Children with autism spectrum disorder show reduced adaptation to number.

Autism is known to be associated with major perceptual atypicalities. We have recently proposed a general model to account for these atypicalities in Bayesian terms, suggesting that autistic individuals underuse predictive information or priors. We tested this idea by measuring adaptation to numerosity stimuli in children diagnosed with autism spectrum disorder (ASD). After exposure to large numbers of items, stimuli with fewer items appear to be less numerous (and vice versa). We found that children with ASD adapted much less to numerosity than typically developing children, although their precision for numerosity discrimination was similar to that of the typical group. This result reinforces recent findings showing reduced adaptation to facial identity in ASD and goes on to show that reduced adaptation is not unique to faces (social stimuli with special significance in autism), but occurs more generally, for both parietal and temporal functions, probably reflecting inefficiencies in the adaptive interpretation of sensory signals. These results provide strong support for the Bayesian theories of autism.

Effects of Improvisational Music Therapy vs Enhanced Standard Care on Symptom Severity Among Children With Autism Spectrum Disorder: The TIME-A Randomized Clinical Trial.

Importance: Music therapy may facilitate skills in areas affected by autism spectrum disorder (ASD), such as social interaction and communication. Objective: To evaluate effects of improvisational music therapy on generalized social communication skills of children with ASD. Design, Setting, and Participants: Assessor-blinded, randomized clinical trial, conducted in 9 countries and enrolling children aged 4 to 7 years with ASD. Children were recruited from November 2011 to November 2015, with follow-up between January 2012 and November 2016. Interventions: Enhanced standard care (n = 182) vs enhanced standard care plus improvisational music therapy (n = 182), allocated in a 1:1 ratio. Enhanced standard care consisted of usual care as locally available plus parent counseling to discuss parents' concerns and provide information about ASD. In improvisational music therapy, trained music therapists sang or played music with each child, attuned and adapted to the child's focus of attention, to help children develop affect sharing and joint attention. Main Outcomes and Measures: The primary outcome was symptom severity over 5 months, based on the Autism Diagnostic Observation Schedule (ADOS), social affect domain (range, 0-27; higher scores indicate greater severity; minimal clinically important difference, 1). Prespecified secondary outcomes included parent-rated social responsiveness. All outcomes were also assessed at 2 and 12 months. Results: Among 364 participants randomized (mean age, 5.4 years; 83% boys), 314 (86%) completed the primary end point and 290 (80%) completed the last end point. Over 5 months, participants assigned to music therapy received a median of 19 music therapy, 3 parent counseling, and 36 other therapy sessions, compared with 3 parent counseling and 45 other therapy sessions for those assigned to enhanced standard care. From baseline to 5 months, mean ADOS social affect scores estimated by linear mixed-effects models decreased from 14.08 to 13.23 in the music therapy group and from 13.49 to 12.58 in the standard care group (mean difference, 0.06 [95% CI, -0.70 to 0.81]; P = .88), with no significant difference in improvement. Of 20 exploratory secondary outcomes, 17 showed no significant difference. Conclusions and Relevance: Among children with autism spectrum disorder, improvisational music therapy, compared with enhanced standard care, resulted in no significant difference in symptom severity based on the ADOS social affect domain over 5 months. These findings do not support the use of improvisational music therapy for symptom reduction in children with autism spectrum disorder. Trial Registration: isrctn.org Identifier: ISRCTN78923965.

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Impact of sleep disorders on behavioral issues in preschoolers with autism spectrum disorder.

Background: Sleep disorders are one of the most common problems in children with Autism Spectrum Disorder (ASD). However, they often tend to be underdiagnosed and incorrectly treated in clinical practice. This study aims to identify sleep disorders in preschool children with ASD and to explore their relationship with the core symptoms of autism, the child's developmental and cognitive level as well as the psychiatric comorbidities. Methods: We recruited 163 preschool children with a diagnosis of ASD. The Children's Sleep Habits Questionnaire (CSHQ) assessed sleep conditions. Multiple standardized tests were used to evaluate intellectual abilities, the presence of repetitive behaviors (through the Repetitive Behavior Scale-Revised), as well as the emotional-behavioral problems and the psychiatric comorbidities (through the Child Behavior Checklist -CBCL 11/2-5). Results: The results showed that poor disorders had consistently higher scores in all areas assessed by the CSHQ and on the CBCL across all domains. The correlational analysis showed that severe sleep disorders were associated with higher scores in internalizing, externalizing, and total problems at the CBCL syndromic scales, and in all DSM-oriented CBCL subscales. Moreover, we found that the association between sleep disorders and restricted and repetitive behaviors (RRBs) is explained by the anxiety-related symptoms. Conclusion: Based on these findings, the study recommends that screening for sleep problems followed by early intervention should constitute a routine part of clinical practice for children with ASD.

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.

Contextual Information Modulates Pupil Size in Autistic Children.

Recent Bayesian models suggest that perception is more "data-driven" and less dependent on contextual information in autistic individuals than others. However, experimental tests of this hypothesis have given mixed results, possibly due to the lack of objectivity of the self-report methods typically employed. Here we introduce an objective no-report paradigm based on pupillometry to assess the processing of contextual information in autistic children, together with a comparison clinical group. After validating in neurotypical adults a child-friendly pupillometric paradigm, in which we embedded test images within an animation movie that participants watched passively, we compared pupillary response to images of the sun and meaningless control images in children with autism vs. age- and IQ-matched children presenting developmental disorders unrelated to the autistic spectrum. Both clinical groups showed stronger pupillary constriction for the sun images compared with control images, like the neurotypical adults. However, there was no detectable difference between autistic children and the comparison group, despite a significant difference in pupillary light responses, which were enhanced in the autistic group. Our report introduces an objective technique for studying perception in clinical samples and children. The lack of statistically significant group differences in our tests suggests that autistic children and the comparison group do not show large differences in perception of these stimuli. This opens the way to further studies testing contextual processing at other levels of perception.

Behavioral and emotional problems of toddlers with autism spectrum disorder: Effects of parents' sociocultural level and individual factors.

BACKGROUND: Toddlers with autism spectrum disorder (ASD) show higher prevalence and severity of Behavioral and Emotional Problems (BEP) than their peers without ASD. AIMS: Investigating the effects of parental factors, i.e., mothers' and fathers' age and Sociocultural Level (Socioeconomic Status, Cultural Capital, and Social Capital), and individual factors, i.e., toddles' age, birth order, general development, autism symptom severity, and adaptive behavior, on the expression of BEP in toddlers with ASD. METHODS: Participants were 148 toddlers with ASD (aged 18-37 months) and both their parents. BEP were measured with the Child Behavior Checklist 1½-5 (CBCL) Syndrome and Pervasive developmental problems (PDD) DSM-oriented scales, general development with the Griffiths Mental Development Scales (GMDS), autism symptom severity with the Autism Diagnostic Observation Schedule-2 (ADOS-2), and adaptive behavior with the Vineland-II Adaptive behavior composite. RESULTS: Vineland-IIAdaptive behavior composite was negatively associated with the majority of the CBCL scales. In contrast, the ADOS-2 Restrictive and repetitive behavior was negatively and the ADOS-2 Social affect, toddlers' age, and birth order were positively associated with only a few of the CBCL scales (e.g., PDD). GMDS scores were not associated with any CBCL scales. Mothers' age and fathers' Cultural Capital and Social Capital dimensions were negatively associated with specific CBCL scales, even when considered in addition to individuals' factors. CONCLUSIONS: Individual and parental factors simultaneously affect the expression of BEP and should be considered for clinical decisions.

Individual and Environmental Factors Affecting Adaptive Behavior of Toddlers with Autism Spectrum Disorder: Role of Parents' Socio-cultural Level.

The effects of environmental factors [including Socio-Economic Status, Cultural Capital, and Social Capital (Socio-Cultural Level) of both parents] on the Vineland-II adaptive behavior dimensions of toddlers with autism spectrum disorder (ASD), in addition to individual factors, was investigated in 148 Italian toddlers (82% males), aged 18 to 37 months with ASD. Toddlers' age and Griffiths Mental Development Scales general development affected all of the adaptive behavior dimensions, with negative and positive associations, respectively. The Child Behavior Checklist comorbid conditions were negatively associated with some adaptive behavior dimensions while the ADOS-2 Social affect only with the communication dimension. Mothers' and fathers' specific Socio-Cultural Level dimensions were positively associated with toddlers' specific adaptive behavior dimensions with the same magnitude as comorbid conditions.

An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex and heterogeneous genetic etiology. While a proportion of ASD risk is attributable to common variants, rare copy-number variants (CNVs) and protein-disrupting single-nucleotide variants (SNVs) have been shown to significantly contribute to ASD etiology. We analyzed a homogeneous cohort of 127 ASD Italian families genotyped with the Illumina PsychArray, to perform an integrated analysis of CNVs and SNVs and to assess their contribution to ASD risk. We observed a higher burden of rare CNVs, especially deletions, in ASD individuals versus unaffected controls. Furthermore, we identified a significant enrichment of rare CNVs intersecting ASD candidate genes reported in the SFARI database. Family-based analysis of rare SNVs genotyped by the PsychArray also indicated an increased transmission of rare SNV variants from heterozygous parents to probands, supporting a multigenic model of ASD risk with significant contributions of both variant types. Moreover, our study reinforced the evidence for a significant role of VPS13B, WWOX, CNTNAP2, RBFOX1, MACROD2, APBA2, PARK2, GPHN, and RNF113A genes in ASD susceptibility. Finally, we showed that the PsychArray, besides providing useful genotyping data in psychiatric disorders, is a valuable and cost-efficient tool for genic CNV detection, down to 10 kb.

Sex Differences in Autism Spectrum Disorder: An Investigation on Core Symptoms and Psychiatric Comorbidity in Preschoolers.

Findings regarding sex differences in autism spectrum disorder (ASD), as far as core symptoms and psychiatric comorbidities (PC) are concerned, are inconsistent, inconclusive, or conflicting among studies. The lower prevalence of ASD in females than in males and the age and intelligence quotient (IQ) heterogeneity among samples made it difficult to investigate these differences. This case-control study tries to deepen the impact of sex differences on core symptoms of autism and PC in 214 preschoolers with ASD (mean age, 45.26) without impairment in non-verbal IQ (nvIQ ≥70). A total of 107 ASD females (mean age, 44.51 ± 13.79 months) were matched one by one with 107 males (mean age, 46.01 ± 13.42 months) for chronological age (±6 months) and nvIQ (±6 points). We used the Autism Diagnostic Observation Schedule 2 (ADOS-2) and the Child Behavior Checklist (CBCL) 1.5-5 to explore autism severity and PC. The results highlight that ASD females did not significantly differ from ASD males regarding the severity of autism. Statistically significant lower levels of emotionally reactive (p = 0.005, η2 = 0.04), anxious-depressed (p = 0.001, η 2 = 0.05), internalizing problems (p = 0.04, η 2 = 0.02), and DSM-Oriented Scales anxiety problems (p = 0.02, η 2 = 0.04) in ASD females than in ASD males were also detected. Our findings of no difference in the autism severity and lower internalizing problems in females than males with ASD extend the knowledge of autism in females during preschool years. Compared to other similar studies on this topic, we can state that these results are not supported by differences in nvIQ between sexes nor by the presence of cognitive impairment. It confirms the need for clinicians to consider sex differences when describing autism psychopathology.

Further characterization of the new microdeletion syndrome of 16p11.2-p12.2.

Using aCGH, we have identified a pericentromeric deletion, spanning about 8.2 Mb, within 16p11.2-p12.2 in a patient with developmental delay (DD) and dysmorphic features. This deletion arose de novo and is flanked by segmental duplications. The proposita was the only child of healthy nonconsanguineous parents, born after an uneventful pregnancy, at 40 weeks gestation, by normal delivery. She was referred to us at age 3 10/12 years for evaluation of DD and absent speech. On examination, there were a flat face; low-set, posteriorly rotated ears; high-arched palate; hypotonic face; right single palmar crease; long, thin fingers; and a sacral dimple. Her height was at the 50th centile, weight at the 25th, and OFC at the 30th. Results of DNA FraX, HRB chromosomes, metabolic work-up, audiologic evaluation, brain MRI, electroencephalogram, and heart/abdomen ultrasonography were normal. When last seen, aged 8 years, she had a moderate intellectual disability (ID) and poor speech. She was hyperactive with short attention span and difficulty in concentration, but, based on formal testing, did not have autism. Our patient shows common clinical features to the four individuals described by Ballif et al. [Ballif et al. (2007); Nat Genet 39:1071-1073], and further characterizes the new microdeletion syndrome of 16p11.2-p12.2. aCGH suggests that the deletions of all cases share the same distal breakpoint. Of note, the proximal breakpoint of our proposita overlaps the distal breakpoint of the autistic patients studied by Kumar et al. [Kumar et al. (2008); Hum Mol Genet 17:628-638] and Weiss et al. [Weiss et al. (2008); N Eng J Med 358:667-675], confirming that the 16p region carrying susceptibility to autism is more centromeric. Our observation further defines two different, contiguous 16p genomic regions, responsible for a distinct MCA/ID syndrome, and for autism, respectively.

Construction of Past and Future Events in Children and Adolescents with ASD: Role of Self-relatedness and Relevance to Decision-Making.

We studied episodic memory and future thinking for self-relevant and other-relevant events at different levels of retrieval support, theory of mind, and delay discounting in ASD children and adolescents (ASDs). Compared to typically developing controls, ASDs produced fewer internal (episodic) but a similar number of external (semantic) details while remembering past events, imagining future events, and imagining future events happening to others, indicating a general impairment of event construction. This deficit was driven by group differences under high retrieval support, and therefore unlikely to depend on self-initiated retrieval/construction deficits. ASDs' event construction impairment related to the severity of ASD symptoms, and to theory of mind deficits. ASDs, however, showed normal delay discounting, highlighting preserved forms of future-based decision-making in ASD.

Olfactory Processing in Male Children with Autism: Atypical Odor Threshold and Identification.

Sensory issues are of great interest in ASD diagnosis. However, their investigation is mainly based on external observation (parent reports), with methodological limitations. Unobtrusive olfactory assessment allows studying autism neurosensoriality. Here, 20 male children with high-functioning ASD and 20 matched controls were administered a complete olfactory test battery, assessing olfactory threshold, identification and discrimination. ASD children show lower sensitivity (p = 0.041), lower identification (p = 0.014), and intact odor discrimination (p = 0.199) than controls. Comparing olfactory and clinical scores, a significant correlation was found in ASD between olfactory threshold and the CBCL social problems (p = 0.011) and aggressive behavior (p = 0.012) sub-scales. The pattern featuring peripheral hyposensitivity, high-order difficulties in odor identification and regular subcortical odor discrimination is discussed in light of hypo-priors hypothesis for autism.

Behavioral Phenotype of ASD Preschoolers with Gastrointestinal Symptoms or Food Selectivity.

This study investigated the prevalence and type of gastrointestinal (GI) and food selectivity (FS) symptoms in 163 preschoolers with ASD, and their possible links with core ASD features and emotional/behavioural problems. 40.5% of children with ASD had at least one severe GI symptom or FS. Preschoolers with and without GI symptoms and with and without FS were significantly different on several emotional/behavioural problems and restrictive/repetitive behaviours, whereas they did not differ significantly on performance IQ and autistic severity. The GI plus FS group presented with Sleep Problems, Self-injurious Behaviors and Anxiety Problems. Results indicated the need for early identification of GI disturbances and FS in order to design tailored intervention for these symptoms frequently associated to challenging behaviours in ASD.

Spatial and motion integration in children with autism.

Neuropsychological and psychophysical studies report controversial results regarding local-global visual processing and motion perception in autism. Here, we investigate contour integration and motion perception in an accurately diagnosed sample of autistic children, using low-level psychophysical tasks. We measured detection thresholds for a closed chain of Gabor patches, for different values of inter-element distance and we measured coherency thresholds of optic flow motion stimuli. Both experiments show comparable performances between autistics and normal subjects, demonstrating no evidence of early perceptual integration deficits. Some improvement in performance with age is detected in both groups.

Application of the Repetitive Behavior Scale-Revised--Italian version--in preschoolers with autism spectrum disorder.

Restricted repetitive and stereotyped patterns of behavior, interests, and activities (RRB) are mandatory features for a diagnosis of Autism Spectrum Disorder (ASD) according to the Diagnostic and Statistical Manual of mental disorders-fifth edition (DSM-5). Despite the strong diagnostic role of RRB, their expressiveness and their relationship with other clinical/demographic features in ASD is not fully elucidated. The Italian version of the Repetitive Behavior Scale-Revised (RBS-R) was applied to a relatively large sample of preschool-aged children with ASD who underwent a comprehensive clinical assessment. The relationship between RRB and sex, age, non-verbal IQ, autism severity, as well as the diagnostic accuracy of the RBS-R were explored. Stereotyped and Ritualistic/Sameness behaviors were the most common RRB in preschoolers with ASD, without widespread differences between males and females. No significant correlations between RRB and chronological age, or non-verbal IQ were detected. The expressiveness of ritualistic/sameness behaviors positively correlated with autism severity, assessed through the Calibrated Severity Score (CSS) derived from the Autism Diagnostic Observation Schedule (ADOS). Receiver Operator Characteristic (ROC) analysis showed high diagnostic accuracy using the Global Rating Score, which represents the judgment of the parents of as the RRB affect the child's life. However, while the Global Rating Score performed well, the remaining subscales did not. This investigation extends the limited research on early pattern and associated features of RRB in young children with ASD. The use of the RBS-R may increase the knowledge of the RRB complexity and variability and in turn improve the diagnostic and therapeutic procedures within the autistic spectrum.

An android for enhancing social skills and emotion recognition in people with autism.

It is well documented that the processing of social and emotional information is impaired in people with autism. Recent studies have shown that individuals, particularly those with high functioning autism, can learn to cope with common social situations if they are made to enact possible scenarios they may encounter in real life during therapy. The main aim of this work is to describe an interactive life-like facial display (FACE) and a supporting therapeutic protocol that will enable us to verify if the system can help children with autism to learn, identify, interpret, and use emotional information and extend these skills in a socially appropriate, flexible, and adaptive context. The therapeutic setup consists of a specially equipped room in which the subject, under the supervision of a therapist, can interact with FACE. The android display and associated control system has automatic facial tracking, expression recognition, and eye tracking. The treatment scheme is based on a series of therapist-guided sessions in which a patient communicates with FACE through an interactive console. Preliminary data regarding the exposure to FACE of two children are reported.

Development and evaluation of a social robot platform for therapy in autism.

People with ASD (Autism Spectrum Disorders) have difficulty in managing interpersonal relationships and common life social situations. A modular platform for Human Robot Interaction and Human Machine Interaction studies has been developed to manage and analyze therapeutic sessions in which subjects are driven by a psychologist through simulated social scenarios. This innovative therapeutic approach uses a humanoid robot called FACE capable of expressing and conveying emotions and empathy. Using FACE as a social interlocutor the psychologist can emulate real life scenarios where the emotional state of the interlocutor is adaptively adjusted through a semi closed loop control algorithm which uses the ASD subject's inferred "affective" state as input. Preliminary results demonstrate that the platform is well accepted by ASDs and can be consequently used as novel therapy for social skills training.

Neural correlates of texture and contour integration in children with autism spectrum disorders.

In this study, we have used an electrophysiological paradigm to investigate the neural correlates of the visual integration of local signals across space to generate global percepts in a group of low functioning autistic kids. We have analyzed the amplitude of key harmonics of the Visual Evoked Potentials (VEPs) recorded while participants observed orientation-based texture and contour stimuli, forming coherent global patterns, alternating with visual patterns in which the same number of local elements were randomly oriented in order to loose any globally organized feature. Comparing the results of the clinical sample with those obtained in an age-matched control group, we have observed that in the texture conditions the 1st and 3rd harmonics, containing signature of global form processing (Norcia, Pei, Bonneh, Hou, Sampath, & Pettet, 2005), were present in the control group, while in the experimental group only the 1st harmonic was present. In the Contour condition the 1st harmonic was not present for both groups while the 3rd harmonic was significantly present in the control group but absent in the group with autism. Moreover, the amount of organization required to elicit significant 1st harmonic response in the texture condition was higher in the clinical group. The present results bring additional support to the idea that texture and contour processing are supported by independent mechanisms in normal vision. Autistic vision would thus be characterized by a preserved, perhaps weaker texture mechanism, possibly mediated by feedback interactions between visual areas, and by a disfunction of the mechanism supporting contour processing, possibly mediated by long-range intra-cortical connections. Within this framework, the residual ability to detect contours shown in psychophysical studies could be due to the contribution of the texture mechanism to contour processing.