Interleukin-23 levels in umbilical cord blood are associated with neurodevelopmental trajectories in infancy.

Our previous study, which aimed to understand the early neurodevelopmental trajectories of children with and without neurodevelopmental disorders, identified five classes of early neurodevelopmental trajectories, categorized as high normal, normal, low normal, delayed, and markedly delayed. This investigation involved measurement using the Mullen Scale of Early Learning in a representative sample of Japanese infants followed up from the age of 0 to 2 years (Nishimura et al., 2016). In the present study, we investigated the potential association between cytokine concentrations in umbilical cord serum with any of the five classes of neurodevelopmental trajectories previously assigned, as follows: high normal (N = 85, 13.0%), normal (N = 322, 49.1%), low normal (N = 137, 20.9%), delayed (N = 87, 13.3%), and markedly delayed (N = 25, 3.8%) in infancy. Decreased interleukin (IL)-23 levels in the cord blood were associated with the markedly delayed class, independent of potential confounders (odds ratio, 0.44; 95%confidence interval: 0.26-0.73). Furthermore, IL-23 levels decreased as the developmental trajectory became more delayed, demonstrating that IL-23 plays an important role in development, and is useful for predicting the developmental trajectory at birth.

Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

The association between screen time and genetic risks for neurodevelopmental disorders in children.

Whether longer screen time in infancy increases risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and ADHD has long been debated, but no causal relationship between the two remains has been established. Using ongoing longitudinal cohort data, we found that in children 24 to 40 months of age, the genetic risk of ASD was associated with longer screen time and that of ADHD with an increase in screen time over time. These data suggest that prolonged screen time may not be a cause of the genetic risk for NDD, but an early sign of NDDs.

Interaction of genetic liability for attention deficit hyperactivity disorder (ADHD) and perinatal inflammation contributes to ADHD symptoms in children.

Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8-9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (ß [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (ß [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (ß [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (ß [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; ß [SE], 0.664[0.152]; P < 0.001 for the high-risk group). Conclusion: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8-9 with genetically higher risk for ADHD.

Lower Availability of Mitochondrial Complex I in Anterior Cingulate Cortex in Autism: A Positron Emission Tomography Study.

OBJECTIVE: Mitochondrial dysfunction has been implicated in the pathophysiology of autism spectrum disorder (ASD) in previous studies of postmortem brain or peripheral samples. The authors investigated whether and where mitochondrial dysfunction occurs in the living brains of individuals with ASD and to identify the clinical correlates of detected mitochondrial dysfunction. METHODS: This case-control study used positron emission tomography (PET) with 2-tert-butyl-4-chloro-5-{6-[2-(2-[18F]fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF), a radioligand that binds to the mitochondrial electron transport chain complex I, to examine the topographical distribution of mitochondrial dysfunction in living brains of individuals with ASD. Twenty-three adult males with high-functioning ASD, with no psychiatric comorbidities and free of psychotropic medication, and 24 typically developed males with no psychiatric diagnoses, matched with the ASD group on age, parental socioeconomic background, and IQ, underwent [18F]BCPP-EF PET measurements. Individuals with mitochondrial disease were excluded by clinical evaluation and blood tests for abnormalities in lactate and pyruvate levels. RESULTS: Among the brain regions in which mitochondrial dysfunction has been reported in postmortem studies of autistic brains, participants with ASD had significantly decreased [18F]BCPP-EF availability specifically in the anterior cingulate cortex compared with typically developed participants. The regional specificity was revealed by a significant interaction between diagnosis and brain regions. Moreover, the lower [18F]BCPP-EF availability in the anterior cingulate cortex was significantly correlated with the more severe ASD core symptom of social communication deficits. CONCLUSIONS: This study provides direct evidence to link in vivo brain mitochondrial dysfunction with ASD pathophysiology and its communicational deficits. The findings support the possibility that mitochondrial electron transport chain complex I is a novel therapeutic target for ASD core symptoms.

Preliminary efficacy of cognitive-behavioral therapy on emotion regulation in adults with autism spectrum disorder: A pilot randomized waitlist-controlled study.

Previous studies have demonstrated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in children on the autism spectrum. However, no studies have elucidated the clinical utility of cognitive-behavioral therapy in improving emotion regulation in autistic adults. The aim of the present pilot study was to explore the preliminary clinical utility of a group-based cognitive-behavioral therapy program designed to address emotion regulation skills in autistic adults. We conducted a clinical trial based on a previously reported protocol; 31 participants were randomly allocated to the intervention group and 29 to the waitlist control group. The intervention group underwent an 8-week program of cognitive-behavioral therapy sessions. Two participants from the intervention group withdrew from the study, leaving 29 participants (93.5%) in the group. Compared with the waitlist group, the cognitive-behavioral therapy group exhibited significantly greater pre-to-post (Week 0-8) intervention score improvements on the attitude scale of the autism spectrum disorder knowledge and attitude quiz (t = 2.21, p = 0.03, d = 0.59) and the difficulty describing feelings scale of the 20-item Toronto Alexithymia Scale (t = -2.07, p = 0.04, d = -0.57) in addition to pre-to-follow-up (Week 0-16) score improvements on the emotion-oriented scale of the Coping Inventory for Stressful Situations (t = -2.14, p = 0.04, d = -0.59). Our study thus provides preliminary evidence of the efficacy of the group-based cognitive-behavioral therapy program on emotion regulation in autistic adults, thereby supporting further evaluation of the effectiveness of the cognitive-behavioral therapy program in the context of a larger randomized clinical trial. However, the modest and inconsistent effects underscore the importance of continued efforts to improve the cognitive-behavioral therapy program beyond current standards.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Trajectories of Adaptive Behaviors During Childhood in Females and Males in the General Population.

Little is known about the trajectory patterns and sex differences in adaptive behaviors in the general population. We examined the trajectory classes of adaptive behaviors using a representative sample and examined whether the class structure and trajectory patterns differed between females and males. We further explored sex differences in neurodevelopmental traits in each latent class. Participants (n = 994) were children in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study)-a prospective birth cohort study. Adaptive behaviors in each domain of communication, daily living skills, and socialization were evaluated at five time points when participants were 2.7, 3.5, 4.5, 6, and 9 years old using the Vineland Adaptive Behavior Scales-Second Edition. Parallel process multigroup latent class growth analysis extracted sex-specific trajectory classes. Neurodevelopmental traits of children at age 9, autistic traits, attention deficit hyperactivity disorder (ADHD) traits, and cognitive ability were examined for females and males in each identified class. A 4-class model demonstrated the best fit. Moreover, a 4-class model that allowed for differences in class probabilities and means of growth parameters between females and males provided a better fit than a model assuming no sex differences. In the communication domain, females scored higher than their male counterparts in all four classes. In the daily living skills and socialization domains, the two higher adaptive classes (Class 1: females, 18.6%; males, 17.8%; Class 2: females, 48.8%; males, 49.8%) had similar trajectories for males and females, whereas in the two lower adaptive behavior classes (Class 3: females, 27.5%; males, 29.4%; Class 4: females, 5.1%; males, 3.0%), females had higher adaptive scores than their male counterparts. In Class 4, females were more likely to have autistic and ADHD traits exceeding the cutoffs, while males were more likely to have below-average IQ. Different trajectories in females and males suggest that adaptive skills may require adjustment based on the sex of the child, when standardizing scores, in order to achieve better early detection of skill impairment.

Application of a Machine Learning Algorithm for Structural Brain Images in Chronic Schizophrenia to Earlier Clinical Stages of Psychosis and Autism Spectrum Disorder: A Multiprotocol Imaging Dataset Study.

BACKGROUND AND HYPOTHESIS: Machine learning approaches using structural magnetic resonance imaging (MRI) can be informative for disease classification; however, their applicability to earlier clinical stages of psychosis and other disease spectra is unknown. We evaluated whether a model differentiating patients with chronic schizophrenia (ChSZ) from healthy controls (HCs) could be applied to earlier clinical stages such as first-episode psychosis (FEP), ultra-high risk for psychosis (UHR), and autism spectrum disorders (ASDs). STUDY DESIGN: Total 359 T1-weighted MRI scans, including 154 individuals with schizophrenia spectrum (UHR, n = 37; FEP, n = 24; and ChSZ, n = 93), 64 with ASD, and 141 HCs, were obtained using three acquisition protocols. Of these, data regarding ChSZ (n = 75) and HC (n = 101) from two protocols were used to build a classifier (training dataset). The remainder was used to evaluate the classifier (test, independent confirmatory, and independent group datasets). Scanner and protocol effects were diminished using ComBat. STUDY RESULTS: The accuracy of the classifier for the test and independent confirmatory datasets were 75% and 76%, respectively. The bilateral pallidum and inferior frontal gyrus pars triangularis strongly contributed to classifying ChSZ. Schizophrenia spectrum individuals were more likely to be classified as ChSZ compared to ASD (classification rate to ChSZ: UHR, 41%; FEP, 54%; ChSZ, 70%; ASD, 19%; HC, 21%). CONCLUSION: We built a classifier from multiple protocol structural brain images applicable to independent samples from different clinical stages and spectra. The predictive information of the classifier could be useful for applying neuroimaging techniques to clinical differential diagnosis and predicting disease onset earlier.

Extrastriatal dopamine D2/3 receptor binding, functional connectivity, and autism socio-communicational deficits: a PET and fMRI study.

The social motivation hypothesis of autism proposes that social communication symptoms in autism-spectrum disorder (ASD) stem from atypical social attention and reward networks, where dopamine acts as a crucial mediator. However, despite evidence indicating that individuals with ASD show atypical activation in extrastriatal regions while processing reward and social stimuli, no previous studies have measured extrastriatal dopamine D2/3 receptor (D2/3R) availability in ASD. Here, we investigated extrastriatal D2/3R availability in individuals with ASD and its association with ASD social communication symptoms using positron emission tomography (PET). Moreover, we employed a whole-brain multivariate pattern analysis of resting-state functional magnetic resonance imaging (fMRI) to identify regions where functional connectivity atypically correlates with D2/3R availability depending on ASD diagnosis. Twenty-two psychotropic-free males with ASD and 24 age- and intelligence quotient-matched typically developing males underwent [11C]FLB457 PET, fMRI, and clinical symptom assessment. Participants with ASD showed lower D2/3R availability throughout the D2/3R-rich extrastriatal regions of the dopaminergic pathways. Among these, the posterior region of the thalamus, which primarily comprises the pulvinar, displayed the largest effect size for the lower D2/3R availability, which correlated with a higher score on the Social Affect domain of the Autism Diagnostic Observation Schedule-2 in participants with ASD. Moreover, lower D2/3R availability was correlated with lower functional connectivity of the thalamus-superior temporal sulcus and cerebellum-medial occipital cortex, specifically in individuals with ASD. The current findings provide novel molecular evidence for the social motivation theory of autism and offer a novel therapeutic target.

Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

A 2-year longitudinal follow-up of quantitative assessment neck tics in Tourette's syndrome.

BACKGROUND: Neck motor tics in Tourette's syndrome can cause severe neck complications. Although addressed in a few longitudinal studies, the clinical course of Tourette's syndrome has not been quantitatively assessed. We had previously developed a method for quantifying the angular movements of neck tics using a compact gyroscope. Here, we present a follow-up study aimed at elucidating the clinical course of neck tics at both the group and individual levels. METHODS: Eleven patients with Tourette's syndrome from our previous study participated in the present study, and their neck tics were recorded during a 5-min observation period. The severity of neck symptoms was assessed using the Yale Global Tic Severity Scale. The peak angular velocities and accelerations, tic counts, and severity scores in our previous study (baseline) and the present study (2-year follow-up) were compared at the group and individual levels. The individual level consistency between baseline and follow-up were calculated using intra-class correlation coefficients (ICCs, one-way random, single measure). RESULTS: At the group level, no significant change was observed between baseline and follow-up. At the individual level, angular velocity (ICC 0.73) and YGTSS scores (ICC 0.75) had substantial consistency over the two time points, and angular acceleration (ICC 0.59) and tic counts (ICC 0.69) had moderate consistency. CONCLUSIONS: The intensity and frequency of neck tics did not change over time. Therefore, quantification of angular neck motor tics will aid in identifying patients with neck tics at high risk for severe neck complications.

Association Between Genetic Risks for Obesity and Working Memory in Children.

Introduction: Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated. Methods: In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory. Results: A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (ß[SE], -1.807 [0.668]; p = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (ß[SE], -2.020 [6.39]; p = 0.002, corrected), negative regulation of GTPase activity (ß[SE], 2.001 [0.630]; p = 0.002, corrected), and regulation of gene expression epigenetic (ß[SE], -2.119 [0.664]; p = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children. Conclusion: Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.

Children with special health care needs and mothers' anxiety/depression: Findings from the Tokyo Teen Cohort study.

AIM: Children with special health care needs (CSHCN) are those who require more care for their physical, developmental, or emotional differences than their typically developing peers. Among a wide range of burdens that caregivers of CSHCN experience, the mental burden of caregivers is still not well investigated. This study aimed at examining the relationship between caring for CSHCN and mothers' anxiety/depression. METHODS: This study used data from the Tokyo Early Adolescence Survey, a population-based cross-sectional survey. Using screening questionnaires, we evaluated the prevalence of CSHCN and identified their primary caregivers. Focusing on mothers as caregivers, we analyzed the relationship between having CSHCN and mothers' anxiety/depression, and between the severity of children's condition and mothers' anxiety/depression. We further determined what mediates these relationships using path analyses. RESULTS: Among 4003 participants, we identified 502 CSHCN (12.5%), and 93% of responding caregivers were mothers. We found that mothers with CSHCN were significantly more anxious/depressed than those without CSHCN, which was closely related to the severity of children's condition. The mediation effect of social support on the relation between CSHCN and mothers' anxiety/depression was statistically significant. CONCLUSION: Mothers of CSHCN were more anxious/depressed than other mothers in this study. Social support was indicated to have a significant mediating effect on the relationship between CSHCN and mothers' anxiety/depression. Our results suggest that considering ways to offer social support may effectively relieve the mental stress experienced by mothers of CSHCN.

A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin ß-cluster genes in the developing brain.

Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin ß (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.

Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms.

BACKGROUND: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. METHODS: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. RESULTS: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (PFDR = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (PFDR = 0.006, r = - 0.485, N = 43) and deteriorations between 2 and 4 weeks (PFDR = 0.032, r = 0.415, N = 37). LIMITATIONS: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. CONCLUSION: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy. TRIAL REGISTRATION: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264).

Associations Among Maternal Metabolic Conditions, Cord Serum Leptin Levels, and Autistic Symptoms in Children.

INTRODUCTION: Accumulating evidence has shown that maternal metabolic conditions, such as pre-pregnancy overweight, diabetes mellitus, and hypertensive disorders of pregnancy (HDP) are potential risk factors of autism spectrum disorder (ASD). However, it remains unclear how these maternal conditions lead to neurodevelopmental outcomes in the offspring, including autistic symptoms. Leptin, an adipokine that has pro-inflammatory effects and affects fetal neurodevelopment, is a candidate mediator of the association between maternal metabolic factors and an increased risk of ASD. However, whether prenatal exposure to leptin mediates the association between maternal metabolic conditions and autistic symptoms in children has not been investigated yet. METHODS: This study investigated the associations between mothers' metabolic conditions (pre-pregnancy overweight, diabetes mellitus during or before pregnancy, and HDP), leptin concentrations in umbilical cord serum, and autistic symptoms among 762 children from an ongoing cohort study, using generalized structural equation modeling. We used the Social Responsive Scale, Second Edition (SRS-2) at 8-9 years old to calculate total T-scores. Additionally, we used the T-scores for two subdomains: Social Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB). RESULTS: Umbilical cord leptin levels were associated with pre-pregnancy overweight [coefficient = 1.297, 95% confidence interval (CI) 1.081-1.556, p = 0.005] and diabetes mellitus (coefficient = 1.574, 95% CI 1.206-2.055, p = 0.001). Furthermore, leptin levels were significantly associated with SRS-2 total T-scores (coefficient = 1.002, 95% CI 1.000-1.004, p = 0.023), SCI scores (coefficient = 1.002, 95% CI 1.000-1.004, p = 0.020), and RRB scores (coefficient = 1.001, 95% CI 1.000-1.003, p = 0.044) in children. Associations between maternal metabolic factors and autistic symptoms were not significant. DISCUSSION: The present study uncovered an association between cord leptin levels and autistic symptoms in children, while maternal metabolic conditions did not have an evident direct influence on the outcome. These results imply that prenatal pro-inflammatory environments affected by maternal metabolic conditions may contribute to the development of autistic symptoms in children. The findings warrant further investigation into the role of leptin in the development of autistic symptoms.

Unique Morphometric Features of the Cerebellum and Cerebellocerebral Structural Correlation Between Autism Spectrum Disorder and Schizophrenia.

Background: Although cerebellar morphological involvement has been increasingly recognized in autism spectrum disorder (ASD) and schizophrenia (SZ), the extent to which there are morphological differences between them has not been definitively quantified. Furthermore, although previous studies have demonstrated increased anatomical cerebellocerebral correlations in both conditions, differences between their associations have not been well characterized. Methods: We compared cerebellar volume between males with ASD (n = 31), males with SZ (n = 28), and typically developing males (n = 49). A total of 31 cerebellar subregions were investigated with the cerebellum segmented into their constituent lobules, in gray matter (GM) and white matter (WM) separately. Additionally, structural correlations with the contralateral cerebrum were analyzed for each cerebellar lobule. Results: We found significantly larger WM volume in the bilateral lobules VI and Crus I in the ASD group than in other groups. While WM or GM volumes of these right lobules had positive associations with ASD symptoms, there was a negative association between GM volume of the right Crus I and SZ symptoms. We further observed, in the ASD group specifically, significant correlations between WM of the right lobule VI and WM of the left frontal pole (r = 0.67) and between GM of the right lobule VI and the left caudate (r = 0.60). Conclusions: Our findings support evidence that cerebellar morphology is involved in ASD and SZ with different mechanisms. Furthermore, this study showed that these biological differences require consideration when determining diagnostic criteria and treatment for these disorders.

Neurochemical evidence for differential effects of acute and repeated oxytocin administration.

A discrepancy in oxytocin's behavioral effects between acute and repeated administrations indicates distinct underlying neurobiological mechanisms. The current study employed a combination of human clinical trial and animal study to compare neurochemical changes induced by acute and repeated oxytocin administrations. Human study analyzed medial prefrontal metabolite levels by using 1H-magnetic resonance spectroscopy, a secondary outcome in our randomized, double-blind, placebo-controlled crossover trial of 6 weeks intranasal administrations of oxytocin (48 IU/day) and placebo within-subject design in 17 psychotropic-free high-functioning men with autism spectrum disorder. Medial prefrontal transcript expression levels were analyzed in adult male C57BL/6J mice after intraperitoneal injection of oxytocin or saline either once (200 ng/100 µL/mouse, n = 12) or for 14 consecutive days (200 ng/100 µL/mouse/day, n = 16). As the results, repeated administration of oxytocin significantly decreased the medial prefrontal N-acetylaspartate (NAA; p = 0.043) and glutamate-glutamine levels (Glx; p = 0.001), unlike the acute oxytocin. The decreases were inversely and specifically associated (r = 0.680, p = 0.004 for NAA; r = 0.491, p = 0.053 for Glx) with oxytocin-induced improvements of medial prefrontal functional MRI activity during a social judgment task not with changes during placebo administrations. In wild-type mice, we found that repeated oxytocin administration reduced medial frontal transcript expression of N-methyl-D-aspartate receptor type 2B (p = 0.018), unlike the acute oxytocin, which instead changed the transcript expression associated with oxytocin (p = 0.0004) and neural activity (p = 0.0002). The present findings suggest that the unique sensitivity of the glutamatergic system to repeated oxytocin administration may explain the differential behavioral effects of oxytocin between acute and repeated administration.