Recognizing biological motion and emotions from point-light displays in autism spectrum disorders

One of the main characteristics of Autism Spectrum Disorder (ASD) are problems with social interaction and communication. Here, we explored ASD-related alterations in 'reading' body language of other humans. Accuracy and reaction times were assessed from two observational tasks involving the recognition of 'biological motion' and 'emotions' from point-light displays (PLDs). Eye movements were recorded during the completion of the tests. Results indicated that typically developed-participants were more accurate than ASD-subjects in recognizing biological motion or emotions from PLDs. No accuracy differences were revealed on two control-tasks (involving the indication of color-changes in the moving point-lights). Group differences in reaction times existed on all tasks, but effect sizes were higher for the biological and emotion recognition tasks. Biological motion recognition abilities were related to a person's ability to recognize emotions from PLDs. However, ASD-related atypicalities in emotion recognition could not entirely be attributed to more basic deficits in biological motion recognition, suggesting an additional ASD-specific deficit in recognizing the emotional dimension of the point light displays. Eye movements were assessed during the completion of tasks and results indicated that ASD-participants generally produced more saccades and shorter fixation-durations compared to the control-group. However, especially for emotion recognition, these altered eye movements were associated with reductions in task-performance.     

The co-morbidity burden of children and young adults with autism spectrum disorders

Objectives

Use electronic health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden of ASD in children and young adults.

Study Design

A retrospective prevalence study was performed using a distributed query system across three general hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with ASD were characterized by their co-morbidities and conversely, the prevalence of ASD within these comorbidities was measured. The comorbidity prevalence of the younger (Age<18 years) and older (Age 18–34 years) individuals with ASD was compared.

Results

19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58–14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89–2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13–0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72–6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41–10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3–0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26–0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79–1.14%). Autoimmune disorders (excluding DM1 and IBD) were not significantly different at 0.67% vs. 0.68% (95% CI −0.14-0.13%). Three of the studied comorbidities increased significantly when comparing ages 0–17 vs 18–34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I (0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel disorders (without IBD) and epilepsy did not change significantly.

Conclusions

The comorbidities of ASD encompass disease states that are significantly overrepresented in ASD with respect to even the patient populations of tertiary health centers. This burden of comorbidities goes well beyond those routinely managed in developmental medicine centers and requires broad multidisciplinary management that payors and providers will have to plan for.     

Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders

Background

Accumulating evidence suggests that dysregulation of the immune system is involved in the pathophysiology of autism spectrum disorders (ASD). The aim of the study was to explore immunological markers in peripheral plasma samples from non-medicated subjects with high-functioning ASD.

Methodology/Principal Findings

A multiplex assay for cytokines and chemokines was applied to plasma samples from male subjects with high-functioning ASD (n = 28) and matched controls (n = 28). Among a total of 48 analytes examined, the plasma concentrations of IL-1β, IL-1RA, IL-5, IL-8, IL-12(p70), IL-13, IL-17 and GRO-α were significantly higher in subjects with ASD compared with the corresponding values of matched controls after correction for multiple comparisons.

Conclusion/Significance

The results suggest that abnormal immune responses as assessed by multiplex analysis of cytokines may serve as one of the biological trait markers for ASD.     

Paraoxonase 1 activities and polymorphisms in autism spectrum disorders

Autism spectrum disorders (ASD) comprise a complex and heterogeneous group of conditions of unknown aetiology, characterized by significant disturbances in social, communicative and behavioural functioning. Recent studies suggested a possible implication of the high-density lipoprotein associated esterase/lactonase paraoxonase 1 (PON1) in ASD. In the present study, we aimed at investigating the PON1 status in a group of 50 children with ASD as compared to healthy age and sex matched control participants. We evaluated PON1 bioavailability (i.e. arylesterase activity) and catalytic activity (i.e. paraoxonase activity) in plasma using spectrophotometric methods and the two common polymorphisms in the PON1 coding region (Q192R, L55M) by employing Light Cycler real-time PCR. We found that both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with less active variants of the PON1 gene was found. The PON1 phenotype, inferred from the two-dimensional enzyme analysis, had a similar distribution in the ASD group and the control group. In conclusion, both the bioavailability and the catalytic activity of PON1 are impaired in ASD, despite no association with the Q192R and L55M polymorphisms in the PON1 gene and a normal distribution of the PON1 phenotype.     

Mutation screening of melatonin-related genes in patients with autism spectrum disorders

Background

One consistent finding in autism spectrum disorders (ASD) is a decreased level of the pineal gland hormone melatonin and it has recently been demonstrated that this decrease to a large extent is due to low activity of the acetylserotonin O-methyltransferase (ASMT), the last enzyme in the melatonin synthesis pathway. Moreover, mutations in the ASMT gene have been identified, including a splice site mutation, that were associated with low ASMT activity and melatonin secretion, suggesting that the low ASMT activity observed in autism is, at least partly, due to variation within the ASMT gene.

Methods

In the present study, we have investigated all the genes involved in the melatonin pathway by mutation screening of AA-NAT (arylalkylamine N-acetyltransferase), ASMT, MTNR1A, MTNR1B (melatonin receptor 1A and 1B) and GPR50 (G protein-coupled receptor 50), encoding both synthesis enzymes and the three main receptors of melatonin, in 109 patients with autism spectrum disorders (ASD). A cohort of 188 subjects from the general population was used as a comparison group and was genotyped for the variants identified in the patient sample.

Results

Several rare variants were identified in patients with ASD, including the previously reported splice site mutation in ASMT (IVS5+2T>C). Of the variants affecting protein sequence, only the V124I in the MTNR1B gene was absent in our comparison group. However, mutations were found in upstream regulatory regions in three of the genes investigated, ASMT, MTNR1A, and MTNR1B.

Conclusions

Our report of another ASD patient carrying the splice site mutation IVS5+2T>C, in ASMT further supports an involvement of this gene in autism. Moreover, our results also suggest that other melatonin related genes might be interesting candidates for further investigation in the search for genes involved in autism spectrum disorders and related neurobehavioral phenotypes. However, further studies of the novel variants identified in this study are warranted to shed light on their potential role in the pathophysiology of these disorders.     

Subtelomeric region of chromosome 2 in patients with autism spectrum disorders

Autism spectrum disorders are severe psychiatric diseases commonly identified in the population. They are diagnosed during childhood and the etiology has been much debated due to their variations and complexity. Onset is early and characterized as communication and social interaction disorders and as repetitive and stereotyped behavior. Autistic disorders may occur together with various genetic and chromosomal diseases. Several chromosomal regions and genes are implicated in the predisposition for these diseases, in particular those with products expressed in the central nervous system. There are reports of autistic and mentally handicapped patients with submicroscopic subtelomeric alterations at the distal end of the long arm of chromosome 2. Additionally, there is evidence that alterations at 2q37 cause brain malformations that result in the autistic phenotype. These alterations are very small and not identified by routine cytogenetics to which patients are normally submitted, which may result in an underestimation of the diagnosis. This study aimed at evaluating the 2q37 region in patients with autistic disorders. Twenty patients were studied utilizing the fluorescence in situ hybridization technique with a specific probe for 2q37. All of them were also studied by the GTC banding technique to identify possible chromosomal diseases. No alterations were observed in the 2q37 region of the individuals studied, and no patient presented chromosomal diseases. This result may be due to the small sample size analyzed. The introduction of routine analysis of the 2q37 region for patients with autistic disorders depends on further studies.     

Elevated rates of testosterone-related disorders in women with autism spectrum conditions

The androgen theory of autism proposes that autism spectrum conditions (ASC) are in part due to elevated fetal testosterone (FT) levels, which are positively correlated with a number of autistic traits and inversely correlated with social development and empathy. A medical questionnaire was completed by n=54 women with ASC, n=74 mothers of children with ASC, and n=183 mothers of typically developing children to test whether women with ASC have an increased rate of testosterone-related medical conditions, and to see whether mothers of children with ASC show similar abnormalities, as part of the 'broader autism phenotype'. Compared to controls, significantly more women with ASC reported (a) hirsutism, (b) bisexuality or asexuality, (c) irregular menstrual cycle, (d) dysmenorrhea, (e) polycystic ovary syndrome, (f) severe acne, (g) epilepsy, (h) tomboyism, and (i) family history of ovarian, uterine, and prostate cancers, tumors, or growths. Compared to controls, significantly more mothers of ASC children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths. These results suggest current hormone abnormalities in women with ASC and their mothers. Direct investigations of serum testosterone levels and genetic susceptibility to high testosterone production or sensitivity in women with ASC would illuminate the origin of these conditions. The relationship between FT and current testosterone levels also needs to be clarified. The present results may be relevant to understanding the increased male risk to developing autism.     

Human plasma glycome in attention-deficit hyperactivity disorder and autism spectrum disorders

Over a half of all proteins are glycosylated, and their proper glycosylation is essential for normal function. Unfortunately, because of structural complexity of nonlinear branched glycans and the absence of genetic template for their synthesis, the knowledge about glycans is lagging significantly behind the knowledge about proteins or DNA. Using a recently developed quantitative high throughput glycan analysis method we quantified components of the plasma N-glycome in 99 children with attention-deficit hyperactivity disorder (ADHD), 81 child and 5 adults with autism spectrum disorder, and a total of 340 matching healthy controls. No changes in plasma glycome were found to associate with autism spectrum disorder, but several highly significant associations were observed with ADHD. Further structural analysis of plasma glycans revealed that ADHD is associated with increased antennary fucosylation of biantennary glycans and decreased levels of some complex glycans with three or four antennas. The design of this study prevented any functional conclusions about the observed associations, but specific differences in glycosylation appears to be strongly associated with ADHD and warrants further studies in this direction.     

Genetics and mitochondrial abnormalities in autism spectrum disorders: a review

We review the current status of the role and function of the mitochondrial DNA (mtDNA) in the etiology of autism spectrum disorders (ASD) and the interaction of nuclear and mitochondrial genes. High lactate levels reported in about one in five children with ASD may indicate involvement of the mitochondria in energy metabolism and brain development. Mitochondrial disturbances include depletion, decreased quantity or mutations of mtDNA producing defects in biochemical reactions within the mitochondria. A subset of individuals with ASD manifests copy number variation or small DNA deletions/duplications, but fewer than 20 percent are diagnosed with a single gene condition such as fragile X syndrome. The remaining individuals with ASD have chromosomal abnormalities (e.g., 15q11-q13 duplications), other genetic or multigenic causes or epigenetic defects. Next generation DNA sequencing techniques will enable better characterization of genetic and molecular anomalies in ASD, including defects in the mitochondrial genome particularly in younger children.     

Profiles of executive function in parents and siblings of individuals with autism spectrum disorders

Delineation of a cognitive endophenotype for autism is useful both for exploring the genetic mechanisms underlying the disorder and for identifying which cognitive traits may be primary to it. This study investigated whether first-degree relatives of individuals with autism spectrum disorders (ASDs) demonstrate a specific profile of performance on a range of components of executive function (EF), to determine whether EF deficits represent possible endophenotypes for autism. Parents and siblings of ASD and control probands were tested on EF tasks measuring planning, set-shifting, inhibition and generativity. ASD parents showed poorer performance than control parents on a test of ideational fluency or generativity, and ASD fathers demonstrated a weakness in set-shifting to a previously irrelevant dimension. ASD siblings revealed a mild reduction in ideational fluency and a weakness in non-verbal generativity when compared with control siblings. Neither ASD parents nor siblings displayed significant difficulties with planning or inhibition. These results indicated that the broad autism phenotype may not be characterized primarily by impairments in planning and cognitive flexibility, as had been previously proposed. Weaknesses in generativity emerged as stronger potential endophenotypes in this study, suggesting that this aspect of EF should play a central role in cognitive theories of autism. However, discrepancies in the EF profile demonstrated by parents and siblings suggest that factors related to age or parental responsibility may affect the precise pattern of deficits observed.     

High prevalence of serum folate receptor autoantibodies in children with autism spectrum disorders

Abstract

Background: Supplementation of folic acid by pregnant mothers is thought to lower the risk of autism spectrum disorders (ASDs) in the offspring. Folic acid is taken up by cells via receptors with high affinity for folate and reduced folic acid derivatives. However, this is blocked by the presence of folate receptor autoantibodies (FRAA). Cerebral FRAA have been detected with high frequency in children with ASDs, suggesting the existence of a link between folic acid uptake and disease aetiology.

Methods: We investigated the frequency of FRAA in serum samples from 40 children with ASDs and 42 gender- and age-matched children with typical development (TD). Serum FRAA concentrations were measured by enzyme-linked immunosorbent assay.

Results: We found a significant difference in the frequency of serum FRAA in the two study cohorts. Serum FRAA were present in 77.5% (31/40) of children with ASDs compared with 54.8% (23/42) of TD children (p?=?0.03746, Fischer’s exact test). Thus, serum FRAA are more prevalent in children with ASDs than in TD children.

Conclusions: Our data suggest that children with ASDs may have defects in folic acid absorption that play a role in the onset of ASDs.     

Serum levels of glial fibrillary acidic protein and Nogo-A in children with autism spectrum disorders

Context: Improved biomarkers would facilitate the diagnosis and treatment of autism spectrum disorders (ASD).

Objective: Our objective was to examine the levels of Nogo-A and glial fibrillary acidic protein (GFAP) in children with ASD.

Materials and methods: Serum concentrations of GFAP and Nogo-A were determined by enzyme-linked immunosorbent assay.

Results: In this preliminary study, we found that serum Nogo-A was not found significantly different between groups, while serum levels of GFAP were significantly lower in ASD than controls.

Discussion and conclusions: It will be of great interest to determine other potential causes of elevated serum levels of GFAP, and whether this elevation has any phenotypic effect.     

Intact automatic imitation of human and robot actions in autism spectrum disorders

The existence of a specialized imitation module in humans is hotly debated. Studies suggesting a specific imitation impairment in individuals with autism spectrum disorders (ASD) support a modular view. However, the voluntary imitation tasks used in these studies (which require socio-cognitive abilities in addition to imitation for successful performance) cannot support claims of a specific impairment. Accordingly, an automatic imitation paradigm (a 'cleaner' measure of imitative ability) was used to assess the imitative ability of 16 adults with ASD and 16 non-autistic matched control participants. Participants performed a prespecified hand action in response to observed hand actions performed either by a human or a robotic hand. On compatible trials the stimulus and response actions matched, while on incompatible trials the two actions did not match. Replicating previous findings, the Control group showed an automatic imitation effect: responses on compatible trials were faster than those on incompatible trials. This effect was greater when responses were made to human than to robotic actions ('animacy bias'). The ASD group also showed an automatic imitation effect and a larger animacy bias than the Control group. We discuss these findings with reference to the literature on imitation in ASD and theories of imitation.     

A comparison of urinary mercury between children with autism spectrum disorders and control children

Background

Urinary mercury concentrations are used in research exploring mercury exposure. Some theorists have proposed that autism is caused by mercury toxicity. We set out to test whether mercury concentrations in the urine of children with autism were significantly increased or decreased compared to controls or siblings.

Methods

Blinded cohort analyses were carried out on the urine of 56 children with autism spectrum disorders (ASD) compared to their siblings (n = 42) and a control sample of children without ASD in mainstream (n = 121) and special schools (n = 34).

Results

There were no statistically significant differences in creatinine levels, in uncorrected urinary mercury levels or in levels of mercury corrected for creatinine, whether or not the analysis is controlled for age, gender and amalgam fillings.

Conclusions

This study lends no support for the hypothesis of differences in urinary mercury excretion in children with autism compared to other groups. Some of the results, however, do suggest further research in the area may be warranted to replicate this in a larger group and with clear measurement of potential confounding factors.     

Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia

Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.     

Interhemispheric differences in the spectral power and coherence of EEG rhythms in children with autism spectrum disorders

Electroencephalographic examination of boys aged 4–9 years with autism spectrum disorders (ASDs) showed spectral power values and coherence in high-frequency bands (20–60 Hz) in various brain areas were higher than normal. Differences in spectral power were greater in the anterior areas of the left hemisphere; differences in coherence, in the right anterior and posterior areas. Interhemispheric differences typical of healthy subjects were absent in the children with ASDs. The spectral power of the θ rhythm was lower in autism, especially in the left hemisphere. The spectral power of the α rhythm in the autistic children was lower than normal, especially in the posterior areas of the left hemisphere. The μ rhythm was higher than normal in spectral power and was localized in the right, rather than left, anterior areas. The children were examined again after corrective procedures. The α-rhythm spectral power increased (became closer to the norm) in the left posterior areas, while the γ-rhythm spectral power decreased (became closer to the norm) in the right anterior areas in some of the autistic children. The electrophysiological changes were associated with improved psychological testing results, especially in nonverbal measures.     

ANS: aberrant neurodevelopment of the social cognition network in adolescents with autism spectrum disorders

Background

Autism spectrum disorders (ASD) are characterized by aberrant neurodevelopment. Although the ASD brain undergoes precocious growth followed by decelerated maturation during early postnatal period of childhood, the neuroimaging approach has not been empirically applied to investigate how the ASD brain develops during adolescence.

Methodology/Principal Findings

We enrolled 25 male adolescents with high functioning ASD and 25 typically developing controls for voxel-based morphometric analysis of structural magnetic resonance image. Results indicate that there is an imbalance of regional gray matter volumes and concentrations along with no global brain enlargement in adolescents with high functioning ASD relative to controls. Notably, the right inferior parietal lobule, a role in social cognition, have a significant interaction of age by groups as indicated by absence of an age-related gain of regional gray matter volume and concentration for neurodevelopmental maturation during adolescence.

Conclusions/Significance

The findings indicate the neural correlates of social cognition exhibits aberrant neurodevelopment during adolescence in ASD, which may cast some light on the brain growth dysregulation hypothesis. The period of abnormal brain growth during adolescence may be characteristic of ASD. Age effects must be taken into account while measures of structural neuroimaging have been clinically put forward as potential phenotypes for ASD.     

A systems biological study on the comorbidity of autism spectrum disorders and bipolar disorder

Autism Spectrum Disorder (ASD) is a "spectrum" of disorders, characterized by varying degrees of symptoms ranging from mild to severe. Among Psychiatric disorders, Autism Spectrum Disorders have the strongest evidence for a genetic basis, yet the search for specific genes contributing to these often devastating developmental syndromes has proven extraordinarily difficult. Bipolar Disorder (BP) is a manic-depressive disorder whose symptoms are characterized by extremities in moods. It is also called as the "Mood disorder". BP, like, ASD also has a strong genetic basis and identification of the candidate genes still remains an ongoing effort. Literature studies point to the hypothesis that ASD and BP have good chances of comorbidity and that they may share common pathways for their manifestation. But this hypothesis has not been worked on in depth. Thus, the study focuses on identifying the chances of their comorbidity by identifying their common pathways and the genes involved in the pathways and also discuss the degree of chances of their comorbidity based on the genes involved in the common pathways. Networks for the genes are also constructed to represent their commonness or uniqueness for the disorders.     

White matter connectivity in children with autism spectrum disorders: a tract-based spatial statistics study

Background

Autism spectrum disorders (ASD) are associated with widespread alterations in white matter (WM) integrity. However, while a growing body of studies is shedding light on microstructural WM alterations in high-functioning adolescents and adults with ASD, literature is still lacking in information about whole brain structural connectivity in children and low-functioning patients with ASD. This research aims to investigate WM connectivity in ASD children with and without mental retardation compared to typically developing controls (TD).

Methods

Diffusion tensor imaging (DTI) was performed in 22 young children with ASD (mean age: 5.54 years) and 10 controls (mean age: 5.25 years). Data were analysed both using the tract-based spatial statistics (TBSS) and the tractography. Correlations were investigated between the WM microstructure in the identified altered regions and the productive language level.

Results

The TBSS analysis revealed widespread increase of fractional anisotropy (FA) in major WM pathways. The tractographic approach showed an increased fiber length and FA in the cingulum and in the corpus callosum and an increased mean diffusivity in the indirect segments of the right arcuate and the left cingulum. Mean diffusivity was also correlated with expressive language functioning in the left indirect segments of the arcuate fasciculus.

Conclusions

Our study confirmed the presence of several structural connectivity abnormalities in young ASD children. In particular, the TBSS profile of increased FA that characterized the ASD patients extends to children a finding previously detected in ASD toddlers only. The WM integrity abnormalities detected may be relevant to the pathophysiology of ASD, since the structures involved participate in some core atypical characteristics of the disorder.