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.

Effects of functional polymorphisms of opioid receptor mu 1 and catechol-O-methyltransferase on the neural processing of pain.

AIM: Pain is reconstructed by brain activities and its subjectivity comes from an interplay of multiple factors. The current study aims to understand the contribution of genetic factors to the neural processing of pain. Focusing on the single-nucleotide polymorphism (SNP) of opioid receptor mu 1 (OPRM1) A118G (rs1799971) and catechol-O-methyltransferase (COMT) val158met (rs4680), we investigated how the two pain genes affect pain processing. METHOD: We integrated a genetic approach with functional neuroimaging. We extracted genomic DNA information from saliva samples to genotype the SNP of OPRM1 and COMT. We used a percept-related model, in which two different levels of perceived pain intensities ("low pain: mildly painful" vs "high pain: severely painful") were employed as experimental stimuli. RESULTS: Low pain involves a broader network relative to high pain. The distinct effects of pain genes were observed depending on the perceived pain intensity. The effects of low pain were found in supramarginal gyrus, angular gyrus, and anterior cingulate cortex (ACC) for OPRM1 and in middle temporal gyrus for COMT. For high pain, OPRM1 affected the insula and cerebellum, while COMT affected the middle occipital gyrus and ACC. CONCLUSION: OPRM1 primarily affects sensory and cognitive components of pain processing, while COMT mainly influences emotional aspects of pain processing. The interaction of the two pain genes was associated with neural patterns coding for high pain and neural activation in the ACC in response to pain. The proteins encoded by the OPRM1 and COMT may contribute to the firing of pain-related neurons in the human ACC, a critical center for subjective pain experience.

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.

The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults.

DNA methylation age has been used in recent studies as an epigenetic marker of accelerated cellular aging, whose contribution to the brain structural changes was lately acknowledged. We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. Using the multi-tissue method (Horvath S. DNA methylation age of human tissues and cell types. 2013. Genome Biol 14), epigenetic age was computed with saliva sample. Epigenetic age acceleration was derived from residuals after adjusting epigenetic age for chronological age. Multiple regression models were computed for 148 brain regions for surface area, cortical thickness, and volume using epigenetic age or accelerated epigenetic age as a predictor and controlling for sex. Epigenetic age was associated with surface area reduction of the left insula. It was also associated with cortical thinning and volume reduction in multiple regions, with prominent changes of cortical thickness in the left temporal regions and of volume in the bilateral orbital gyri. Finally, accelerated epigenetic age was negatively associated with right cuneus gyrus volume. Our findings suggest that understanding the mechanisms of epigenetic age acceleration in young individuals may yield valuable insights into the relationship between epigenetic aging and the cortical change and on the early development of neurocognitive pathology among young adults.

Impact of stable environments on maltreated children.

BACKGROUND: The development of the ability to understand others' facial expressions is thought to be dependent on the environment in which one has been reared. METHODS: This study compared the ability to understand others' facial expressions between 15 children who were in an unstable environment, 11 children who had been maltreated before and were in a stable environment, like a foster family, and 33 children who had never been maltreated. We used the Reading the Mind in the Eyes Test (RMET) as measure. RESULTS: Children who were in an unstable environment scored higher on the RMET than children who had never been maltreated. CONCLUSIONS: The results suggested that hypersensitivity to others' facial expressions might be an adaptive response to a harmful environment and that it might decline when in a stable environment because such sensitivity is no longer needed.

Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial.

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 < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

Paradoxical changes in mood-related behaviors on continuous social isolation after weaning.

Continuous social isolation (SI) from an early developmental stage may have different effects in youth and adulthood. Moreover, SI is reported to impair neuronal plasticity. In this study, we used post-weaning rats to compare the impact of continuous SI on depressive-like, anxiety-related, and fear-related behaviors and neuronal plasticity in puberty and adulthood. Furthermore, we assessed the effect of lithium on behavioral changes and neuronal plasticity. Continuous SI after weaning induced depressive-like behaviors in puberty; however, in adulthood, depressive-like and anxiety-related behaviors did not increase, but-paradoxically-decreased in comparison with the controls. The decreased expression of neuronal plasticity-related proteins in the hippocampus in puberty was more prominent in the prefrontal cortex and hippocampus in adulthood. In contrast, SI after weaning tended to decrease fear-related behaviors in puberty, a decrease which was more prominent in adulthood with increased neuronal plasticity-related protein expression in the amygdala. Lithium administration over the last 14 days of the SI-induced period removed the behavioral and expression changes of neuronal plasticity-related proteins observed in puberty and adulthood. Our findings suggest that the extension of the duration of SI from an early developmental stage does not simply worsen depressive-like behaviors; rather, it induces a behavior linked to neuronal plasticity damage. Lithium may improve behavioral changes in puberty and adulthood by reversing damage to neuronal plasticity. The mechanisms underlying the depressive-like and anxiety-related behaviors may differ from those underlying fear-related behaviors.

Thalamic Volume Is Related to Increased Anterior Thalamic Radiations in Children with Reactive Attachment Disorder.

Reactive attachment disorder (RAD) is associated with childhood maltreatment and affects approximately 1% of the general population. Recent data suggest that childhood maltreatment is associated with brain alterations in white and gray matter. However, the neural mechanisms of RAD-related brain alterations remain unknown. Herein, we evaluated the white matter pathways and gray matter volumes in 31 and 41 age-matched children with RAD and typical development (TD), respectively, by analyzing T1- and diffusion-weighted images. An increased fractional anisotropy (FA) and axial diffusivity in the anterior thalamic radiations (ATR) and an increased volume in the bilateral pallidum and right thalamus were observed in children with RAD compared with those with TD. Moreover, the volume of the thalamus was associated with increased ATR FA in children with RAD. Our study confirmed the existence of atypical neurodevelopment processes in the thalamus, pallidum, and ATR in children with RAD and highlighted an interdependent relationship between the alterations in the thalamus and ATR. These findings may help to improve our understanding of the comprehensive neural mechanisms of RAD.

Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism.

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.

The Effects of COMT Polymorphism on Cortical Thickness and Surface Area Abnormalities in Children with ADHD.

The catechol-O-methyltransferase (COMT) gene is associated with frontal cortex development and the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, how the COMT gene impacts brain structure and behavior in ADHD remains unknown. In the present study, we identify the effect of COMT on cortical thickness and surface area in children with ADHD and children with typically developing (TD) using a machine learning approach. In a sample of 39 children with ADHD and 34 age- and IQ-matched TD children, we found that cortical thickness and surface area differences were predominantly observed in the frontal cortex. Furthermore, a path analysis revealed that a COMT genotype affected abnormal development of the frontal cortex in terms of both cortical thickness and surface area and was associated with working memory changes in children with ADHD. Our study confirms that the role of COMT in ADHD is not restricted to the development of behavior but may also affect the cortical thickness and surface area. Thus, our findings may help to improve the understanding of the neuroanatomic basis for the relationship between the COMT genotype and ADHD pathogenesis.

Self-Face Recognition Begins to Share Active Region in Right Inferior Parietal Lobule with Proprioceptive Illusion During Adolescence.

We recently reported that right-side dominance of the inferior parietal lobule (IPL) in self-body recognition (proprioceptive illusion) task emerges during adolescence in typical human development. Here, we extend this finding by demonstrating that functional lateralization to the right IPL also develops during adolescence in another self-body (specifically a self-face) recognition task. We collected functional magnetic resonance imaging (fMRI) data from 60 right-handed healthy children (8-11 years), adolescents (12-15 years), and adults (18-23 years; 20 per group) while they judged whether a presented face was their own (Self) or that of somebody else (Other). We also analyzed fMRI data collected while they performed proprioceptive illusion task. All participants performed self-face recognition with high accuracy. Among brain regions where self-face-related activity (Self vs. Other) developed, only right IPL activity developed predominantly for self-face processing, with no substantial involvement in other-face processing. Adult-like right-dominant use of IPL emerged during adolescence, but was not yet present in childhood. Adult-like common activation between the tasks also emerged during adolescence. Adolescents showing stronger right-lateralized IPL activity during illusion also showed this during self-face recognition. Our results suggest the importance of the right IPL in neuronal processing of information associated with one's own body in typically developing humans.

Development of Right-hemispheric Dominance of Inferior Parietal Lobule in Proprioceptive Illusion Task.

Functional lateralization can be an indicator of brain maturation. We have consistently shown that, in the adult brain, proprioceptive processing of muscle spindle afferents generating illusory movement of the right hand activates inferior frontoparietal cortical regions in a right-side dominant manner in addition to the cerebrocerebellar motor network. Here we provide novel evidence regarding the development of the right-dominant use of the inferior frontoparietal cortical regions in humans using this task. We studied brain activity using functional magnetic resonance imaging while 60 right-handed blindfolded healthy children (8-11 years), adolescents (12-15 years), and young adults (18-23 years) (20 per group) experienced the illusion. Adult-like right-dominant use of the inferior parietal lobule (IPL) was observed in adolescents, while children used the IPL bilaterally. In contrast, adult-like lateralized cerebrocerebellar motor activation patterns were already observable in children. The right-side dominance progresses during adolescence along with the suppression of the left-sided IPL activity that emerges during childhood. Therefore, the neuronal processing implemented in the adult's right IPL during the proprioceptive illusion task is likely mediated bilaterally during childhood, and then becomes right-lateralized during adolescence at a substantially later time than the lateralized use of the cerebrocerebellar motor system for kinesthetic processing.

Depressive mood modulates the anterior lateral CA1 and DG/CA3 during a pattern separation task in cognitively intact individuals: a functional MRI study.

Although patients with major depressive disorder typically have a reduced hippocampal volume, particularly in the cornu ammonis 1 (CA1), animal studies suggest that depressive mood is related to the dentate gyrus (DG). In this study, our objective was to clarify which hippocampal subregions are functionally associated with depressive mood in humans. We conducted a functional MRI (fMRI) study on 27 cognitively intact volunteers. Subjects performed a modified version of a delayed matching-to-sample task in an MRI scanner to investigate pattern separation-related activity during each phase of encoding, delay, and retrieval. In each trial, subjects learned a pair of sample cues. Functional MR images were acquired at a high spatial resolution, focusing on the hippocampus. Subjects also completed the Beck Depression Inventory (BDI), a questionnaire about depressive mood. Depending on the similarity between sample cues, activity in the DG/CA3 and medial CA1 in the anterior hippocampus changed only during encoding. Furthermore, the DG/CA3 region was more active during successful encoding trials compared to false trials. Activity in the DG/CA3 and lateral CA1 was negatively correlated with BDI scores. These results suggest that the DG/CA3 is the core region for pattern separation during the encoding phase and interacts with the medial CA1, depending on the similarity of the stimuli, to achieve effective encoding. Impaired activity in the DG/CA3, as well as in the lateral CA1, was found to be associated with depressive symptoms, even at a subclinical level.

Mirtazapine Monotherapy for Antipsychotics-refractory Psychosis in a Patient with Very-late-onset Schizophrenia-like Psychosis: A Case Report.

Very-late-onset schizophrenia-like psychosis (VLOSLP) is a condition in which psychotic symptoms emerge after the age of 60 years. Given its heterogeneous nature, VLOSLP remains a diagnostic and therapeutic dilemma. Here, we report a case of a 68-year-old patient with psychosis refractory to antipsychotics who was successfully treated with mirtazapine monotherapy. This case suggests that mirtazapine monotherapy may be effective for the treatment of patients with antipsychotic- refractory VLOSLP.

Psychometrics of rating scales for externalizing disorders in Japanese outpatients: The ADHD-Rating Scale-5 and the Disruptive Behavior Disorders Rating Scale.

OBJECTIVES: This study validated the Japanese version of the Attention-Deficit/Hyperactivity Disorder-Rating Scale-5 (ADHD-RS-5) and the Disruptive Behavior Disorders Rating Scale. We extended the ADHD-RS-5 by adding the oppositional defiant disorder and conduct disorder subscales to compare the two rating scales psychometrically. METHODS: We examined the internal consistency, test-retest reliability, construct validity and criterion validity of the two rating scales in 135 Japanese outpatients aged 6-18 years. RESULTS: The internal consistency and test-retest reliability were good for all the subscales of the two rating scales except for the conduct disorder subscale of the ADHD-RS-5 extended. Good construct validity was revealed by expected correlational patterns between subscales from the two rating scales and the Children Behavior Checklist. The criterion validity was good for all the subscales of the two rating scales rated by parents, while teacher-ratings revealed substantially lower predictive ability for all the subscales. Agreement between parent- and teacher-ratings of the two rating scales was generally moderate and using predictive ratings alone of both ratings showed the best predictive ability among the integration methods examined. CONCLUSION: The two rating scales have sound psychometric properties and will aid in screening and severity assessment of externalizing disorders in Japanese clinical settings.

Cross-cultural variation in experiences of acceptance, camouflaging and mental health difficulties in autism: A registered report.

Recent findings suggest that stigma and camouflaging contribute to mental health difficulties for autistic individuals, however, this evidence is largely based on UK samples. While studies have shown cross-cultural differences in levels of autism-related stigma, it is unclear whether camouflaging and mental health difficulties vary across cultures. Hence, the current study had two aims: (1) to determine whether significant relationships between autism acceptance, camouflaging, and mental health difficulties replicate in a cross-cultural sample of autistic adults, and (2) to compare these variables across cultures. To fulfil these aims, 306 autistic adults from eight countries (Australia, Belgium, Canada, Japan, New Zealand, South Africa, the United Kingdom, and the United States) completed a series of online questionnaires. We found that external acceptance and personal acceptance were associated with lower levels of depression but not camouflaging or stress. Higher camouflaging was associated with elevated levels of depression, anxiety, and stress. Significant differences were found across countries in external acceptance, personal acceptance, depression, anxiety, and stress, even after controlling for relevant covariates. Levels of camouflaging also differed across countries however this effect became non-significant after controlling for the covariates. These findings have significant implications, identifying priority regions for anti-stigma interventions, and highlighting countries where greater support for mental health difficulties is needed.