Yoko Kamio

Altered white matter fractional anisotropy and social impairment in children with autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) have severe difficulties in social interaction and communication, as well as restricted and/or stereotyped patterns of behavior. Previous studies have suggested that abnormal neural connectivity might be associated with higher information processing dysfunction involving social impairment. However, the white matter structure in ASD is poorly understood. To explore this, we conducted a voxel-based, whole-brain diffusion tensor imaging (DTI) analysis to determine fractional anisotropy (FA), λ(1), λ(2) and λ(3) in high-functioning children with ASD compared with age-, gender-, and handedness-matched healthy control participants. We then investigated whether DTI parameters were associated with behaviorally measured social function. We found that FA and λ(1) were significantly lower in the ASD group than in the control group in the white matter around left dorsolateral prefrontal cortex (DLPFC), posterior superior temporal sulcus/temporo-parietal junction, right temporal pole, amygdala, superior longitudinal fasciculus, occipitofrontal fasciculus, mid- and left anterior corpus callosum, and mid- and right anterior cingulate cortex. The FA value in the left DLPFC was negatively correlated with the degree of social impairment in children with ASD. Higher λ(1) values were observed in the cerebellar vermis lobules in the ASD group. The white matter alterations in children with ASD were around cortical regions that play important roles in social cognition and information integration. These DTI results and their relationship to social impairment add to evidence of cerebral and cerebellar white matter structural abnormalities in ASD.

Paradoxical Autonomic Response to Mental Tasks in Autism

Autonomic responses to mental tasks requiring sustained attention were examined in individuals with autism and age- and ability-matched controls. Cardiac autonomic function (CAF) was evaluated based on heart rate variability. While the control group showed a significant decrease in the parasympathetic function during mental tasks, the autistic group showed no significant changes in CAF. When examined individually, parasympathetic function was suppressed in all subjects in the control group. On the other hand, parasympathetic function was activated in half of the autistic subjects. The paradoxical autonomic response suggests that some autistic subjects were more stressed under ‘resting’ conditions than while performing mechanical or repetitive mental tasks. The results seem to support autonomic hyperarousal in some people with autism.

Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity: A Randomized Trial

IMPORTANCE Sociocommunicational deficits make it difficult for individuals with autism spectrum disorders (ASD) to understand communication content with conflicting verbal and nonverbal information. Despite growing prospects for oxytocin as a therapeutic agent for ASD, no direct neurobiological evidence exists for oxytocins beneficial effects on this core symptom of ASD. This is slowing clinical application of the neuropeptide. OBJECTIVE To directly examine whether oxytocin has beneficial effects on the sociocommunicational deficits of ASD using both behavioral and neural measures. DESIGN, SETTING, AND PARTICIPANTS At the University of Tokyo Hospital, we conducted a randomized, double-blind, placebo-controlled, within-subject-crossover, single-site experimental trial in which intranasal oxytocin and placebo were administered. A total of 40 highly functioning men with ASD participated and were randomized in the trial. INTERVENTIONS Single-dose intranasal administration of oxytocin (24 IU) and placebo. MAIN OUTCOMES AND MEASURES Using functional magnetic resonance imaging, we examined effects of oxytocin on behavioral neural responses of the participants to a social psychological task. In our previous case-control study using the same psychological task, when making decisions about social information with conflicting verbal and nonverbal contents, participants with ASD made judgments based on nonverbal contents less frequently with longer time and could not induce enough activation in the medial prefrontal cortex. Therefore, our main outcomes and measures were the frequency of the nonverbal information-based judgments (NVJs), the response time for NVJs, and brain activity of the medial prefrontal cortex during NVJs. RESULTS Intranasal oxytocin enabled the participants to make NVJs more frequently (P = .03) with shorter response time (P = .02). During the mitigated behavior, oxytocin increased the originally diminished brain activity in the medial prefrontal cortex (P < .001). Moreover, oxytocin enhanced functional coordination in the area (P < .001), and the magnitude of these neural effects was predictive of the behavioral effects (P ≤ .01). CONCLUSIONS AND RELEVANCE These findings provide the first neurobiological evidence for oxytocins beneficial effects on sociocommunicational deficits of ASD and give us the initial account for neurobiological mechanisms underlying any beneficial effects of the neuropeptide. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: UMIN000002241 and UMIN000004393.

Long-Term Memory in High-Functioning Autism: Controversy on Episodic Memory in Autism Reconsidered

Two studies were conducted to examine the nature of verbal long-term memory (LTM) in people with autism. In Study 1, undergraduate students showed better LTM and more verbal associations for concrete than abstract nouns. Probability of recall of the nouns strongly correlated with the number of associations with those nouns. In Study 2, unlike controls, autistic subjects did not show superior recall of concrete over abstract nouns despite overall comparable performance. A highly significant correlation between probability of recall and associative value was found only in the controls. Furthermore, there was an unusual correlation between LTM performance and a nonverbal measure in the autistic group. The results were discussed in terms of the relation between episodic memory and semantic memory.

Normative data and psychometric properties of the strengths and difficulties questionnaire among Japanese school-aged children

BackgroundAlthough child mental health problems are among the most important worldwide issues, development of culturally acceptable mental health services to serve the clinical needs of children and their families is especially lacking in regions outside Europe and North America. The Strengths and Difficulties Questionnaire (SDQ), which was developed in the United Kingdom and is now one of the most widely used measurement tools for screening child psychiatric symptoms, has been translated into Japanese, but culturally calibrated norms for Japanese schoolchildren have yet to be established. To this end, we examined the applicability of the Japanese versions of the parent and teacher SDQs by establishing norms and extending validation of its psychometric properties to a large nationwide sample, as well as to a smaller clinical sample.MethodsThe Japanese versions of the SDQ were completed by parents and teachers of schoolchildren aged 7 to 15 years attending mainstream classes in primary or secondary schools in Japan. Data were analyzed to describe the population distribution and gender/age effects by informant, cut-off scores according to banding, factor structure, cross-scale correlations, and internal consistency for 24,519 parent ratings and 7,977 teacher ratings from a large nationwide sample. Inter-rater and test-retest reliabilities and convergent and divergent validities were confirmed for a smaller validation sample (total n = 128) consisting of a clinical sample with any mental disorder and community children without any diagnoses.ResultsMeans, standard deviations, and banding of normative data for this Japanese child population were obtained. Gender/age effects were significant for both parent and teacher ratings. The original five-factor structure was replicated, and strong cross-scale correlations and internal reliability were shown across all SDQ subscales for this population. Inter-rater agreement was satisfactory, test-retest reliability was excellent, and convergent and divergent validities were satisfactory for the validation sample, with some differences between informants.ConclusionsThis study provides evidence that the Japanese version of the SDQ is a useful instrument for parents and teachers as well as for research purposes. Our findings also emphasize the importance of establishing culturally calibrated norms and boundaries for the instrument’s use.

A nationwide survey on quality of life and associated factors of adults with high-functioning autism spectrum disorders

The psychosocial outcomes of individuals with high-functioning autism spectrum disorder (HFASD) appear to be diverse and are often poor relative to their intellectual or language level. To identify predictive variables that are potentially ameliorable by therapeutic intervention, this study investigated self-reported psychosocial quality of life and associated factors for adults with HFASD. All participants (n = 154) had a diagnosis of autism spectrum disorder, were over 18 years of age, lived in the community, and had used one or more support services during the survey period. The results demonstrated that psychosocial quality of life was lower than that of the general Japanese adult population. Environmental factors, such as mother’s support and early diagnosis, were associated with better quality of life, and aggressive behaviors were associated with poorer quality of life, while expressive language level at preschool years, a conventional outcome predictor, did not predict quality of life. These results emphasize that quality of life measures should be included as outcome indicators in treating individuals with HFASD.

Verbal Association for Simple Common Words in High-Functioning Autism.

We investigated conceptual relationships in semantic memory using an indirect priming technique in high-functioning autistic adolescents and their controls who were matched for age, verbal IQ, performance IQ, and nonverbal reasoning ability. The prime was a single word and the target task was completing a word fragment that was semantically related or unrelated to the prime word. The autistic subjects and controls showed similar semantic priming effects, indicating intact conceptual relationships for simple common words in those with autism. Only in the autistic group was a significant correlation found between performance for the related items and two nonverbal cognitive measures, which suggests a possibility that semantic processing in individuals with autism might be qualitatively different from that in controls.

Autism-Associated Gene Expression in Peripheral Leucocytes Commonly Observed between Subjects with Autism and Healthy Women Having Autistic Children

Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder.

Comprehensive Comparison of Self-administered Questionnaires for Measuring Quantitative Autistic Traits in Adults

We comprehensively compared all available questionnaires for measuring quantitative autistic traits (QATs) in terms of reliability and construct validity in 3,147 non-clinical and 60 clinical subjects with normal intelligence. We examined four full-length forms, the Subthreshold Autism Trait Questionnaire (SATQ), the Broader Autism Phenotype Questionnaire, the Social Responsiveness Scale2-Adult Self report (SRS2-AS), and the Autism-Spectrum Quotient (AQ). The SRS2-AS and the AQ each had several short forms that we also examined, bringing the total to 11 forms. Though all QAT questionnaires showed acceptable levels of test–retest reliability, the AQ and SRS2-AS, including their short forms, exhibited poor internal consistency and discriminant validity, respectively. The SATQ excelled in terms of classical test theory and due to its short length.

Autistic-Like Traits in Adult Patients with Mood Disorders and Schizophrenia

Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic-like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.