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Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder’s core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, −0.57; 95% CI, −1.27 to 0.13; P = 0.023) and confirmatory trials (−0.41; −0.62 to −0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen’s d = −0.78; 95% CI, −1.21 to −0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen’s d = −0.46; 95% CI, −0.90 to −0.01) and 6 weeks (P = 0.10, Cohen’s d = −0.35; 95% CI, −0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen’s d = −1.24; 95% CI, −1.71 to −0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals’ facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

This case–control study aimed to assess oxidative stress alterations in autism spectrum disorder (ASD). We used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a non-behavioural diagnostic tool for children with ASD. Serum samples of 39 children with ASD and 58 age-matched children with typical development were analysed. The ASD group showed decreased hydroxyl radical (·OH) and singlet oxygen scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against superoxide (O2·−) and alkoxyl radical (RO·) were increased in the ASD group suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of ·OH, O2·−, and RO· scavenging activities predicted ASD with high odds ratio (50.4), positive likelihood (12.6), and percentage of correct classification (87.0%). Our results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.

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

Abnormalities of lipid metabolism contribute to ASD pathogenesis has been argued, but the mechanisms are not fully understood. We characterized the lipids metabolism in ASD children by lipidomics, and identified the dramatic alterations of 71 metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function. Identified fatty acids (FAs) indicated the correlations with clinical social interaction score of ASD diagnosis as well as lipoproteins-triglyceride concentrations in ASD. We also found the specific reduction of very-low-density lipoprotein (VLDL) in ASD, which showing correlations with a decrease of APOB concentrations in ASD. We further found a significant increase in APOJ known as a sensor for oxidative stress, demonstrating enhancing oxidative stress in ASD is due to VLDL-specific dyslipidemia. These results demonstrate the increases in FAs are due to VLDL-specific degradation, providing novel insights to uncover the mechanisms such as oxidative stress generations via mitochondrial dysfunction underlying ASD pathology. Funding Statement: This work was supported by the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.M.; the Grant-in-Aid for Scientific Research on Innovative Areas (#21200014) from MEXT to H.M.; SENSHIN Medical Research Foundation to H.M. and N.U.; Hamamatsu Foundation for Science and Technology Promotion to H.M.; the Grant-in-Aid for Early-Career Scientists (18K14814) from the Japan Society for the Promotion of Science (JSPS) to N.U.; Takeda Science Foundation to H.M. and N.U.; The Osaka Medical Research Foundation for Intractable Diseases to N.U.; Research Grant for Public Health Science to N.U.; Eli Lilly Japan Research Grant to N.U.; the Grant for Life Cycle Medicine from Faculty of Medical Sciences, University of Fukui to N.U. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All procedures were approved by the Ethics Committee of the University of Fukui and the Hamamatsu University School of Medicine, and were conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare of Japan. All participants were given a complete description of the study and provided written informed consent from their parent and/or legal guardian before enrolled.

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18–48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P

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

Background Previous research studies have assessed the relationship between attention to social information and peripheral (e.g., plasma and salivary) oxytocin (OT) levels in typically developing (TD) children and children with autism spectrum disorder (ASD). A relationship between them was observed in TD children, but not in children with ASD. However, this relationship remains unexamined in other age groups. To clarify whether this lack of association is maintained throughout development in individuals with ASD, we aimed to assess the relationship between salivary OT levels and attention to social information in adolescents and adults with and without ASD. Methods We recruited male adolescents and adults with ASD (n = 17) and TD participants (n = 24). Using the all-in-one eye-tracking system Gazefinder, we measured the percentage fixation time allocated to social information. We also measured the salivary OT levels and Autism Spectrum Quotient (AQ) of participants. Subsequently, we confirmed group differences and conducted a correlation analysis to investigate the relationships between these three measures. Results Salivary OT levels did not show any significant difference between the ASD and TD groups and were negatively correlated with the AQ in the whole-group analysis, but not in within-group analysis. Individuals with ASD had significantly lower percentage fixation times than did TD individuals for eye regions in human faces with/without mouth motion, for upright biological motion, and for people regions in the people and geometry movies. The percentage of fixation for geometric shapes in the people and geometry movies was significantly higher in the ASD than in the TD group. In the TD group, salivary OT levels were positively correlated with percentage fixation times for upright biological motion and people and negatively correlated with inverted biological motion and geometry. However, no significant correlations were found in the ASD group. Conclusions Our exploratory results suggest that salivary OT levels in adolescents and adults with ASD are less indicative of attention to social stimuli than they are in TD adolescents and adults. It is suggested that their association is slightly weaker in adolescents and adults with ASD and that this attenuated relationship appears to be maintained throughout development.

In recent years, research focusing on childhood has reported that communication difficulties in autism spectrum disorder (ASD) are related to the social reciprocity difficulties inherent to ASD, as well as severe social anxiety and decreased verbal fluency. However, there have been no reports regarding these correlations and causal relationships in adulthood. The aim of this study was to reveal the effects of social reciprocity, social anxiety, and letter fluency on communicative behaviors in adults with ASD (n = 33, aged 18–43 years, mean age = 27.88 years) and to compare these to typically developing (TD) adults (n = 35, 19–40 years, mean age = 28.03 years). We validated a model using structural equation modeling in which social reciprocity not only directly affected communicative behaviors, but also indirectly affected communicative behaviors mediated by social anxiety and verbal fluency. The results of the structural equation modeling showed that communicative behaviors patterns differed between the ASD and TD groups, as the ASD group had high goodness of fit with the hypothesis model while the TD group had low goodness of fit. These findings signify that in ASD, in addition to problems in social reciprocity, social anxiety (fear) is a risk factor for worsening communicative behaviors difficulties.

Background Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. Methods An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. Findings Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. Interpretation Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. Funding This study was supported mainly by MEXT, Japan.

Autism spectrum disorder (ASD) is characterized by problems with reciprocal social interaction, repetitive behaviours/narrow interests, and impairments in the social cognition and emotional processing necessary for intention-based moral judgements. The aim of this study was to examine the information used by early adolescents with and without ASD when they judge story protagonists as good or bad. We predicted that adolescents with ASD would use protagonists' behaviour, while typically developing (TD) adolescents would use protagonists' characteristics when making the judgements. In Experiment 1, we measured sentence by sentence reading times and percentages for good or bad judgements. In Experiment 2, two story protagonists were presented and the participants determined which protagonist was better or worse. Experiment 1 results showed that the adolescents with ASD used protagonist behaviours and outcomes, whereas the TD adolescents used protagonist characteristics, behaviours, and outcomes. In Experiment 2, TD adolescents used characteristics information when making "bad" judgements. Taken together, in situations in which participants cannot go back and assess (Experiment 1), and in comparable situations in which all information is available (Experiment 2), adolescents with ASD do not rely on information about individual characteristics when making moral judgements., 悪い子の良い行動から何を読み取るか? : 自閉スペクトラム症を持つ小学生・中学生の善悪判断. 京都大学プレスリリース. 2016-11-30.

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Background Gaze abnormality is a diagnostic criterion for autism spectrum disorder (ASD). However, few easy-to-use clinical tools exist to evaluate the unique eye-gaze patterns of ASD. Recently, we developed Gazefinder, an all-in-one eye-tracking system for early detection of ASD in toddlers. Because abnormal gaze patterns have been documented in various ASD age groups, we predicted that Gazefinder might also detect gaze abnormality in adolescents and adults. In this study, we tested whether Gazefinder could identify unique gaze patterns in adolescents and adults with ASD. Methods We measured the percentage of eye fixation time allocated to particular objects depicted in movies (i.e., eyes and mouth in human face movies, upright and inverted biological motion in movies that presented these stimuli simultaneously, and people and geometry in movies that presented these stimuli simultaneously) by male adolescents and adults with ASD (N = 26) and age-matched males with typical development (TD; N = 35). We compared these percentages between the two groups (ASD and TD) and with scores on the social responsiveness scale (SRS). Further, we conducted discriminant analyses to determine if fixation times allocated to particular objects could be used to discriminate between individuals with and without ASD. Results Compared with the TD group, the ASD group showed significantly less fixation time at locations of salient social information (i.e., eyes in the movie of human faces without lip movement and people in the movie of people and geometry), while there were no significant groupwise differences in the responses to movies of human faces with lip movement or biological motion. In a within-group correlation analysis, a few of the fixation-time items correlated with SRS, although most of them did not. No items significantly correlated with SRS in both ASD and TD groups. The percentage fixation times to eyes and people, which exhibited large effect sizes for the group difference, could differentiate ASD and TD with a sensitivity of 81.0 % and a specificity of 80.0 %. Conclusions These findings suggest that Gazefinder is potentially a valuable and easy-to-use tool for objectively measuring unique gaze patterns and discriminating between ASD and TD in male adolescents and adults. Electronic supplementary material The online version of this article (doi:10.1186/s13229-016-0083-y) contains supplementary material, which is available to authorized users.