Auditory Processing in High-Functioning Adolescents with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder including abnormalities in perceptual processing. We measure perception in a battery of tests across speech (filtering, phoneme categorization, multisensory integration) and music (pitch memory, meter categorization, harmonic priming). We found that compared to controls, the ASD group showed poorer filtering, less audio-visual integration, less specialization for native phonemic and metrical categories, and a higher instance of absolute pitch. No group differences were found in harmonic priming. Our results are discussed in a developmental framework where culture-specific knowledge acquired early compared to late in development is most impaired, perhaps because of early-accelerated brain growth in ASD. These results suggest that early auditory remediation is needed for good communication and social functioning.     

Testing Sensory and Multisensory Function in Children with Autism Spectrum Disorder

In addition to impairments in social communication and the presence of restricted interests and repetitive behaviors, deficits in sensory processing are now recognized as a core symptom in autism spectrum disorder (ASD). Our ability to perceive and interact with the external world is rooted in sensory processing. For example, listening to a conversation entails processing the auditory cues coming from the speaker (speech content, prosody, syntax) as well as the associated visual information (facial expressions, gestures). Collectively, the “integration” of these multisensory (i.e., combined audiovisual) pieces of information results in better comprehension. Such multisensory integration has been shown to be strongly dependent upon the temporal relationship of the paired stimuli. Thus, stimuli that occur in close temporal proximity are highly likely to result in behavioral and perceptual benefits – gains believed to be reflective of the perceptual system''s judgment of the likelihood that these two stimuli came from the same source. Changes in this temporal integration are expected to strongly alter perceptual processes, and are likely to diminish the ability to accurately perceive and interact with our world. Here, a battery of tasks designed to characterize various aspects of sensory and multisensory temporal processing in children with ASD is described. In addition to its utility in autism, this battery has great potential for characterizing changes in sensory function in other clinical populations, as well as being used to examine changes in these processes across the lifespan.     

Clinical Characteristics of Children with Autism Spectrum Disorder and Co-Occurring Epilepsy

Objectives

To estimate the prevalence of epilepsy in children with Autism Spectrum Disorder (ASD) and to determine the demographic and clinical characteristics of children with ASD and epilepsy in a large patient population.

Methods

Cross-sectional study using four samples of children with ASD for a total of 5,815 participants with ASD. The prevalence of epilepsy was estimated from a population-based sample. Children with and without epilepsy were compared on demographic and clinical characteristics. Multivariate logistic regression was used to examine the association between demographic and clinical characteristics and epilepsy.

Results

The average prevalence of epilepsy in children with ASD 2–17 years was 12.5%; among children aged 13 years and older, 26% had epilepsy. Epilepsy was associated with older age, lower cognitive ability, poorer adaptive and language functioning, a history of developmental regression and more severe ASD symptoms. The association between epilepsy and the majority of these characteristics appears to be driven by the lower IQ of participants with epilepsy. In a multivariate regression model, only age and cognitive ability were independently associated with epilepsy. Children age 10 or older had 2.35 times the odds of being diagnosed with epilepsy (p<.001) and for a one standard deviation increase in IQ, the odds of having epilepsy decreased by 47% (p<.001).

Conclusion

This is among the largest studies to date of patients with ASD and co-occurring epilepsy. Based on a representative sample of children with ASD, the average prevalence of epilepsy is approximately 12% and reaches 26% by adolescence. Independent associations were found between epilepsy and older age and lower cognitive ability. Other risk factors, such as poor language and developmental regression, are not associated with epilepsy after controlling for IQ. These findings can help guide prognosis and alert clinicians to patients with ASD who are at increased risk for epilepsy.     

Abnormal Pre-Attentive Arousal in Young Children with Autism Spectrum Disorder Contributes to Their Atypical Auditory Behavior: An ERP Study

Auditory sensory modulation difficulties and problems with automatic re-orienting to sound are well documented in autism spectrum disorders (ASD). Abnormal preattentive arousal processes may contribute to these deficits. In this study, we investigated components of the cortical auditory evoked potential (CAEP) reflecting preattentive arousal in children with ASD and typically developing (TD) children aged 3-8 years. Pairs of clicks (‘S1’ and ‘S2’) separated by a 1 sec S1-S2 interstimulus interval (ISI) and much longer (8-10 sec) S1-S1 ISIs were presented monaurally to either the left or right ear. In TD children, the P50, P100 and N1c CAEP components were strongly influenced by temporal novelty of clicks and were much greater in response to the S1 than the S2 click. Irrespective of the stimulation side, the ‘tangential’ P100 component was rightward lateralized in TD children, whereas the ‘radial’ N1c component had higher amplitude contralaterally to the stimulated ear. Compared to the TD children, children with ASD demonstrated 1) reduced amplitude of the P100 component under the condition of temporal novelty (S1) and 2) an attenuated P100 repetition suppression effect. The abnormalities were lateralized and depended on the presentation side. They were evident in the case of the left but not the right ear stimulation. The P100 abnormalities in ASD correlated with the degree of developmental delay and with the severity of auditory sensory modulation difficulties observed in early life. The results suggest that some rightward-lateralized brain networks that are crucially important for arousal and attention re-orienting are compromised in children with ASD and that this deficit contributes to sensory modulation difficulties and possibly even other behavioral deficits in ASD.     

SHANK1 Deletions in Males with Autism Spectrum Disorder

Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.     

Reduced Personal Space in Individuals with Autism Spectrum Disorder

Maintaining an appropriate distance from others is important for establishing effective communication and good interpersonal relations. Autism spectrum disorder (ASD) is a developmental disorder associated with social difficulties, and it is thus worth examining whether individuals with ASD maintain typical or atypical degrees of social distance. Any atypicality of social distancing may impact daily social interactions. We measured the preferred distances when individuals with ASD and typically developing (TD) individuals approached other people (a male experimenter) and objects (a coat rack with clothes) or when other people approached them. Individuals with ASD showed reduced interpersonal distances compared to TD individuals. The same tendency was found when participants judged their preferred distance from objects. In addition, when being approached by other people, both individuals with ASD and TD individuals maintained larger interpersonal distances when there was eye contact, compared to no eye contact. These results suggest that individuals with ASD have a relatively small personal space, and that this atypicality exists not only for persons but also for objects.     

Progressively Increased M50 Responses to Repeated Sounds in Autism Spectrum Disorder with Auditory Hypersensitivity: A Magnetoencephalographic Study

The aim of this study was to investigate the differential time-course responses of the auditory cortex to repeated auditory stimuli in children with autism spectrum disorder (ASD) showing auditory hypersensitivity. Auditory-evoked field values were obtained from 21 boys with ASD (12 with and 9 without auditory hypersensitivity) and 15 age-matched typically developing controls. M50 dipole moments were significantly increased during the time-course study only in the ASD with auditory hypersensitivity compared with those for the other two groups. The boys having ASD with auditory hypersensitivity also showed more prolonged response duration than those in the other two groups. The response duration was significantly related to the severity of auditory hypersensitivity. We propose that auditory hypersensitivity is associated with decreased inhibitory processing, possibly resulting from an abnormal sensory gating system or dysfunction of inhibitory interneurons.     

Prospective,Blinded Exploratory Evaluation of the PlayWisely Program in Children with Autism Spectrum Disorder

The purpose of the study was to explore a low-cost intervention that targets an increasingly common developmental disorder. The study was a blinded, exploratory evaluation of the PlayWisely program on autism symptoms and essential learning foundation skills (attention, recognition, and memory skills) in children with a diagnosis of autism, autism spectrum disorder (ASD), pervasive developmental disorder – not otherwise specified (PDD-NOS), and Asperger syndrome (AS). Eighteen children, 1 to 10 years of age, were evaluated using the Childhood Autism Rating Scale, Second Edition (CARS2); the PlayWisely Interactive Test of Attention, Recognition, and Memory Skills; Autism Treatment Evaluation Checklist (ATEC), and the Modified Checklist for Autism in Toddlers (M-CHAT). There were significant treatment effects for the PlayWisely measure on the Yellow Sets that examine recognition; Purple Sets that examine brain region agility and early memory skills; Blue Sets that examine phonemic awareness and recognition; and for the Total Sets, with a similar trend toward improvement in the Green Sets that examine perception and Red Sets that examine attention. No other measures reached statistical significance. The results suggest that PlayWisely can improve recognition, brain region agility, phonemic awareness, letter recognition, and early memory skills in ASD. It was observed by the parents, coaches, and study investigators that the children who were less than 3 years of age showed improvements in autism symptoms; however, the group was too small to reach statistical significance. Future studies are needed to see if this intervention can mitigate autism symptoms in very young children with ASD.     

Quality of Life of Taiwanese Adults with Autism Spectrum Disorder

Background

To date, few recent studies have investigated the quality of life of adults with autism spectrum disorder (ASD). It remains unclear how individuals with ASD view their own quality of life.

Objective

The primary purpose of this study was to compare the quality of life scores among adults with ASD with those of a non-ASD control group and the Taiwanese health population reference group.

Methods

The study comprised 41 adults with ASD (M age = 26.9, SD = 5.0), and without intellectual disabilities (IQ>70). A comparison sample of 41 adults without ASD was selected by matching the age and sex of the participants with ASD. A validated measure, the Taiwanese version of the World Health Organization Quality of Life-BREF (WHOQOL-BREF), was used. Independent t-tests were performed to examine the differences in the quality of life between groups.

Results

The highest quality of life was scored in the environment domain, followed by the physical health and psychological health domains. The lowest quality of life score was found in the social relationship domain. Adults with ASD scored significantly lower in all domains than did the non-ASD control group. Additionally, adults with ASD scored significantly lower in the physical health, psychological health, and social relationship domains than did the Taiwanese health population reference group. Comorbid psychiatric disorders, self-rated health status, and perceived happiness were correlated with quality of life among adults with ASD.

Conclusion

The preliminary findings suggest that adults with ASD need more supportive social contexts and interventions to promote their quality of life. Based on our findings, social relationship must be considered in designing and applying treatment programs for adults with ASD.     

Violations of Personal Space by Individuals with Autism Spectrum Disorder

The ability to maintain an appropriate physical distance (i.e., interpersonal distance) from others is a critical aspect of social interaction and contributes importantly to real-life social functioning. In Study 1, using parent-report data that had been acquired on a large number of individuals (ages 4–18 years) for the Autism Genetic Resource Exchange and the Simons Simplex Collection, we found that those with Autism Spectrum Disorder (ASD; n = 766) more often violated the space of others compared to their unaffected siblings (n = 766). This abnormality held equally across ASD diagnostic categories, and correlated with clinical measures of communication and social functioning. In Study 2, laboratory experiments in a sample of high-functioning adults with ASD demonstrated an altered relationship between interpersonal distance and personal space, and documented a complete absence of personal space in 3 individuals with ASD. Furthermore, anecdotal self-report from several participants confirmed that violations of social distancing conventions continue to occur in real-world interactions through adulthood. We suggest that atypical social distancing behavior offers a practical and sensitive measure of social dysfunction in ASD, and one whose psychological and neurological substrates should be further investigated.     

Impaired Perception of Facial Motion in Autism Spectrum Disorder

Facial motion is a special type of biological motion that transmits cues for socio-emotional communication and enables the discrimination of properties such as gender and identity. We used animated average faces to examine the ability of adults with autism spectrum disorders (ASD) to perceive facial motion. Participants completed increasingly difficult tasks involving the discrimination of (1) sequences of facial motion, (2) the identity of individuals based on their facial motion and (3) the gender of individuals. Stimuli were presented in both upright and upside-down orientations to test for the difference in inversion effects often found when comparing ASD with controls in face perception. The ASD group’s performance was impaired relative to the control group in all three tasks and unlike the control group, the individuals with ASD failed to show an inversion effect. These results point to a deficit in facial biological motion processing in people with autism, which we suggest is linked to deficits in lower level motion processing we have previously reported.     

Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress. The inhibition of neurite outgrowth and expression of synaptic factors are observed in ASD. Similarly, ER stress suppresses the neurite outgrowth and expression of synaptic factors. Additionally, hyperplasia of the brain is observed in patients with ASD. ER stress also enhances neuronal differentiation. Synaptic factors, such as cell adhesion molecule and shank, play important roles in the formation of neural circuits. Thus, ER stress is associated with the abnormalities of neuronal differentiation, neurite outgrowth, and synaptic protein expression. ER stress elevates the expression of the ubiquitin-protein ligase HRD1 for the degradation of unfolded proteins. HRD1 expression significantly increased in the middle frontal cortex in the postmortem of patients with ASD. Moreover, HRD1 silencing improved the abnormalities induced by ER stress. Because other ubiquitin ligases are related with neurite outgrowth, ER stress may be related to the pathogenesis of neuronal developmental diseases via abnormalities of neuronal differentiation or maturation.     

Behavioral,Cognitive, and Motor Preparation Deficits in a Visual Cued Spatial Attention Task in Autism Spectrum Disorder

Abnormalities in motor skills have been regarded as part of the symptomatology characterizing autism spectrum disorder (ASD). It has been estimated that 80 % of subjects with autism display “motor dyspraxia” or clumsiness that are not readily identified in a routine neurological examination. In this study we used behavioral measures, event-related potentials (ERP), and lateralized readiness potential (LRP) to study cognitive and motor preparation deficits contributing to the dyspraxia of autism. A modified Posner cueing task was used to analyze motor preparation abnormalities in children with autism and in typically developing children (N = 30/per group). In this task, subjects engage in preparing motor response based on a visual cue, and then execute a motor movement based on the subsequent imperative stimulus. The experimental conditions, such as the validity of the cue and the spatial location of the target stimuli were manipulated to influence motor response selection, preparation, and execution. Reaction time and accuracy benefited from validly cued targets in both groups, while main effects of target spatial position were more obvious in the autism group. The main ERP findings were prolonged and more negative early frontal potentials in the ASD in incongruent trials in both types of spatial location. The LRP amplitude was larger in incongruent trials and had stronger effect in the children with ASD. These effects were better expressed at the earlier stages of LRP, specifically those related to response selection, and showed difficulties at the cognitive phase of stimulus processing rather that at the motor execution stage. The LRP measures at different stages reflect the chronology of cognitive aspects of movement preparation and are sensitive to manipulations of cue correctness, thus representing very useful biomarker in autism dyspraxia research. Future studies may use more advance and diverse manipulations of movement preparation demands in testing more refined specifics of dyspraxia symptoms to investigate functional connectivity abnormalities underlying motor skills deficits in autism.     

Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.     

Stereological Study of Amygdala Glial Populations in Adolescents and Adults with Autism Spectrum Disorder

The amygdala undergoes aberrant development in autism spectrum disorder (ASD). We previously found that there are reduced neuron numbers in the adult postmortem amygdala from individuals with ASD compared to typically developing controls. The current study is a comprehensive stereological examination of four non-neuronal cell populations: microglia, oligodendrocytes, astrocytes, and endothelial cells, in the same brains studied previously. We provide a detailed neuroanatomical protocol for defining each cell type that may be applied to other studies of the amygdala in neurodevelopmental and psychiatric disorders. We then assess whether cell numbers and average volumes differ between ASD and typically developing brains. We hypothesized that a reduction in neuron numbers in ASD might relate to altered immune function and/or aberrant microglial activation, as indicated by increased microglial number and cell body volume. Overall, average non-neuronal cell numbers and volumes did not differ between ASD and typically developing brains. However, there was evident heterogeneity within the ASD cohort. Two of the eight ASD brains displayed strong microglial activation. Contrary to our original hypothesis, there was a trend toward a positive correlation between neuronal and microglial numbers in both ASD and control cases. There were fewer oligodendrocytes in the amygdala of adult individuals with ASD ages 20 and older compared to typically developing controls. This finding may provide a possible sign of altered connectivity or impaired neuronal communication that may change across the lifespan in ASD.     

Maternal Conditions and Perinatal Characteristics Associated with Autism Spectrum Disorder and Intellectual Disability

Background

As well as being highly comorbid conditions, autism spectrum disorders (ASD) and intellectual disability (ID) share a number of clinically-relevant phenomena. This raises questions about similarities and overlap in diagnosis and aetiological pathways that may exist for both conditions.

Aims

To examine maternal conditions and perinatal factors for children diagnosed with an ASD, with or without ID, and children with ID of unknown cause, compared with unaffected children.

Methods

The study population comprised all live singleton births in Western Australia (WA) between January 1984 and December 1999 (N = 383,153). Univariate and multivariate multinomial logistic regression models were applied using a blocked modelling approach to assess the effect of maternal conditions, sociodemographic factors, labour and delivery characteristics and neonatal outcomes.

Results

In univariate analyses mild-moderate ID was associated with pregnancy hypertension, asthma, urinary tract infection, some types of ante-partum haemorrhage, any type of preterm birth, elective C-sections, breech presentation, poor fetal growth and need for resuscitation at birth, with all factors showing an increased risk. Severe ID was positively associated with poor fetal growth and need for resuscitation, as well as any labour or delivery complication. In the multivariate analysis no maternal conditions or perinatal factors were associated with an increased risk of ASD without ID. However, pregnancy hypertension and small head circumference were associated with a reduced risk (OR = 0.64, 95% CI: 0.43, 0.94; OR = 0.58, 95% CI: 0.34, 0.96, respectively). For ASD with ID, threatened abortion before 20 weeks gestation and poor fetal growth were associated with an increased risk.

Conclusion

Findings show that indicators of a poor intrauterine environment are associated with an elevated risk of ID, while for ASD, and particularly ASD without ID, the associations are much weaker. As such, these findings highlight the importance of accounting for the absence or presence of ID when examining ASD, if we are to improve our understanding of the causal pathways associated with these conditions.     

Atypical Integration of Motion Signals in Autism Spectrum Conditions

Vision in Autism Spectrum Conditions (ASC) is characterized by enhanced perception of local elements, but impaired perception of global percepts. Deficits in coherent motion perception seem to support this characterization, but the roots and robustness of such deficits remain unclear. We aimed to investigate the dynamics of the perceptual decision-making network known to support coherent motion perception. In a series of forced-choice coherent motion perception tests, we parametrically varied a single stimulus dimension, viewing duration, to test whether the rate at which evidence is accumulated towards a global decision is atypical in ASC. 40 adult participants (20 ASC) performed a classic motion discrimination task, manually indicating the global direction of motion in a random-dot kinematogram across a range of coherence levels (2–75%) and stimulus-viewing durations (200–1500 ms). We report a deficit in global motion perception at short viewing durations in ASC. Critically, however, we found that increasing the amount of time over which motion signals could be integrated reduced the magnitude of the deficit, such that at the longest duration there was no difference between the ASC and control groups. Further, the deficit in motion integration at the shortest duration was significantly associated with the severity of autistic symptoms in our clinical population, and was independent from measures of intelligence. These results point to atypical integration of motion signals during the construction of a global percept in ASC. Based on the neural correlates of decision-making in global motion perception our findings suggest the global motion deficit observed in ASC could reflect a slower or more variable response from the primary motion area of the brain or longer accumulation of evidence towards a decision-bound in parietal areas.