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A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism

Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist d-clycoserine has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that rats selectively bred for low rates of play-induced pro-social ultrasonic vocalizations (USVs) can be used to model certain core symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play-induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism.

from Neuroscience and Biobehavioral Reviews

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A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism

Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist d-clycoserine has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that rats selectively bred for low rates of play-induced pro-social ultrasonic vocalizations (USVs) can be used to model certain core symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play-induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism.

from Neuroscience and Biobehavioral Reviews

Lack of eyeblink entrainments in autism spectrum disorders

Interpersonal synchrony is the temporal coordination of movements between individuals during social interactions. For example, it has been shown that listeners synchronize their eyeblinks to a speaker’s eyeblinks, especially at breakpoints of speech, when viewing a close-up video clip of the speaker’s face. We hypothesized that this interpersonal synchronous behavior would not be observed in individuals with autism spectrum disorders (ASD), which are characterized by impaired social communication. To test this hypothesis, we examined eyeblink entrainments in adults with ASD. As we reported previously, the eyeblinks of adults without ASD were significantly synchronized with the speaker’s eyeblinks at pauses in his speech when they viewed the speaker’s entire face. However, the significant eyeblink synchronization disappeared when adults without ASD viewed only the speaker’s eyes or mouth, suggesting that information from the whole face, including information from both the eyes and the mouth, was necessary for eyeblink entrainment. By contrast, the ASD participants did not show any eyeblink synchronization with the speaker, even when viewing the speaker’s eyes and mouth simultaneously. The lack of eyeblink entrainment to the speaker in individuals with ASD suggests that they are not able to temporally attune themselves to others’ behaviors. The deficits in temporal coordination may impair effective social communication with others.

from Neuropsychologia

Brief Report: Faces Cause Less Distraction in Autism

Individuals with autism have difficulties interpreting face cues that contribute to deficits of social communication. When faces need to be processed for meaning they fail to capture and hold the attention of individuals with autism. In the current study we illustrate that faces fail to capture attention in a typical manner even when they are non-functional to task completion. In a visual search task with a present butterfly target an irrelevant face distracter significantly slows performance of typical individuals. However, participants with autism (n = 28; mean 10 years 4 months) of comparable non-verbal ability are not distracted by the faces. Interestingly, there is a significant relationship between level of functioning on the autism spectrum and degree of face capture or distraction.

from the Journal of Autism and Developmental Disorders

Teaching Paraprofessionals of Students With Autism to Implement Pivotal Response Treatment in Inclusive School Settings Using a Brief Video Feedback Training Package

Given that students with autism spend the majority of their days in school settings, largely supported by paraprofessionals, it is important that these paraprofessionals receive adequate training. The author investigated a training package consisting of modeling and video-based feedback as a means of enabling paraprofessionals to implement Pivotal Response Treatment (PRT) in the inclusive school setting. A multiple baseline design across four paraprofessional -focal student pairs was employed. The findings suggest that the training package was effective and efficient in improving paraprofessional PRT implementation and levels of involvement as well as social communication target behaviors of the students with autism. Generalization across activities and students, maintenance, and social validity were also assessed.

from Focus on Autism and Other Developmental Disabilities

Neurocognitive and Behavioral Outcomes of Younger Siblings of Children with Autism Spectrum Disorder at Age Five

Later-born siblings of children with Autism Spectrum Disorders (ASD) are at increased risk for ASD as well as qualitatively similar traits not meeting clinical cutoffs for the disorder. This study examined age five neurocognitive and behavioral outcomes of 39 younger siblings of children with ASD (Sibs-ASD) and 22 younger siblings of typically developing children (Sibs-TD) previously assessed in a longitudinal investigation starting in the second year of life. There were few group differences between Sibs-TD and Sibs-ASD on global measures of IQ, language, or behavior problems. Sibs-ASD did show vulnerabilities on measures of executive functioning, social cognition, and repetitive behaviors. These results highlight the importance of following sibling risk groups over an extended time period and employing measures targeting broader aspects of development.

from the Journal of Autism and Developmental Disorders

Early Childhood Predictors of the Social Competence of Adults with Autism

Longitudinal research into adult outcomes in autism remains limited. Unlike previous longitudinal examinations of adult outcome in autism, the twenty participants in this study were evaluated across multiple assessments between early childhood (M = 3.9 years) and adulthood (M = 26.6 years). In early childhood, responsiveness to joint attention (RJA), language, and intelligence were assessed. In adulthood, the parents of participants responded to interviews assessing the adaptive functioning, autistic symptomology and global functioning of their children. RJA and early childhood language predicted a composite measure of adult social functioning and independence. Early childhood language skills and intelligence predicted adult adaptive behaviors. RJA predicted adult non-verbal communication, social skills and symptoms. Adaptive behaviors changed with development, but symptoms of autism did not. Additional factors associated with adult outcomes are discussed.

from the Journal of Autism and Developmental Disorders

Initiating and responding to joint attention bids in children with autism: A review of the literature

Joint attention is a skill that involves coordinating the attention of at least two individuals towards an object or event. Although it is seen as a critical skill in early child development, it is frequently absent in children with autism and has been linked to poorer language outcomes for those children. As a result, multiple interventions have been developed to teach children with autism to respond to, and initiate, bids for joint attention. These interventions, however, differ widely both in terms of procedures used and in whether they focus on teaching children to respond to, or initiate, bids for joint attention. This literature review was conducted to document research gaps and intervention similarities between joint attention intervention studies for children with autism. The specific intent of this review was to determine whether researchers teach responding and initiating separately or sequentially, describe the extent to which procedures differ among studies, and identify whether social or non-social consequences are used during joint attention training. Implications for the treatment of joint attention deficits are discussed and recommendations to both researchers and practitioners are provided.

from Research in Developmental Disabilities

New Autism Diagnostic Interview-Revised Algorithms for Toddlers and Young Preschoolers from 12 to 47 Months of Age

Autism Diagnostic Interview-Revised (Rutter et al. in Autism diagnostic interview-revised. Western Psychological Services, Los Angeles, 2003) diagnostic algorithms specific to toddlers and young preschoolers were created using 829 assessments of children aged from 12 to 47 months with ASD, nonspectrum disorders, and typical development. The participants were divided into three more homogeneous groups by language level and age. Items that best differentiated the diagnostic groups were selected and arranged into domains based on multifactor item-response analyses. Using the new algorithms for toddlers and preschool children, we were able to improve sensitivity and specificity compared to the previously developed algorithm.

from the European Archives of Oto-Rhino-Laryngology

Associations Between Syntax and the Lexicon Among Children With or Without ASD and Language Impairment

Five groups of children defined by presence or absence of syntactic deficits and autism spectrum disorders (ASD) took vocabulary tests and provided sentences, definitions, and word associations. Children with ASD who were free of syntactic deficits demonstrated age-appropriate word knowledge. Children with ASD plus concomitant syntactic language impairments (ASDLI) performed similarly to peers with specific language impairment (SLI) and both demonstrated sparse lexicons characterized by partial word knowledge and immature knowledge of word-to-word relationships. This behavioral overlap speaks to the robustness of the syntax–lexicon interface and points to a similarity in the ASDLI and SLI phenotypes.

from the Journal of Autism and Developmental Disorders

Brief Report: Performance Pattern Differences Between Children with Autism Spectrum Disorders and Attention Deficit-Hyperactivity Disorder on Measures of Verbal Intelligence

Performance patterns on verbal subtests from the WISC-IV were compared between a clinically-referred sample of children with either autism spectrum disorders (ASD) or attention deficit/hyperactivity disorder (ADHD). Children with ASD demonstrated a statistically significant stepwise pattern where performance on Similarities was best, followed by Vocabulary, then Comprehension. Although children with ASD and ADHD share multiple behavioral features, this pattern was not observed for those with ADHD. Greater deficits in social reasoning and verbal formulation for children with ASD (compared to ADHD) are hypothesized to account for this observed difference in their performance pattern. Clinical implications, including use of this identified pattern in combination with other symptoms suggestive of ASD in referral decision making are discussed.

from the Journal of Autism and Developmental Disorders

The effect of a psycho-educational program on CARS scores and short sensory profile in autistic children

Conclusion
Individually tailored psycho-educational therapy had a significant effect on autism severity according to CARS. Changes in the SSP scores were not significant.

from the European Journal of Paediatric Neurology

CNTNAP2 variants affect early language development in the general population

Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males, 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers, and with a consistent direction of effect (rs2710102, p = .0239; rs759178, p = .0248). Based on these findings we performed analyses of four-marker haplotypes of rs2710102-rs759178-rs17236239-rs2538976, and identified significant association (haplotype TTAA, p = .049; haplotype GCAG, p = .0014). Our study suggests that common variants in the exon 13-15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.

from Genes, Brain, and Behavior

Phonology and vocal behavior in toddlers with autism spectrum disorders

The purpose of this study is to examine the phonological and other vocal productions of children, 18–36 months, with autism spectrum disorder (ASD) and to compare these productions to those of age-matched and language-matched controls. Speech samples were obtained from 30 toddlers with ASD, 11 age-matched toddlers and 23 language-matched toddlers during either parent–child or clinician–child play sessions. Samples were coded for a variety of speech-like and nonspeech vocalization productions. Toddlers with ASD produced speech-like vocalizations similar to those of language-matched peers, but produced significantly more atypical nonspeech vocalizations when compared to both control groups. Toddlers with ASD show speech-like sound production that is linked to their language level, in a manner similar to that seen in typical development. The main area of difference in vocal development in this population is in the production of atypical vocalizations. Findings suggest that toddlers with ASDs do not tune into the language model of their environment. Failure to attend to the ambient language environment negatively impacts the ability to acquire spoken language.

from Autism Research

Neural correlates of language comprehension in autism spectrum disorders: When language conflicts with world knowledge

In individuals with ASD, difficulties with language comprehension are most evident when higher-level semantic-pragmatic language processing is required, for instance when context has to be used to interpret the meaning of an utterance. Until now, it is unclear at what level of processing and for what type of context these difficulties in language comprehension occur. Therefore, in the current fMRI study, we investigated the neural correlates of the integration of contextual information during auditory language comprehension in 24 adults with ASD and 24 matched control participants. Different levels of context processing were manipulated by using spoken sentences that were correct or contained either a semantic or world knowledge anomaly. Our findings demonstrated significant differences between the groups in inferior frontal cortex that were only present for sentences with a world knowledge anomaly. Relative to the ASD group, the control group showed significantly increased activation in left inferior frontal gyrus (LIFG) for sentences with a world knowledge anomaly compared to correct sentences. This effect possibly indicates reduced integrative capacities of the ASD group. Furthermore, world knowledge anomalies elicited significantly stronger activation in right inferior frontal gyrus (RIFG) in the control group compared to the ASD group. This additional RIFG activation probably reflects revision of the situation model after new, conflicting information. The lack of recruitment of RIFG is possibly related to difficulties with exception handling in the ASD group.

from Neuropsychologia