Atypical Mismatch Negativity in Response to Emotional Voices in People with Autism Spectrum Conditions

Autism Spectrum Conditions (ASC) are characterized by heterogeneous impairments of social reciprocity and sensory processing. Voices, similar to faces, convey socially relevant information. Whether voice processing is selectively impaired remains undetermined. This study involved recording mismatch negativity (MMN) while presenting emotionally spoken syllables dada and acoustically matched nonvocal sounds to 20 subjects with ASC and 20 healthy matched controls. The people with ASC exhibited no MMN response to emotional syllables and reduced MMN to nonvocal sounds, indicating general impairments of affective voice and acoustic discrimination. Weaker angry MMN amplitudes were associated with more autistic traits. Receiver operator characteristic analysis revealed that angry MMN amplitudes yielded a value of 0.88 (p<.001). The results suggest that people with ASC may process emotional voices in an atypical fashion already at the automatic stage. This processing abnormality can facilitate diagnosing ASC and enable social deficits in people with ASC to be predicted.     

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.     

Stronger Neural Modulation by Visual Motion Intensity in Autism Spectrum Disorders

Theories of autism spectrum disorders (ASD) have focused on altered perceptual integration of sensory features as a possible core deficit. Yet, there is little understanding of the neuronal processing of elementary sensory features in ASD. For typically developed individuals, we previously established a direct link between frequency-specific neural activity and the intensity of a specific sensory feature: Gamma-band activity in the visual cortex increased approximately linearly with the strength of visual motion. Using magnetoencephalography (MEG), we investigated whether in individuals with ASD neural activity reflect the coherence, and thus intensity, of visual motion in a similar fashion. Thirteen adult participants with ASD and 14 control participants performed a motion direction discrimination task with increasing levels of motion coherence. A polynomial regression analysis revealed that gamma-band power increased significantly stronger with motion coherence in ASD compared to controls, suggesting excessive visual activation with increasing stimulus intensity originating from motion-responsive visual areas V3, V6 and hMT/V5. Enhanced neural responses with increasing stimulus intensity suggest an enhanced response gain in ASD. Response gain is controlled by excitatory-inhibitory interactions, which also drive high-frequency oscillations in the gamma-band. Thus, our data suggest that a disturbed excitatory-inhibitory balance underlies enhanced neural responses to coherent motion in ASD.     

Decreased Coherent Motion Discrimination in Autism Spectrum Disorder: The Role of Attentional Zoom-Out Deficit

Autism spectrum disorder (ASD) has been associated with decreased coherent dot motion (CDM) performance, a task that measures magnocellular sensitivity as well as fronto-parietal attentional integration processing. In order to clarify the role of spatial attention in CDM tasks, we measured the perception of coherently moving dots displayed in the central or peripheral visual field in ASD and typically developing children. A dorsal-stream deficit in children with ASD should predict a generally poorer performance in both conditions. In our study, however, we show that in children with ASD, CDM perception was selectively impaired in the central condition. In addition, in the ASD group, CDM efficiency was correlated to the ability to zoom out the attentional focus. Importantly, autism symptoms severity was related to both the CDM and attentional zooming-out impairment. These findings suggest that a dysfunction in the attentional network might help to explain decreased CDM discrimination as well as the “core” social cognition deficits of 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.     

HERVs Expression in Autism Spectrum Disorders

Background

Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism.

Methods

The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods.

Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.

Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.     

The Cost of Autism Spectrum Disorders

Objective

A diagnosis of an autism spectrum disorders is usually associated with substantial lifetime costs to an individual, their family and the community. However, there remains an elusive factor in any cost-benefit analysis of ASD diagnosis, namely the cost of not obtaining a diagnosis. Given the infeasibility of estimating the costs of a population that, by its nature, is inaccessible, the current study compares expenses between families whose children received a formal ASD diagnosis immediately upon suspecting developmental atypicality and seeking advice, with families that experienced a delay between first suspicion and formal diagnosis.

Design

A register based questionnaire study covering all families with a child with ASD in Western Australia.

Participants

Families with one or more children diagnosed with an ASD, totalling 521 children diagnosed with an ASD; 317 records were able to be included in the final analysis.

Results

The median family cost of ASD was estimated to be AUD $34,900 per annum with almost 90% of the sum ($29,200) due to loss of income from employment. For each additional symptom reported, approximately $1,400 cost for the family per annum was added. While there was little direct influence on costs associated with a delay in the diagnosis, the delay was associated with a modest increase in the number of ASD symptoms, indirectly impacting the cost of ASD.

Conclusions

A delay in diagnosis was associated with an indirect increased financial burden to families. Early and appropriate access to early intervention is known to improve a child''s long-term outcomes and reduce lifetime costs to the individual, family and society. Consequently, a per symptom dollar value may assist in allocation of individualised funding amounts for interventions rather than a nominal amount allocated to all children below a certain age, regardless of symptom presentation, as is the case in Western Australia.     

Vocal Identity Recognition in Autism Spectrum Disorder

Voices can convey information about a speaker. When forming an abstract representation of a speaker, it is important to extract relevant features from acoustic signals that are invariant to the modulation of these signals. This study investigated the way in which individuals with autism spectrum disorder (ASD) recognize and memorize vocal identity. The ASD group and control group performed similarly in a task when asked to choose the name of the newly-learned speaker based on his or her voice, and the ASD group outperformed the control group in a subsequent familiarity test when asked to discriminate the previously trained voices and untrained voices. These findings suggest that individuals with ASD recognized and memorized voices as well as the neurotypical individuals did, but they categorized voices in a different way: individuals with ASD categorized voices quantitatively based on the exact acoustic features, while neurotypical individuals categorized voices qualitatively based on the acoustic patterns correlated to the speakers'' physical and mental properties.     

Time Domain Analysis of Heart Rate Variability Signals in Valence Recognition for Children with Autism Spectrum Disorder (ASD)

BackgroundAutism Spectrum Disorder (ASD) is a neurodevelopmental condition that is characterized by various social impairments. Children with ASD have major difficulties in expressing themselves, resulting in stress and meltdowns. Understanding their hidden feelings and needs may help in tackling and avoiding such strenuous behaviors.ObjectiveThis research aims to aid the parents and caretakers of children with ASD to understand the hidden and unexpressed emotional state by using physiological signals obtained from wearable devices.MethodsHere, electrocardiogram (ECG) signals pertaining to two valence states (‘like’ and ‘dislike’) were recorded from twenty children (10 Control and 10 children with ASD). The heart rate variability (HRV) signals were then obtained from the ECG signals using the Pan-Tompkins's algorithm. The statistical, higher order statistics (HOS) and geometrical features which were statistically significant were trained using the K Nearest Neighbor (KNN) and Ensemble Classifier algorithms.ResultsThe findings of our analysis indicate that the integration of major statistical features resulted in an overall average accuracy of 84.8% and 75.3% using HRV data for the control and test population, respectively. Similarly, geometrical features resulted in a maximum average accuracy of 84.8% and 74.2% for control and test population respectively. The decreased HRV in the test population indicates the presence of autonomic dysregulation in children with ASD when compared to their control peers.     

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.     

Electrophysiological and Behavioral Outcomes of Berard Auditory Integration Training (AIT) in Children with Autism Spectrum Disorder

Autism is a pervasive developmental disorder of childhood characterized by deficits in social interaction, language, and stereotyped behaviors along with a restricted range of interests. It is further marked by an inability to perceive and respond to social and emotional signals in a typical manner. This might due to the functional disconnectivity of networks important for specific aspects of social cognition and behavioral control resulting in deficits of sensory information integration. According to several recent theories sensory processing and integration abnormalities may play an important role in impairments of perception, cognition, and behavior in individuals with autism. Among these sensory abnormalities, auditory perception distortion may contribute to many typical symptoms of autism. The present study used Berard’s technique of auditory integration training (AIT) to improve sound integration in children with autism. It also aimed to understand the abnormal neural and functional mechanisms underlying sound processing distortion in autism by incorporating behavioral, psychophysiological and neurophysiological outcomes. It was proposed that exposure to twenty 30-min AIT sessions (total 10 h of training) would result in improved behavioral evaluation scores, improve profile of cardiorespiratory activity, and positively affect both early [N1, mismatch negativity (MMN)] and late (P3) components of evoked potentials in auditory oddball task. Eighteen children with autism spectrum disorder (ASD) participated in the study. A group of 16 typically developing children served as a contrast group in the auditory oddball task. Autonomic outcomes of the study reflected a linear increase of heart rate variability measures and respiration rate. Comparison of evoked potential characteristics of children with ASD versus typically developing children revealed several group difference findings, more specifically, a delayed latency of N1 to rare and frequent stimuli, larger MMN; higher P3a to frequent stimuli, and at the same time delayed latency of P3b to rare stimuli in the autism group. Post-AIT changes in evoked potentials could be summarized as a decreased magnitude of N1 to rare stimuli, marginally lower negativity of MMN, and decrease of the P3a to frequent stimuli along with delayed latency and higher amplitude of the P3b to the rare stimuli. These evoked potential changes following completion of Berard AIT course are in a positive direction, making them less distinct from those recorded in age-matched group of typical children, thus could be considered as changes towards normalization. Parental questionnaires clearly demonstrated improvements in behavioral symptoms such as irritability, hyperactivity, repetitive behaviors and other important behavioral domains. The results of the study propose that more controlled research is necessary to document behavioral and psychophysiological changes resulting from Berard AIT and to provide explanation of the neural mechanisms of how auditory integration training may affect behavior and psychophysiological responses of children with ASD.     

Anticipatory Smooth Eye Movements in Autism Spectrum Disorder

Smooth pursuit eye movements are important for vision because they maintain the line of sight on targets that move smoothly within the visual field. Smooth pursuit is driven by neural representations of motion, including a surprisingly strong influence of high-level signals representing expected motion. We studied anticipatory smooth eye movements (defined as smooth eye movements in the direction of expected future motion) produced by salient visual cues in a group of high-functioning observers with Autism Spectrum Disorder (ASD), a condition that has been associated with difficulties in either generating predictions, or translating predictions into effective motor commands. Eye movements were recorded while participants pursued the motion of a disc that moved within an outline drawing of an inverted Y-shaped tube. The cue to the motion path was a visual barrier that blocked the untraveled branch (right or left) of the tube. ASD participants showed strong anticipatory smooth eye movements whose velocity was the same as that of a group of neurotypical participants. Anticipatory smooth eye movements appeared on the very first cued trial, indicating that trial-by-trial learning was not responsible for the responses. These results are significant because they show that anticipatory capacities are intact in high-functioning ASD in cases where the cue to the motion path is highly salient and unambiguous. Once the ability to generate anticipatory pursuit is demonstrated, the study of the anticipatory responses with a variety of types of cues provides a window into the perceptual or cognitive processes that underlie the interpretation of events in natural environments or social situations.     

神经元增殖与孤独症谱系障碍大脑过度生长

在患儿发育早期,某一亚类孤独症谱系障碍（autism spectrum disorders, ASDs）大脑呈过度生长趋势。研究发现,部分伴随有大脑过度增生的患者局部脑区神经元数目异常增多。进一步研究表明,神经元的增殖紊乱与局部脑区神经元数目异常增多密切相关。本综述从ASDs相关信号分子对神经元增殖的调控入手,归纳总结近年来基于神经元增殖调控异常的ASDs大脑过度增生的分子机制研究,为探究ASDs的发病机制提供一个重要的突破口。     

Future Prospects for Epigenetics in Autism Spectrum Disorder

Molecular Diagnosis & Therapy - Despite decades of investigation into the genetics of autism spectrum disorder (ASD), a current consensus in the field persists that ASD risk is too...     

谷氨酸-谷氨酰胺循环异常与孤独症谱系障碍研究进展

孤独症谱系障碍（autism spectrum disorder,ASD）是一种多病因神经发育性疾病,人群患病率高,病因复杂多样,包括炎症、自身免疫、基因异常等,但具体发病机制尚不清楚。在哺乳动物中枢神经系统（central nervous system,CNS）中,谷氨酸是最主要的兴奋性神经递质,也是一种潜在的神经毒素,其引起的兴奋毒性可能导致神经细胞的死亡。而星形胶质细胞和神经元之间谷氨酸-谷氨酰胺的代谢偶联,防止了过量的谷氨酸扩散到周围神经元上,进而避免了神经元的过度兴奋,对神经元起到保护作用。有研究表明,谷氨酸-谷氨酰胺循环异常可能为ASD发生的核心机制。因此,对炎症、自身免疫、基因异常等孤独症谱系障碍经典病因与谷氨酸-谷氨酰胺循环之间的联系进行综述,以期为孤独症谱系障碍分型和治疗提供一种新思路。     

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.     

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.     

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.     

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.