Keisuke Inohara

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.

Distinguishing between autism spectrum disorder and attention deficit hyperactivity disorder by using behavioral checklists, cognitive assessments, and neuropsychological test battery

Children with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) share many common symptoms, including attention deficit, behavioral problems, and difficulties with social skills. The aim of this study was to distinguish between ASD and ADHD by identifying the characteristic features of both the disorders, by using multidimensional assessments, including screening behavioral checklists, cognitive assessments, and comprehensive neurological battery. After screening for comorbid disorders, we carefully selected age-, sex-, IQ-, and socio-economic status-matched children with typical development (TD). In the Wechsler Intelligence Scale for children, a lower score was observed for the ASD group than for the TD group in Picture concept, which is a subscale of perceptual reasoning. A lower score was shown by the ADHD group than by the TD group in the spatial working memory test in the Cambridge Neuropsychological Test Automated Battery (CANTAB(®)). Although ASD and ADHD have many similar symptoms, they can be differentiated by focusing on the behavioral and cognitive characteristics of executive function.

Effects of methylphenidate in children with attention deficit hyperactivity disorder: a near-infrared spectroscopy study with CANTAB®

BackgroundA wide range of evidence supports the methylphenidate (MPH)-induced enhancement of prefrontal cortex (PFC) functioning and improvements in behavioral symptoms in patients with attention deficit hyperactivity disorder (ADHD). Although working memory (WM) has been hypothesized to be impaired in patients with ADHD, no pharmacological studies have examined visuospatial WM (VSWM) with near-infrared spectroscopy (NIRS).Study aimThe present study was designed to investigate the acute effects of MPH on neuropsychological performance and hemodynamic activation in children with ADHD during VSWM tasks.MethodsThe subject group included 10 boys and 1 girl previously diagnosed with ADHD. Two VSWM tasks of differing degrees of difficulty were conducted. This is the first study on the pharmacological effects of MPH in children with ADHD to evaluate hemodynamic responses in the PFC with simultaneous NIRS.ResultsNo significant differences were found in the scores for both spatial working memory (SWM) and score of spatial span (SSP) tasks between the MPH-off and MPH–on conditions. However, a significant MPH-effect on changes in oxy-hemoglobin levels in the PFC was found only in the SWM task.ConclusionThese findings suggest that PFC activation might be affected by MPH, depending on the degree of difficulty of the particular task. Although the MPH-induced change on behavior may or may not be obvious, NIRS measurements might be useful for assessing the psychological effects of MPH even when performance changes were not observed in the cognitive tasks.

Altered frontal pole development affects self-generated spatial working memory in ADHD.

BACKGROUND Spatial working memory (SWM) dysfunction is a feature of attention deficit hyperactivity disorder (ADHD). Previous studies suggested that behavioral performance in self-generated SWM improves through development in children with and without ADHD. Nevertheless, developmental changes in the neural underpinnings of self-generated SWM are unknown. METHOD Using near-infrared spectroscopy, hemodynamic activity in the prefrontal cortex (PFC) was measured in 30 children with ADHD (9.5 ± 1.6 years-old) and 35 TD children (9.0 ± 1.6 years-old) while they performed a self-generated SWM task. We then investigated correlations between age and behavioral performance, and between age and hemodynamic activity in the PFC for each group. RESULTS Both groups showed a negative correlation with age and number of errors [ADHD: r(28)=-0.37, p=0.040; TD: r(33)=-0.59, p<0.001], indicating that self-generated SWM improves through development. The TD group showed a positive correlation between age and oxygenated hemoglobin in the frontal pole [10ch: r(33)=0.41, p=0.013; 11ch; r(33)=0.44, p=0.008] and bilateral lateral PFC [4ch: r(33)=0.34, p=0.049; 13ch; r(33)=0.54, p=0.001], while no significant correlation was found in the ADHD group. Furthermore, regression slopes for the frontal pole significantly differed between the TD and ADHD groups [10ch: t(61)=2.35, p=0.021; 11ch: t(61)=2.05, p=0.044]. CONCLUSION Children with ADHD showed abnormalities in functional maturation of the frontal pole, which plays a role in manipulating and maintaining information associated with self-generated behavior.

Episodic memory retrieval for story characters in high-functioning autism.

BackgroundThe objective of this study was to examine differences in episodic memory retrieval between individuals with autism spectrum disorder (ASD) and typically developing (TD) individuals. Previous studies have shown that personality similarities between readers and characters facilitated reading comprehension. Highly extraverted participants read stories featuring extraverted protagonists more easily and judged the outcomes of such stories more rapidly than did less extraverted participants. Similarly, highly neurotic participants judged the outcomes of stories with neurotic protagonists more rapidly than did participants with low levels of neuroticism. However, the impact of the similarity effect on memory retrieval remains unclear. This study tested our ‘similarity hypothesis’, namely that memory retrieval is enhanced when readers with ASD and TD readers read stories featuring protagonists with ASD and with characteristics associated with TD individuals, respectively.MethodsEighteen Japanese individuals (one female) with high-functioning ASD (aged 17 to 40 years) and 17 age- and intelligence quotient (IQ)-matched Japanese (one female) TD participants (aged 22 to 40 years) read 24 stories; 12 stories featured protagonists with ASD characteristics, and the other 12 featured TD protagonists. Participants read a single sentence at a time and pressed a spacebar to advance to the next sentence. After reading all 24 stories, they were asked to complete a recognition task about the target sentence in each story.ResultsTo investigate episodic memory in ASD, we analyzed encoding based on the reading times for and readability of the stories and retrieval processes based on the accuracy of and response times for sentence recognition. Although the results showed no differences between ASD and TD groups in encoding processes, they did reveal inter-group differences in memory retrieval. Although individuals with ASD demonstrated the same level of accuracy as did TD individuals, their patterns of memory retrieval differed with respect to response times.ConclusionsIndividuals with ASD more effectively retrieved ASD-congruent than ASD-incongruent sentences, and TD individuals retrieved stories with TD more effectively than stories with ASD protagonists. Thus, similarity between reader and story character had different effects on memory retrieval in the ASD and TD groups.

Sex-different abnormalities in the right second to fourth digit ratio in Japanese individuals with autism spectrum disorders

BackgroundThe prevalence of autism spectrum disorders (ASDs) is higher in men than in women. The extreme male brain theory proposes that excessive prenatal testosterone activity could be a risk factor for ASDs. However, it is unclear whether prenatal sex hormone activity is a risk factor for women. The ratio of the length of the second to fourth digits (2D:4D) is considered to be a biomarker of the prenatal ratio of testosterone to estrogen. Therefore, this study compared the 2D:4D ratios of women with and without ASDs to determine if prenatal sex hormone activity could be a risk factor for ASDs in women.MethodsThe study included 35 Japanese men with ASDs, 17 Japanese women with ASDs, 59 typically developed (TD) Japanese men, and 57 TD Japanese women. We measured digit lengths and compared the 2D:4D ratios among the four groups. We also examined the relationship between the 2D:4D ratio and the autism-spectrum quotient score of each group.ResultsIn our cohort, men with ASDs tended to have lower right-hand 2D:4D ratios relative to TD men. In contrast, the right 2D:4D ratios in women with ASDs were higher compared to those of TD women. No significant correlations were found between the 2D:4D ratios and the autism-spectrum quotient scores in any group. The higher right 2D:4D ratios in women could not be explained by age or full-scale intelligent quotients. This group difference was not found for the left 2D:4D or right–left 2D:4D ratios.ConclusionsWe found a reverse direction of abnormality in the right 2D:4D ratio for men and women with ASDs. It has been posited that high prenatal testosterone levels lead to a lower 2D:4D ratio. However, a recent animal study showed that testosterone injection to dam leads to a higher right 2D:4D ratio especially for female offspring, which might be mediated by abnormal adipose accumulation in the fingertip. Therefore, the present findings suggest that high prenatal testosterone could be a risk factor both for Japanese men and women with ASDs, elucidating one potential etiology of ASDs in women.

Decision making processes based on social conventional rules in early adolescents with and without autism spectrum disorders.

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.