Autism Research

Neuroligin‐3 is a member of the class of cell adhesion proteins that mediate synapse development and have been implicated in autism. Mice with the human R451C mutation (NL3), identical to the point mutation found in two brothers with autism spectrum disorders, were generated and phenotyped in multiple behavioral assays with face validity to the diagnostic symptoms of autism. No differences between NL3 and their wildtype (WT) littermate controls were detected on measures of juvenile reciprocal social interaction, adult social approach, cognitive abilities, and resistance to change in a spatial habit, findings which were replicated in several cohorts of males and females. Physical and procedural abilities were similar across genotypes on measures of general health, sensory abilities, sensorimotor gating, motor functions, and anxiety‐related traits. Minor developmental differences were detected between NL3 and WT, including slightly different rates of somatic growth, slower righting reflexes at postnatal days 2–6, faster homing reflexes in females, and less vocalizations on postnatal day 8 in males. Significant differences in NL3 adults included somewhat longer latencies to fall from the rotarod, less vertical activity in the open field, and less acoustic startle to high decibel tones. The humanized R451C mutation in mice did not result in apparent autism‐like phenotypes, but produced detectable functional consequences that may be interpreted in terms of physical development and/or reduced sensitivity to stimuli.

Since the impairments associated with autism spectrum disorder (ASD) tend to persist or worsen from childhood into adulthood, it is of critical importance to examine how the brain develops over this growth epoch. We report initial findings on whole and regional longitudinal brain development in 100 male participants with ASD (226 high‐quality magnetic resonance imaging [MRI] scans; mean inter‐scan interval 2.7 years) compared to 56 typically developing controls (TDCs) (117 high‐quality scans; mean inter‐scan interval 2.6 years) from childhood into adulthood, for a total of 156 participants scanned over an 8‐year period. This initial analysis includes between one and three high‐quality scans per participant that have been processed and segmented to date, with 21% having one scan, 27% with two scans, and 52% with three scans in the ASD sample; corresponding percentages for the TDC sample are 30%, 30%, and 40%. The proportion of participants with multiple scans (79% of ASDs and 68% of TDCs) was high in comparison to that of large longitudinal neuroimaging studies of typical development. We provide volumetric growth curves for the entire brain, total gray matter (GM), frontal GM, temporal GM, parietal GM, occipital GM, total cortical white matter (WM), corpus callosum, caudate, thalamus, total cerebellum, and total ventricles. Mean volume of cortical WM was reduced significantly. Mean ventricular volume was increased in the ASD sample relative to the TDCs across the broad age range studied. Decreases in regional mean volumes in the ASD sample most often were due to decreases during late adolescence and adulthood. The growth curve of whole brain volume over time showed increased volumes in young children with autism, and subsequently decreased during adolescence to meet the TDC curve between 10 and 15 years of age. The volume of many structures continued to decline atypically into adulthood in the ASD sample. The data suggest that ASD is a dynamic disorder with complex changes in whole and regional brain volumes that change over time from childhood into adulthood. Autism Res 2015, 8: 82–93. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.

Rối loạn phổ tự kỷ (ASD) và rối loạn ngôn ngữ đặc hiệu (SLI) là các rối loạn phát triển biểu hiện bằng các thiếu hụt ngôn ngữ, nhưng vẫn chưa rõ chúng phát sinh từ các nguyên nhân tương tự hay không. Các thiếu hụt ngôn ngữ đã được mô tả ở các thành viên trong gia đình của trẻ em mắc ASD và SLI, nhưng rất ít nghiên cứu đã định lượng chúng. Trong nghiên cứu này, chúng tôi đã xem xét IQ, khả năng ngôn ngữ và đọc của trẻ em ASD và SLI cùng với người thân cấp một của chúng để xác định liệu những khó khăn về ngôn ngữ mà một số trẻ ASD gặp phải có phải là vấn đề gia đình hay không, và để hiểu rõ hơn về mức độ giao thoa giữa các rối loạn này cùng với các kiểu hình rộng hơn của chúng. Số liệu tham gia bao gồm 52 trẻ em tự kỷ, 36 trẻ em mắc SLI, cùng với anh chị em và cha mẹ của chúng. Nhóm ASD được chia thành những trẻ có (ALI, n=32) và không có (ALN, n=20) thiếu hụt ngôn ngữ. Mối quan hệ giữa mức độ nghiêm trọng của ASD và hiệu suất ngôn ngữ cũng đã được xem xét ở các trường hợp ASD. Các trường hợp ALI và SLI đã thể hiện hiệu suất tương tự trên hầu hết các chỉ số trong khi các trường hợp ALN đạt điểm cao hơn. Điểm ngôn ngữ của các trường hợp ALN và ALI không có mối liên quan đến điểm của phỏng vấn chẩn đoán tự kỷ - Đã sửa đổi và điểm số của lịch quan sát chẩn đoán tự kỷ. Các người thân của SLI đạt điểm thấp nhất trên tất cả các thang đo, và mặc dù điểm số không nằm trong phạm vi suy giảm, nhưng người thân của trẻ ALI có điểm thấp hơn so với người thân của trẻ ALN ở một số thang đo, mặc dù không phải ở những thang đo thể hiện tính di truyền cao nhất trong SLI. Như vậy, với việc người thân ALI thực hiện tốt hơn so với người thân SLI trong các thang đo về ngôn ngữ, giả thuyết rằng các gia đình ALI và SLI chia sẻ tải trọng di truyền tương tự cho ngôn ngữ không được hỗ trợ mạnh mẽ.

Autism Spectrum Disorder (ASD) is characterized by social impairments that have been related to deficits in social attention, including diminished gaze to faces. Eye‐tracking studies are commonly used to examine social attention and social motivation in ASD, but they vary in sensitivity. In this study, we hypothesized that the ecological nature of the social stimuli would affect participants' social attention, with gaze behavior during more naturalistic scenes being most predictive of ASD vs. typical development. Eighty‐one children with and without ASD participated in three eye‐tracking tasks that differed in the ecological relevance of the social stimuli. In the “Static Visual Exploration” task, static images of objects and people were presented; in the “Dynamic Visual Exploration” task, video clips of individual faces and objects were presented side‐by‐side; in the “Interactive Visual Exploration” task, video clips of children playing with objects in a naturalistic context were presented. Our analyses uncovered a three‐way interaction between Task, Social vs. Object Stimuli, and Diagnosis. This interaction was driven by group differences on one task only—the Interactive task. Bayesian analyses confirmed that the other two tasks were insensitive to group membership. In addition, receiver operating characteristic analyses demonstrated that, unlike the other two tasks, the Interactive task had significant classification power. The ecological relevance of social stimuli is an important factor to consider for eye‐tracking studies aiming to measure social attention and motivation in ASD. Autism Res 2015, 8: 620–628. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

The anterior cingulate cortex (ACC; BA 24) via its extensive limbic and high order association cortical connectivity to prefrontal cortex is a key part of an important circuitry participating in executive function, affect, and socio‐emotional behavior. Multiple lines of evidence, including genetic and imaging studies, suggest that the ACC and gamma‐amino‐butyric acid (GABA) system may be affected in autism. The benzodiazepine binding site on the GABA_A receptor complex is an important target for pharmacotherapy and has important clinical implications. The present multiple‐concentration ligand‐binding study utilized ³H‐muscimol and ³H‐flunitrazepam to determine the number (B_max), binding affinity (K_d), and distribution of GABA_A receptors and benzodiazepine binding sites, respectively, in the ACC in adult autistic and control cases. Compared to controls, the autistic group had significant decreases in the mean density of GABA_A receptors in the supragranular (46.8%) and infragranular (20.2%) layers of the ACC and in the density of benzodiazepine binding sites in the supragranular (28.9%) and infragranular (16.4%) lamina. In addition, a trend for a decrease in for the density of benzodiazepine sites was found in the infragranular layers (17.1%) in the autism group. These findings suggest that in the autistic group this downregulation of both benzodiazepine sites and GABA_A receptors in the ACC may be the result of increased GABA innervation and/or release disturbing the delicate excitation/inhibition balance of principal neurons as well as their output to key limbic cortical targets. Such disturbances likely underlie the core alterations in socio‐emotional behaviors in autism.

A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor‐1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5′ promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family‐based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case–control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12–3.31) for genotype TT and 2.42 (95% CI: 1.38–4.25) for genotype CT compared to genotype CC. Gene–gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.

Background: Biological measurements that distinguish individuals with autism from typically developing individuals and those with other developmental and neuropsychiatric disorders must demonstrate very high performance to have clinical value as potential imaging biomarkers. We hypothesized that further study of white matter microstructure (WMM) in the superior temporal gyrus (STG) and temporal stem (TS), two brain regions in the temporal lobe containing circuitry central to language, emotion, and social cognition, would identify a useful combination of classification features and further understand autism neuropathology. Methods: WMM measurements from the STG and TS were examined from 30 high‐functioning males satisfying full criteria for idiopathic autism aged 7–28 years and 30 matched controls and a replication sample of 12 males with idiopathic autism and 7 matched controls who participated in a previous case–control diffusion tensor imaging (DTI) study. Language functioning, adaptive functioning, and psychotropic medication usage were also examined. Results: In the STG, we find reversed hemispheric asymmetry of two separable measures of directional diffusion coherence, tensor skewness, and fractional anisotropy. In autism, tensor skewness is greater on the right and fractional anisotropy is decreased on the left. We also find increased diffusion parallel to white matter fibers bilaterally. In the right not left TS, we find increased omnidirectional, parallel, and perpendicular diffusion. These six multivariate measurements possess very high ability to discriminate individuals with autism from individuals without autism with 94% sensitivity, 90% specificity, and 92% accuracy in our original and replication samples. We also report a near‐significant association between the classifier and a quantitative trait index of autism and significant correlations between two classifier components and measures of language, IQ, and adaptive functioning in autism.

Mirror neuron system dysfunction may underlie a self–other matching impairment, which has previously been suggested to account for autism. Embodied Cognition Theory, which proposes that action provides a foundation for cognition has lent further credence to these ideas. The hypotheses of a self–other matching deficit and impaired mirror neuron function in autism have now been well supported by studies employing a range of methodologies. However, underlying mechanisms require further exploration to explain how mirror neurons may be involved in attentional and mentalizing processes. Impairments in self–other matching and mirror neuron function are not necessarily inextricably linked and it seems possible that different sub‐populations of mirror neurons, located in several regions, contribute differentially to social cognitive functions. It is hypothesized that mirror neuron coding for action–direction may be required for developing attentional sensitivity to self‐directed actions, and consequently for person‐oriented, stimulus‐driven attention. Mirror neuron networks may vary for different types of social learning such as “automatic” imitation and imitation learning. Imitation learning may be more reliant on self–other comparison processes (based on mirror neurons) that identify differences as well as similarities between actions. Differential connectivity with the amygdala–orbitofrontal system may also be important. This could have implications for developing “theory of mind,” with intentional self–other comparison being relevant to meta‐representational abilities, and “automatic” imitation being more relevant to empathy. While it seems clear that autism is associated with impaired development of embodied aspects of cognition, the ways that mirror neurons contribute to these brain–behavior links are likely to be complex.

The aim of this study was to examine the association between depressive symptoms and several psychosocial constructs (insight into autism symptoms, rumination, desire for social interaction, and satisfaction with social support) that may play a role in the development or maintenance of depression in verbally fluent adolescents and adults with ASD. Participants included 50 individuals with ASD and verbal IQ ≥ 70, aged 16–35 (sample size varied by measure). Elevated depressive symptoms on the Beck Depression Inventory, 2nd edition (BDI‐II), were associated with greater self‐perceived, autism‐related impairments (n = 48), greater rumination (n = 21), and lower perceived social support (n = 37). Rumination tended to moderate the association between self‐perceived autism symptoms and BDI‐II scores (n = 21), and was significantly associated with ASD‐related insistence on sameness behaviors (n = 18). An unexpected relationship between depressive features and social participation and motivation will need to be clarified by longitudinal research. These and similar findings contribute to our understanding of the phenomenology of depression in ASD, which is critical to the development of practical prevention and treatment. Autism Res 2014, 7: 381–391. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.