金井 智恵子

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.

An increasing number of studies have shown that autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share symptoms and aetiologies. However, transdiagnostic comparisons between ASD and ADHD is complicated due to the sex differences within each condition. To clarify the similarities and differences in the cognitive functioning between ASD and ADHD, while considering potential sex differences, this study compared cognitive profiles assessed by the WAIS-III between the four groups created by orthogonally combining diagnosis and sex based on the data from 277 ASD males, 86 ASD females, 99 ADHD males and 64 ADHD females. The analysis revealed three major findings. First, performance IQ and perceptual organization index were higher in ADHD males than in ASD males and ADHD females. Second, Gaussian mixture model fitting revealed two clusters underlying the distribution of subindex scores. The percentage of being classified into the cluster that scored lower in all the subindices was higher in females than in males irrespective of diagnosis. Third, feature importance for classification of ASD and ADHD yielded by random forest classifier, a supervised machine learning algorithm, revealed that autism quotient was most informative feature in classifying ASD and ADHD in males, while the discrepancy between verbal and performance intelligence quotient was in females, indicating that the set of behavioral features contributing to classification differs between males and females. Thus, these findings indicate that sex as well as diagnosis is critical in determining the cognitive profiles of people with ASD and ADHD. LAY SUMMARY: The present study compared profiles of cognitive functions measured by Wechsler Adult Intelligence Scale between males and females with ASD and ADHD. The analyses revealed clear sex differences in cognitive functions in both ASD and ADHD and that the set of cognitive functions useful in classifying ASD and ADHD differed between males and females. Thus, biological sex seems to be a critical factor in determining the cognitive profiles of people with ASD and ADHD.

People with autism spectrum disorder (ASD) exhibit atypicality in various domains of behavior. Previous psychophysiological studies have revealed an atypical pattern of autonomic nervous system (ANS) activation induced by psychosocial stimulation. Thus, it might be feasible to develop a novel assessment tool to evaluate the risk of ASD by measuring ANS activation in response to emotional stimulation. The present study investigated whether people with ASD could be automatically classified from neurotypical adults based solely on physiological data obtained by the recently introduced non-contact measurement of pulse wave. We video-recorded faces of adult males with and without ASD while watching emotion-inducing video clips. Features reflective of ANS activation were extracted from the temporal fluctuation of facial skin coloration and entered into a machine-learning algorithm. Though the performance was modest, the gradient boosting classifier succeeded in classifying people with and without ASD, which indicates that facial skin color fluctuation contains information useful for detecting people with ASD. Taking into consideration the fact that the current study recruited only high-functioning adults who have relatively mild symptoms and probably developed some compensatory strategies, ASD screening by non-contact measurement of pulse wave could be a promising assessment tool to evaluate ASD risk.

Previous studies (Haswell et al. in Nat Neurosci 12:970-972, 2009; Marko et al. in Brain J Neurol 138:784-797, 2015) reported that people with autism rely less on vision for learning to reach in a force field. This suggested a possibility that they have difficulties in extracting force information from visual motion signals, a process called inverse dynamics computation. Our recent study (Takamuku et al. in J Int Soc Autism Res 11:1062-1075, 2018) examined the ability of inverse computation with two perceptual tasks and found similar performances in typical and autistic adults. However, this tested the computation only in the context of sensory perception while it was possible that the suspected disability is specific to the motor domain. Here, in order to address the concern, we tested the use of inverse dynamics computation in the context of motor control by measuring changes in grip timing caused by seeing/not seeing a controlled object. The motion of the object was informative of its inertial force and typical participants improved their grip timing based on the visual feedback. Our interest was on whether the autism participants show the same improvement. While some autism participants showed atypical hand slowing when seeing the controlled object, we found no evidence of abnormalities in the inverse computation in our grip timing task or in a replication of the perceptual task. This suggests that the ability of inverse dynamics computation is preserved not only for sensory perception but also for motor control in adults with autism.

BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have high rates of co-occurrence and share atypical behavioral characteristics, including sensory symptoms. The present diffusion tensor imaging (DTI) study was conducted to examine whether and how white matter alterations are observed in adult populations with developmental disorders (DD) and to determine how brain-sensory relationships are either shared between or distinct to ASD and ADHD. METHODS: We collected DTI data from adult population with DD (a primary diagnosis of ASD: n = 105, ADHD: n = 55) as well as age- and sex-matched typically developing (TD) participants (n = 58). Voxel-wise fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD) were analyzed using tract-based spatial statistics. The severities of sensory symptoms were assessed using the Adolescent/Adult Sensory Profile (AASP). RESULTS: Categorical analyses identified voxel clusters showing significant effects of DD on FA and RD in the posterior portion of the corpus callosum and its extension in the right hemisphere. Furthermore, regression analyses using the AASP scores revealed that slopes in relationships of FA or RD with the degree of sensory symptoms were parallel between the two DDs in large parts of the affected corpus callosum regions. A small but significant cluster did exist showing difference in association between an AASP subscale score and RD across ASD and ADHD. LIMITATIONS: Wide age range of the participants may be oversimplified. CONCLUSIONS: These results indicate that white matter alteration and their relationships to sensory symptoms are largely shared between ASD and ADHD, with localized abnormalities showing significant between-diagnosis differences within DD.

The sunk cost effect, an interesting and well-known decision bias, is pervasive in real life and has been studied in various disciplines. In this study, we modified a task exemplifying the sunk cost effect and used it to evaluate this behavior in individuals with autism spectrum disorder (ASD). The control group exhibited a typical sunk cost effect in our task. We found that the sunk cost effect was lower in the ASD group than in the control group. The results agree with previous evidence of reduced sensitivity to context stimuli in individuals with ASD and extend this finding to the context of the sunk cost effect. Our findings are useful in addressing the practical implications on their socioeconomic behavior.

Inflexible behaviours in people with autism spectrum disorder (ASD) broadly obstruct social communication. Meanwhile, flexibility implicates cognitive control to resolve socially conflicting situations; however, it remains unclear how people with ASD behave in the face of these conflicts in this respect. We used the ultimatum game (UG) and the implicit-association test (IAT) to examine goal-directed/economic flexibility, both of which involve conflict and cognitive control. In addition, we used the Detail and Flexibility Questionnaire (DFlex) to measure inflexible everyday behaviour with diminished cognitive control and attention shifting. We observed the decreased flexibility in participants with ASD (DFlex and IAT); further, their IAT scores positively correlated with DFlex. However, in the UG, contrary to our prediction, participants with ASD accepted unfair offers more frequently than TD. These results suggest that assessing the automatic/attention processing level with the IAT could be a useful approach to study behavioural flexibility among ASD compared with the UG, which might comprise multiple response strategies besides economic rationality. Overall, the severity of inflexible daily behaviours in people with ASD may be associated with a reduced flexible attitude at an automatic level, altered attention processing and decreased cognitive control.

成人期の自閉症スペクトラム(ASD)を対象に、WAIS-IIIでは十分に測ることができない文法、文章読解などのコミュニケーションの基礎となる日本語能力の特徴について検討した。対象者は61名(男性46名、女性15名、平均年齢28.0歳)であった。このうち、臨床群は昭和大学附属烏山病院のASD患者30名(男性24名、女性6名、平均年齢29.8歳)であった。日本語能力試験(JLPT)および日本語検定を用いて調査を実施した。定型発達群、ASD群、両群においてJLPTおよび日本語検定の正答率に有意差があった。ASD群では日本語検定のJ-scoreおよび1つの下位項目の正答率とAQに相関があることが明らかになったが、定型発達群では示されなかった。ASDでは言語理解、特に視覚分析に関する能力が優れており、視覚情報や分析能力を取り入れた言語を用いた方法を取り入れたり、緻密で正確な作業能力を要する就労につながるなど、能力を活かした支援が必要と考えられた。

The cognitive profile differences between adult patients with autism spectrum disorder (ASD) and those with attention-deficit/hyperactivity disorder (ADHD) are not well characterized. We examined the cognitive profiles of adults having either ASD (n = 120) or ADHD (n = 76) with no intellectual disabilities (IQ >= 70) using the Wechsler Intelligence Scale III (WAIS-III). Verbal Intelligence (VIQ) - Performance Intelligence (PIQ) difference discrepancies were detected between the two groups. Information subtest scores of the Verbal Comprehension index and Arithmetic and Digit Span subtests of the Freedom from Distractibility index were significantly higher in ASD than in ADHD, while the Picture Completion subtest was significantly lower in ASD. To our knowledge, this is the first study to evaluate the difference in the cognitive profiles of adults with ASD and those with ADHD based on the WAIS III with a large number of participants. (c) 2016 Elsevier Ltd. All rights reserved.

Background: The insular cortex comprises multiple functionally differentiated sub-regions, each of which has different patterns of connectivity with other brain regions. Such diverse connectivity patterns are thought to underlie a wide range of insular functions, including cognitive, affective, and sensorimotor processing, many of which are abnormal in autism spectrum disorder (ASD). Although past neuroimaging studies of ASD have shown structural and functional abnormalities in the insula, possible alterations in the sub-regional organization of the insula and the functional characteristics of each sub-region have not been examined in the ASD brain. Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 36 adult males with ASD and 38 matched typically developed (TD) controls. A data-driven clustering analysis was applied to rs-fMRI data of voxels in the left and right insula to automatically group voxels with similar intrinsic connectivity pattern into a cluster. After determining the optimal number of clusters based on information theoretic measures of variation of information and mutual information, functional parcellation patterns in both the left and the right insula were compared between the TD and ASD groups. Furthermore, functional profiles of each sub-region were meta-analytically decoded using Neurosynth and were compared between the groups. Results: We observed notable alterations in the anterior sector of the left insula and the middle ventral sub-region of the right insula in the ASD brain. Meta-analytic decoding revealed that whereas the anterior sector of the left insula contained two functionally differentiated sub-regions for cognitive, sensorimotor, and emotional/affective functions in TD brain, only a single functional cluster for cognitive and sensorimotor functions was identified in the anterior sector in the ASD brain. In the right insula, the middle ventral sub-region, which is primarily specialized for sensory-and auditory-related functions, showed a significant volumetric increase in the ASD brain compared with the TD brain. Conclusions: The results indicate an altered organization of sub-regions in specific parts of the left and right insula of the ASD brain. The alterations in the left and right insula may constitute neural substrates underlying abnormalities in emotional/affective and sensory functions in ASD.

We examined the factors that influence ocular fixation control in adults with autism spectrum disorder (ASD) including sensory information, individuals' motor characteristics, and inhibitory control. The ASD group showed difficulty in maintaining fixation especially when there was no fixation target. The fixational eye movement characteristics of individuals were consistent regardless of the presence or absence of a fixation target in the controls, but not in the ASD group. Additionally, fixation stability did not correlate with an ability to suppress reflexive saccades measured by an antisaccade task. These findings suggest that ASD adults have deficits in converting alternative sensory information, such as retinal signals in the peripheral visual field or extraretinal signals, to motor commands when the foveal information is unavailable.

Background: Previous autism research has hypothesized that abnormalities of functional connectivity in autism spectrum disorder (ASD) may vary with the spatial distance between two brain regions. Although several resting-state functional magnetic resonance imaging (rsfMRI) studies have extensively examined long-range (or distant) connectivity in the adult ASD brain, short-range (or local) connectivity has been investigated in less depth. Furthermore, the possible relationship between functional connectivity and brain activity level during the resting state remains unclear. Methods: We acquired rsfMRI data from 50 adults with high-functioning ASD and 50 matched controls to examine the properties of spontaneous brain activity using measures of local and distant connectivity together with a measure of the amplitude of brain activity, known as fractional amplitude of low-frequency fluctuation (fALFF). The two connectivity measures were calculated using a common graph-theoretic framework. We also examined the spatial overlaps between these measures and possible relationships of these disrupted functional measures with autistic traits assessed by the Autism-Spectrum Quotient (AQ). Results: Compared to the controls, participants with ASD exhibited local over-connectivity in the right superior frontal gyrus and middle frontal gyrus, accompanied by local under-connectivity in the bilateral fusiform gyri (FG) and right middle temporal gyrus (MTG). On the other hand, we did not find any significant alterations in distant connectivity. Participants with ASD also exhibited reduced fALFF in the right middle occipital gyrus, lingual gyrus, and FG. Further conjunction and spatial overlap analyses confirmed that the spatial pattern of reduced fALFF substantially overlapped with that of local under-connectivity, demonstrating the co-occurrence of disrupted connectivity and spontaneous activity level in the right inferior occipital gyrus, posterior MTG (pMTG), and FG. Finally, within the ASD group, disrupted local connectivity in the right pMTG significantly correlated with the "social interaction" subscale score of the AQ. Conclusions: These findings revealed local functional disruptions in the occipital and temporal regions, especially the right FG and pMTG, in the form of co-occurrence of spontaneous brain activity level and local connectivity, which may underline social and communicative dysfunctions in adult ASD.

Individuals with autism spectrum disorders (ASD) often have sensory processing abnormalities. However, limited measures that assess these problems in adults with ASD have been developed till date, particularly in Japan. Robertson and Simmons (2012) developed a self-rating scale to investigate sensory sensitivity: the Glasgow Sensory Questionnaire (GSQ). In the present study, we developed a Japanese version of GSQ and investigated sensory abnormalities in adults with ASD. We compared results of the Japanese version of GSQ in adults between an ASD group (n = 64) and a control group (n = 70). In addition, we also administered these individuals with the autism spectrum quotient (AQ), which is a questionnaire for assessing autistic traits. The Japanese version of GSQ scores was significantly higher in the ASD group than that in the control group. The total GSQ score and each sensory subscale showed a positive correlation with AQ in the total study sample. These results indicate that individuals with pronounced autistic traits have more frequent and extreme sensory processing problems compared with that in individuals with less pronounced autistic traits. We also assessed validity of the new test. Cronbach's alpha of the questionnaire was calculated, and its high value indicates that the Japanese version of GSQ has high reliability. (C) 2014 Elsevier Ltd. All rights reserved.

Background: Many individuals with autism spectrum disorders (ASD) have difficulty with verbal communication, which might be due to a lack of spontaneous orientation toward social auditory stimuli. Previous studies have shown that a single dose of oxytocin improves speech comprehension in autism. The primary aim of this study was to investigate whether the orientation behaviors toward human sounds are different for neurotypical (NT) adults and adults with ASD and whether oxytocin has an effect on their orientation behaviors toward human sounds. Methods: This was a randomized, placebo-controlled, within-subject, crossover design study of intranasal oxytocin versus placebo in 13 NT adults and 16 adults with ASD. Subjects were randomized to 24 IU intranasal oxytocin or placebo on different days, and they were blind to the treatment. The participants then listened passively to human and non-human affective sounds while their skin conductance responses (SCRs) and the changes in peripheral blood vessel constriction were monitored as an indicator of spontaneous orientation. The monitored data were analyzed by a mixed-design ANOVA. Results: Oxytocin enhanced the difference between the SCRs to human and non-human sounds in both the NT and ASD groups (F(1,56) = 6.046, p = 0.017). Further correlation coefficient analysis showed significant correlations between this SCR difference and the scores in the autism spectrum quotient 'attention to detail' and 'social skill' subscales and interpersonal reactivity index and social functioning scale in the ASD group. Oxytocin was well tolerated, and no serious adverse effects were reported. Conclusions: The difference in SCRs implies that oxytocin nasal spray may enhance orientation behaviors toward human sounds in the presence of other environmental sounds in both ASD and NT adults.

In the present study, we investigated auditory event-related potentials in adults with Asperger disorder and normal controls using an auditory oddball task and a novelty oddball task. Task performance and the latencies of P300 evoked by both target and novel stimuli in the two tasks did not differ between the two groups. Analysis of variance revealed that there was a significant interaction effect between group and electrode site on the mean amplitude of the P300 evoked by novel stimuli, which indicated that there was an altered distribution of the P300 in persons with Asperger disorder. In contrast, there was no significant interaction effect on the mean P300 amplitude elicited by target stimuli. Considering that P300 comprises two main subcomponents, frontal-central-dominant P3a and parietal-dominant P3b, our results suggested that persons with Asperger disorder have enhanced amplitude of P3a, which indicated activated prefrontal function in this task.

Background: In spite of the relatively high prevalence of pervasive development disorders (PDD), the medical and educational services for persons with PDD are insufficient in Japan. The present study investigated the clinical and psychosocial characteristics of adults with PDD in Japan. Methods: We selected 111 individuals with PDD out of the 257 subjects attending an outpatient clinic for adult PDD at Showa University Karasuyama Hospital, between the period of July 2008 and June of 2009. Sociodemographic factors, psychosocial characteristics, and medication status of the subjects were investigated. Results: The mean age of subjects at the initial visit to a medical organization was 21.4 years however, only 34.2 % were diagnosed as having PDD. These results indicated that persons with PDD are apt to be misdiagnosed. Most of the persons with PDD were unmarried, and lived with their parents. This may be partly due to economic reasons, because the unemployment rate was high in this group. More than 45 % of the subjects with PDD were taking psychoactive medications, which indicated that they carried a high-risk for co-existing mental health problems. Conclusions: The results of the present study indicated that many persons with PDD are socially isolated, in spite of their relatively high level of education, and that these individuals require additional medical and educational services. © 2013, Walter de Gruyter, Berlin/Boston.

Individuals with autism spectrum condition (ASC) are known to excel in some perceptual cognitive tasks, but such developed functions have been often regarded as "islets of abilities" that do not significantly contribute to broader intellectual capacities. However, recent behavioral studies have reported that individuals with ASC have advantages for performing Raven's (Standard) Progressive Matrices (RPM/RSPM), a standard neuropsychological test for general fluid intelligence, raising the possibility that ASC's cognitive strength can be utilized for more general purposes like novel problem solving. Here, the brain activity of 25 adults with high-functioning ASC and 26 matched normal controls (NC) was measured using functional magnetic resonance imaging (fMRI) to examine neural substrates of geometric reasoning during the engagement of a modified version of the RSPM test. Among the frontal and parietal brain regions involved in fluid intelligence, ASC showed larger activation in the left lateral occipitotemporal cortex (LOTC) during an analytic condition with moderate difficulty than NC. Activation in the left LOTC and ventrolateral prefrontal cortex (VLPFC) increased with task difficulty in NC, whereas such modulation of activity was absent in ASC. Furthermore, functional connectivity analysis revealed a significant reduction of activation coupling between the left inferior parietal cortex and the right anterior prefrontal cortex during both figural and analytic conditions in ASC. These results indicate altered pattern of functional specialization and integration in the neural system for geometric reasoning in ASC, which may explain its atypical cognitive pattern, including performance on the Raven's Matrices test.