorimotor difficulties. Voice-evoked response (P1m), which has been suggested as a language development biomarker in young children, remains unexplored for its efficacy in VLBW children. Furthermore, the relation between P1m and sensory difficulties in VLBW children remains unclear. METHODS: 40 children with VLBW were recruited at 5-to-6 years old (26 male, 14 female, mean age of months ± SD, 80.0 ± 4.9). We measured their voice-evoked brain response using child-customized magnetoencephalography (MEG) and examined the relation between P1m and language conceptual inference ability and sensory characteristics. RESULTS: The final sample comprised 36 children (23 boys, 13 girls; ages 61-86 months; gestational ages 24-36 weeks). As a result of multiple regression analysis, voice-evoked P1m in the left hemisphere was correlated significantly with language ability (ß = 0.414 P = 0.015) and sensory hypersensitivity (ß = 0.471 P = 0.005). CONCLUSION: Our findings indicate that the relation between P1m and language conceptual inference ability observed in term children in earlier studies is replicated in VLBW children, and suggests P1m intensity as a biomarker of sensory sensitivity characteristics. IMPACT: We investigated brain functions related to language development and sensory problems in very low birth-weight children. In very low birth weight children at early school age, brain responses to human voices are associated with language conceptual inference ability and sensory hypersensitivity. These findings promote a physiological understanding of both language development and sensory characteristics in very low birth weight children.

Dual-MEG interbrain synchronization during turn-taking verbal interactions between mothers and children.

Verbal interaction and imitation are essential for language learning and development in young children. However, it is unclear how mother-child dyads synchronize oscillatory neural activity at the cortical level in turn-based speech interactions. Our study investigated interbrain synchrony in mother-child pairs during a turn-taking paradigm of verbal imitation. A dual-MEG (magnetoencephalography) setup was used to measure brain activity from interactive mother-child pairs simultaneously. Interpersonal neural synchronization was compared between socially interactive and noninteractive tasks (passive listening to pure tones). Interbrain networks showed increased synchronization during the socially interactive compared to noninteractive conditions in the theta and alpha bands. Enhanced interpersonal brain synchrony was observed in the right angular gyrus, right triangular, and left opercular parts of the inferior frontal gyrus. Moreover, these parietal and frontal regions appear to be the cortical hubs exhibiting a high number of interbrain connections. These cortical areas could serve as a neural marker for the interactive component in verbal social communication. The present study is the first to investigate mother-child interbrain neural synchronization during verbal social interactions using a dual-MEG setup. Our results advance our understanding of turn-taking during verbal interaction between mother-child dyads and suggest a role for social "gating" in language learning.

Visual working memory resolution defined by figural complexity in kindergarten children.

Visual working memory (VWM) allows us to store and manipulate incoming visual information briefly. Information acquisition (i.e., encoding) accuracy is critical for VWM to function properly. The accuracy of very young children's VWM encoding has not been explained adequately in previous studies. Therefore, this study clarified it by manipulating the complexity of the visual stimuli and examining kindergarten children's performance in a recognition task. Furthermore, we examined the relationship between encoding accuracy and the 4- to 6-year-old children's individual traits in a subanalysis, as individual traits (such as IQ and attention to detail-a trait of autism spectrum disorder) reportedly affect VWM capacity. The results revealed that distinguishing between target and probe stimuli becomes more difficult as stimulus and discrimination complexity increase. In addition, this study results in narrow attention (attention to detail) that could contribute to VWM capacity saving if VWM capacity is sufficient. However, if the VWM's capacity is exceeded, the relationship with IQ, such as the simultaneous processing score, is strengthened. This study clarified the degree of accuracy of information retained by preschool children aged 4 to 6 years. In addition to providing basic knowledge about VWM, we believe the findings can be useful in education and other fields.

Asymmetric Complexity in a Pupil Control Model With Laterally Imbalanced Neural Activity in the Locus Coeruleus: A Potential Biomarker for Attention-Deficit/Hyperactivity Disorder.

Locus coeruleus (LC) overactivity, especially in the right hemisphere, is a recognized pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and may be related to inattention. LC activity synchronizes with the kinetics of the pupil diameter and reflects neural activity related to cognitive functions such as attention and arousal. Recent studies highlight the importance of the complexity of the temporal patterns of pupil diameter. Moreover, asymmetrical pupil diameter, which correlates with the severity of inattention, impulsivity, and hyperactivity in ADHD, might be attributed to a left-right imbalance in LC activity. We recently constructed a computational model of pupil diameter based on the newly discovered contralateral projection from the LC to the Edinger-Westphal nucleus (EWN), which demonstrated mechanisms for the complex temporal patterns of pupil kinetics; however, it remains unclear how LC overactivity and its asymmetry affect pupil diameter. We hypothesized that a neural model of pupil diameter control featuring left-right differences in LC activity and projections onto two opponent sides may clarify the role of pupil behavior in ADHD studies. Therefore, we developed a pupil diameter control model reflecting LC overactivity in the right hemisphere by incorporating a contralateral projection from the LC to EWN and evaluated the complexity of the temporal patterns of pupil diameter generated by the model. Upon comparisons with experimentally measured pupil diameters in adult patients with ADHD, the parameter region of interest of the neural model was estimated, which was a region in the two-dimensional plot of complexity versus left-side LC baseline activity and that of the right. A region resulting in relatively high right-side complexity, which corresponded to the pathophysiological indexes, was identified. We anticipate that the discovery of lateralization of complexity in pupil diameter fluctuations will facilitate the development of biomarkers for accurate diagnosis of ADHD.

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.

Kcns3 deficiency disrupts Parvalbumin neuron physiology in mouse prefrontal cortex: Implications for the pathophysiology of schizophrenia.

The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on the expression of multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in the neocortex of subjects with schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. Therefore, to assess the role of Kv9.3 subunits in PV neuron function, we combined gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient mice. Kcns3 mRNA levels were ~ 50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+ channel inactivation. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing. Moreover, Kcns3 deficiency impaired the recruitment of PVBC firing at gamma frequency by stimuli mimicking synaptic input observed during cortical UP states. Our data indicate that Kv9.3 subunits are critical for PVBC physiology and suggest that KCNS3 deficiency in schizophrenia could impair PV neuron firing, possibly contributing to deficits in cortical gamma oscillations in the illness.

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.

Complexity of Body Movements during Sleep in Children with Autism Spectrum Disorder.

Recently, measuring the complexity of body movements during sleep has been proven as an objective biomarker of various psychiatric disorders. Although sleep problems are common in children with autism spectrum disorder (ASD) and might exacerbate ASD symptoms, their objectivity as a biomarker remains to be established. Therefore, details of body movement complexity during sleep as estimated by actigraphy were investigated in typically developing (TD) children and in children with ASD. Several complexity analyses were applied to raw and thresholded data of actigraphy from 17 TD children and 17 children with ASD. Determinism, irregularity and unpredictability, and long-range temporal correlation were examined respectively using the false nearest neighbor (FNN) algorithm, information-theoretic analyses, and detrended fluctuation analysis (DFA). Although the FNN algorithm did not reveal determinism in body movements, surrogate analyses identified the influence of nonlinear processes on the irregularity and long-range temporal correlation of body movements. Additionally, the irregularity and unpredictability of body movements measured by expanded sample entropy were significantly lower in ASD than in TD children up to two hours after sleep onset and at approximately six hours after sleep onset. This difference was found especially for the high-irregularity period. Through this study, we characterized details of the complexity of body movements during sleep and demonstrated the group difference of body movement complexity across TD children and children with ASD. Complexity analyses of body movements during sleep have provided valuable insights into sleep profiles. Body movement complexity might be useful as a biomarker for ASD.

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.

Optimal robot for intervention for individuals with autism spectrum disorders.

With recent rapid advances in technology, human-like robots have begun functioning in a variety of ways. As increasing anecdotal evidence suggests, robots may offer many unique opportunities for helping individuals with autism spectrum disorders (ASD). Individuals with ASD often achieve a higher degree of task engagement through the interaction with robots than through interactions with human trainees. The type and form of robots to be used for individuals with ASD have been meticulously considered. Simple robots and animal robots are acceptable because of their simplicity and the ease of interesting and engaging interactions. Android robots have the benefit of the potential of generalization into daily life to some extent. Considering the affinity between robots and users is important to draw out the potential capabilities of robotic intervention to the fullest extent. In the robotic condition, factors such as the appearance, biological motion, clothes, hairstyle, and disposition are important. Many factors of a user, such as age, sex, and IQ, may also affect the affinity of individuals with ASD toward a robot. The potential end-users of this technology may be unaware or unconvinced of the potential roles of robots in ASD interventions. If trainers have extensive experience in using robots, they can identify many potential roles of robots based on their experience. To date, only a few studies have been conducted in the field of robotics for providing assistance to individuals with ASD, and future studies are needed to realize an optimal robot for this purpose.

Auditory steady-state response at 20 Hz and 40 Hz in young typically developing children and children with autism spectrum disorder.

AIM: The early detection of autistic tendencies in children is essential for providing proper care and education. The auditory steady-state response (ASSR) provides a passive, non-invasive technique for assessing neural synchrony at specific response frequencies in many mental disorders, including autism spectrum disorder (ASD), but few studies have investigated its use in young children. This study investigated the ASSR at 20 Hz and 40 Hz in typically developing (TD) children and children with ASD aged 5-7 years. METHODS: The participants were 23 children with ASD and 32 TD children aged 5-7 years. Using a custom-made magnetoencephalography device, we measured ASSR at 20 Hz and 40 Hz, compared the results between groups, and evaluated the association with intellectual function as measured by Kaufmann Assessment Battery for Children. RESULTS: Responses to 20 Hz and 40 Hz were clearly detected in both groups with no significant difference identified. Consistent with previous findings, right dominance of the 40-Hz ASSR was observed in both groups. In the TD children, the right-side 40-Hz ASSR was correlated with age. The Kaufmann Assessment Battery for Children score was correlated with the left-side 40-Hz ASSR in both groups. CONCLUSION: Right-dominant ASSR was successfully detected in young TD children and children with ASD. No difference in ASSR was observed between the children with ASD and the TD children, although the right-side 40-Hz ASSR increased with age only in the TD children. Left-side 40-Hz ASSR was associated with intelligence score in both groups.

Feasibility of autism-focused public speech training using a simple virtual audience for autism spectrum disorder.

AIM: Public speaking seems to be one of the most anxiety-provoking situations for individuals with autism spectrum disorder (ASD). However, there are few evidence-based interventions. We developed Autism-Focused Public Speech Training using Simple Virtual Audiences (APSV), which differs from a general virtual audience in terms of its simple facial expressions and emphasis on the importance of the eyes. The present study aimed to evaluate the feasibility of APSV as an educational method for individuals with ASD. METHODS: Fifteen male individuals with ASD were randomly assigned to two groups: one group received APSV (n = 8), and the other group (n = 7) received independent study (IS). From Days 2 to 6, participants in the APSV and IS groups were encouraged to read and answer questions often asked in actual public speaking events. Participants in the APSV study group performed this activity in front of the APSV system, while those in the IS group performed in an empty room. Before and after the intervention (Days 1 and 7), the participants in the two groups had a mock public speaking experience in front of 10 people for approximately 10 min. RESULTS: After the training sessions, the participants' self-confidence had improved and salivary cortisol levels were significantly decreased in the APSV group as compared to those in the IS group. APSV improved self-confidence and decreased public speaking stress in individuals with ASD. CONCLUSION: APSV appears to be useful in improving self-confidence and decreasing public speaking stress in individuals with ASD.

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.

Changes in functional connectivity dynamics with aging: A dynamical phase synchronization approach.

The dynamics of the human brain network has attracted broad attention, in recognition of the concept that functional connectivity is not static, but changes its pattern over time, even in the resting state. We hypothesized that analysis of continuously captured time-varying instantaneous phase synchronization between signals from different brain regions might add another dimension to already identified network dynamics. To validate this hypothesis as an aid to elucidating the physiological mechanisms of aging, we examined time-series of instantaneous phase synchronization events in resting-state EEG activity across the brain, in healthy younger and healthy older subjects. We then characterized the temporal dynamics of phase synchronization using multiscale entropy, which quantifies the complexity of brain signal dynamics over multiple time scales. The results of surrogate analyses confirmed that the temporal dynamics of phase synchronization arise from deterministic processes in the neural network system. Group comparison showed region-specific enhanced complexity of temporal dynamics of phase synchronization in older subjects in alpha band predominantly in frontal brain regions, which was not identified by a comparative phase synchronization approach such as phase lag index. Enhanced complexity of temporal dynamics of functional connectivity in older subjects might reflect a general network alteration theory in aging. This is a first report describing the importance of capturing the dynamics of instantaneous phase synchronization and characterizing its temporal organization. Applying this method to neurophysiologic data may provide a novel understanding of dynamical neural network processes in both healthy and pathological conditions.

Characteristics of communication among Japanese children with autism spectrum disorder: A cluster analysis using the Children's Communication Checklist-2.

Some overlap has been suggested among the subtypes of autism spectrum disorder (ASD) in children. The Japanese version of the Children's Communication Checklist-2 (CCC-2) is a useful measure for identifying profiles in relation to communication impairments in children with ASD. The aim of this study was to investigate whether the CCC-2 could identify subtypes in relation to communication impairments in Japanese children with ASD. The study participants were 113 children with ASD but without intellectual disabilities aged 3-12 years. Parents were given the Japanese version of the CCC-2 and asked to rate their children, who were then classified into two groups based on statistical analysis. Significant differences were found between clusters in mean CCC-2 subscales. These results suggest that one subtype was associated with low language competence and strong characteristics of autism, while the other was associated with relatively high language competence and milder characteristics of autism.

Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus.

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.

Enhanced brain signal variability in children with autism spectrum disorder during early childhood.

Extensive evidence shows that a core neurobiological mechanism of autism spectrum disorder (ASD) involves aberrant neural connectivity. Recent advances in the investigation of brain signal variability have yielded important information about neural network mechanisms. That information has been applied fruitfully to the assessment of aging and mental disorders. Multiscale entropy (MSE) analysis can characterize the complexity inherent in brain signal dynamics over multiple temporal scales in the dynamics of neural networks. For this investigation, we sought to characterize the magnetoencephalography (MEG) signal variability during free watching of videos without sound using MSE in 43 children with ASD and 72 typically developing controls (TD), emphasizing early childhood to older childhood: a critical period of neural network maturation. Results revealed an age-related increase of brain signal variability in a specific timescale in TD children, whereas atypical age-related alteration was observed in the ASD group. Additionally, enhanced brain signal variability was observed in children with ASD, and was confirmed particularly for younger children. In the ASD group, symptom severity was associated region-specifically and timescale-specifically with reduced brain signal variability. These results agree well with a recently reported theory of increased brain signal variability during development and aberrant neural connectivity in ASD, especially during early childhood. Results of this study suggest that MSE analytic method might serve as a useful approach for characterizing neurophysiological mechanisms of typical-developing and its alterations in ASD through the detection of MEG signal variability at multiple timescales.

Magnetoencephalography in the study of children with autism spectrum disorder.

Magnetoencephalography (MEG) is a non-invasive neuroimaging technique that provides a measure of cortical neural activity on a millisecond timescale with high spatial resolution. MEG has been clinically applied to various neurological diseases, including epilepsy and cognitive dysfunction. In the past decade, MEG has also emerged as an important investigatory tool in neurodevelopmental studies. It is therefore an opportune time to review how MEG is able to contribute to the study of atypical brain development. We limit this review to autism spectrum disorder (ASD). The relevant published work for children was accessed using PubMed on 5 January 2015. Case reports, case series, and papers on epilepsy were excluded. Owing to their accurate separation of brain activity in the right and left hemispheres and the higher accuracy of source localization, MEG studies have added new information related to auditory-evoked brain responses to findings from previous electroencephalography studies of children with ASD. In addition, evidence of atypical brain connectivity in children with ASD has accumulated over the past decade. MEG is well suited for the study of neural activity with high time resolution even in young children. Although further studies are still necessary, the detailed findings provided by neuroimaging methods may aid clinical diagnosis and even contribute to the refinement of diagnostic categories for neurodevelopmental disorders in the future.

Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

It is widely accepted that malfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01-04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02-SNP03 (rs10014424)-SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia (P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia.