Takashi X. Fujisawa

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

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.

Visual attention for social information and salivary oxytocin levels in preschool children with autism spectrum disorders: an eye-tracking study.

This study was designed to ascertain the relationship between visual attention for social information and oxytocin (OT) levels in Japanese preschool children with autism spectrum disorder (ASD). We hypothesized that poor visual attention for social information and low OT levels are crucially important risk factors associated with ASD. We measured the pattern of gaze fixation for social information using an eye-tracking system, and salivary OT levels by the Enzyme-Linked Immunosorbent Assay (ELISA). There was a positive association between salivary OT levels and fixation duration for an indicated object area in a finger-pointing movie in typically developing (TD) children. However, no association was found between these variables in children with ASD. Moreover, age decreased an individuals attention to people moving and pointed-at objects, but increased attention for mouth-in-the-face recognition, geometric patterns, and biological motions. Thus, OT levels likely vary during visual attention for social information between TD children and those with ASD. Further, aging in preschool children has considerable effect on visual attention for social information.

Assessment of olfactory detection thresholds in children with autism spectrum disorders using a pulse ejection system

BackgroundAtypical responsiveness to olfactory stimuli has been reported as the strongest predictor of social impairment in children with autism spectrum disorders (ASD). However, previous laboratory-based sensory psychophysical studies that have aimed to investigate olfactory sensitivity in children with ASD have produced inconsistent results. The methodology of these studies is limited by several factors, and more sophisticated approaches are required to produce consistent results.MethodsWe measured olfactory detection thresholds in children with ASD and typical development (TD) using a pulse ejection system—a newly developed methodology designed to resolve problems encountered in previous studies. The two odorants used as stimuli were isoamyl acetate and allyl caproate.ResultsForty-three participants took part in this study: 23 (6 females, 17 males) children with ASD and 20 with TD (6 females, 14 males). Olfactory detection thresholds of children with ASD were significantly higher than those of TD children with both isoamyl acetate (2.85 ± 0.28 vs 1.57 ± 0.15; p < 0.001) and allyl caproate ( 3.30 ± 0.23 vs 1.17 ± 0.08; p < 0.001).ConclusionsWe found impaired olfactory detection thresholds in children with ASD. Our results contribute to a better understanding of the olfactory abnormalities that children with ASD experience. Considering the role and effect that odors play in our daily lives, insensitivity to some odorants might have a tremendous impact on children with ASD. Future studies of olfactory processing in ASD may reveal important links between brain function, clinically relevant behavior, and treatment.

Neural Basis of Psychological Growth following Adverse Experiences: A Resting-State Functional MRI Study

Over the past decade, research on the aftereffects of stressful or traumatic events has emphasized the negative outcomes from these experiences. However, the positive outcomes deriving from adversity are increasingly being examined, and such positive changes are described as posttraumatic growth (PTG). To investigate the relationship between basal whole-brain functional connectivity and PTG, we employed resting-state functional magnetic resonance imaging and analyzed the neural networks using independent component analysis in a sample of 33 healthy controls. Correlations were calculated between the network connectivity strength and the Posttraumatic Growth Inventory (PTGI) score. There were positive associations between the PTGI scores and brain activation in the rostral prefrontal cortex and superior parietal lobule (SPL) within the left central executive network (CEN) (respectively, r = 0.41, p < 0.001; r = 0.49, p < 0.001). Individuals with higher psychological growth following adverse experiences had stronger activation in prospective or working memory areas within the executive function network than did individuals with lower psychological growth (r = 0.40, p < 0.001). Moreover, we found that individuals with higher PTG demonstrated stronger connectivity between the SPL and supramarginal gyrus (SMG). The SMG is one of the brain regions associated with the ability to reason about the mental states of others, otherwise known as mentalizing. These findings suggest that individuals with higher psychological growth may have stronger functional connectivity between memory functions within the CEN and social functioning in the SMG, and that their better sociality may result from using more memory for mentalizing during their daily social interactions.

Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: functional MRI study

Background Child maltreatment is a major risk factor for psychopathology, including reactive attachment disorder (RAD). Aims To examine whether neural activity during reward processing was altered in children and adolescents with RAD. Method Sixteen children and adolescents with RAD and 20 typically developing (TD) individuals performed tasks with high and low monetary rewards while undergoing functional magnetic resonance imaging. Results Significantly reduced activity in the caudate and nucleus accumbens was observed during the high monetary reward condition in the RAD group compared with the TD group (P=0.015, family-wise error-corrected cluster level). Significant negative correlations between bilateral striatal activity and avoidant attachment were observed in the RAD and TD groups. Conclusions Striatal neural reward activity in the RAD group was markedly decreased. The present results suggest that dopaminergic dysfunction occurs in the striatum of children and adolescents with RAD, leading towards potential future risks for psychopathology. Declaration of interest None. Copyright and usage

Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population *

Objective: A study in a Caucasian population has identified two single-nucleotide polymorphisms (SNPs) in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population. Methods: We performed a similar association study using families with three individuals (one autistic child and two unaffected parents). A family-based transmission disequilibrium test (TDT) was used to analyze the results. Results: There were significant associations between autism and the two SNPs of ZNF533 gene (rs11885327: χ2=4.5200, P=0.0335; rs1964081: χ2=4.2610, P=0.0390) and the SNP of DOCK4 gene (rs2217262: χ2=5.3430, P=0.0208). Conclusions: Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.

Anorexia Nervosa during Adolescence Is Associated with Decreased Gray Matter Volume in the Inferior Frontal Gyrus

Anorexia nervosa (AN) is an eating disorder characterized by the relentless pursuit to lose weight, mostly through self-starvation, and a distorted body image. AN tends to begin during adolescence among women. However, the underlying neural mechanisms related to AN remain unclear. Using voxel-based morphometry based on magnetic resonance imaging scans, we investigated whether the presence of AN was associated with discernible changes in brain morphology. Participants were 20 un-medicated, right-handed patients with early-onset AN and 14 healthy control subjects. Group differences in gray matter volume (GMV) were assessed using high-resolution, T1-weighted, volumetric magnetic resonance imaging datasets (3T Trio scanner; Siemens AG) and analyzed after controlling for age and total GMV, which was decreased in the bilateral inferior frontal gyrus (IFG) (left IFG: FWE corrected, p < 0.05; right IFG: uncorrected, p < 0.05) of patients with AN. The GMV in the bilateral IFG correlated significantly with current age (left IFG: r = -.481, p < .05; right IFG: r = -.601, p < .01) and was limited to the AN group. We speculate that decreased IFG volume might lead to deficits in executive functioning or inhibitory control within neural reward systems. Precocious or unbalanced neurological trimming within this particular region might be an important factor for the pathogenesis of AN onset.

Reduced visual cortex grey matter volume in children and adolescents with reactive attachment disorder.

Child maltreatment increases the risk for psychiatric disorders throughout childhood and into adulthood. One negative outcome of child maltreatment can be a disorder of emotional functioning, reactive attachment disorder (RAD), where the child displays wary, watchful, and emotionally withdrawn behaviours. Despite its clinical importance, little is known about the potential neurobiological consequences of RAD. The aim of this study was to elucidate whether RAD was associated with alterations in grey matter volume (GMV). High-resolution magnetic resonance imaging datasets were obtained for children and adolescents with RAD (n = 21; mean age = 12.76 years) and typically developing (TD) control subjects (n = 22; mean age = 12.95 years). Using a whole-brain voxel-based morphometry approach, structural images were analysed controlling for age, gender, full scale intelligence quotient, and total brain volume. The GMV was significantly reduced by 20.6% in the left primary visual cortex (Brodmann area 17) of the RAD group compared to the TD group (p = .038, family-wise error-corrected cluster level). This GMV reduction was related to an internalising problem measure of the Strength and Difficulties Questionnaire. The visual cortex has been viewed as part of the neurocircuit regulating the stress response to emotional visual images. Combined with previous studies of adults with childhood maltreatment, early adverse experience (e.g. sensory deprivation) may affect the development of the primary visual system, reflecting in the size of the visual cortex in children and adolescents with RAD. These visual cortex GMV abnormalities may also be associated with the visual emotion regulation impairments of RAD, leading to an increased risk for later psychopathology.

No association between catechol-O-methyltransferase (COMT) genotype and attention deficit hyperactivity disorder (ADHD) in Japanese children.

OBJECTIVE This study ascertained the association between attention deficit/hyperactivity disorder (ADHD) in Japanese children and a polymorphism of catechol-O-methyltransferase (COMT), a dopamine-control gene. The secondary aim of the study was the evaluation of a putative association between methylphenidate (MPH) effect/adverse effects and the COMT genotype. METHODS To ascertain the distribution of the Val158Met variant of COMT, 50 children meeting ADHD inclusion criteria were compared with 32 healthy children. Clinical improvement and the occurrence of adverse effects were measured before and 3 months after MPH administration in children with ADHD, and analyzed for genotype association. Wechsler Intelligence Scale for Children-Third Edition (WISC-III), age, MPH dose were included as co-variables. RESULTS The occurrence of the COMT Val/Val genotype was significantly higher in children with ADHD (χ(2)(1)=7.13, p<0.01). However, there was no significant difference in the Val/Val genotype according to disorder, and WISC and ADHD rating scale scores, after correcting for the interaction between disorder and COMT genotype. Furthermore, no significant difference in MPH effect/adverse effects was observed in association with the COMT genotype in the ADHD group. CONCLUSIONS These results showed a lack of association between the COMT Val/Val genotype and ADHD in Japan.

Developmental changes in social attention and oxytocin levels in infants and children

Oxytocin (OT) signalling represents one of the most critical systems involved in human social behaviour. Although several studies have examined the relationship between social functioning and peripheral OT levels, the association between OT and the development of social attention has not been well studied. Therefore, we investigated the developmental relationship between gaze fixation for social cues and OT levels during young childhood. We examined visual attention using an eye tracking system in infants and children (5–90 months of age) and measured the concentration of OT in saliva samples. We observed a negative association between age and both attention toward social cues and salivary OT levels, and a positive association between age and attention for non-social cues. We also observed that salivary OT levels were modulated by polymorphisms in oxytocin receptor (OXTR) rs53576. Our results suggest that there is an age-dependent association between visual attention for social cues and OT levels in infants and children, and that the development of visual attention to the eyes as social cues is associated with both OXTR polymorphisms and OT levels. Such findings indicate that OT and OXTR status may provide insight into the atypical development of social attention in infants and young children.