Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism

Autism together with Asperger syndrome and pervasive developmental disorder not otherwise specified form a spectrum of conditions (autism spectrum disorders or ASD) that is characterized by disturbances in social behavior, impaired communication and the presence of stereotyped behaviors or circumscribed interests. Recent estimates indicate a prevalence of ASD of 1 per 150 (Kuehn, 2007). The cause(s) of most cases of ASD are unknown but there is an emerging consensus that ASD have multiple etiologies. One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533–537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.     

Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder

Autism spectrum disorder (ASD) is very heterogeneous and multiple subtypes and etiologies likely exist. The maternal immune system has been implicated in the pathogenesis of some forms of ASD. Previous studies have identified the presence of specific maternal IgG autoantibodies with reactivity to fetal brain proteins at 37 and 73 kDa in up to 12% of mothers of children with ASD. The current study evaluates the presence of these autoantibodies in an independent cohort of mothers of 181 preschool-aged male children (131 ASD, 50 typically developing (TD) controls). We also investigated whether ASD children born to mothers with these autism-specific maternal IgG autoantibodies exhibit a distinct neural phenotype by evaluating total brain volume using structural magnetic resonance imaging (MRI). Of the 131 ASD children, 10 (7.6%) were born to mothers with the 37/73 kDa IgG autoantibodies (ASD-IgG). The mothers of the remaining ASD children and all TD controls were negative for these paired autoantibodies. While both ASD groups exhibited abnormal brain enlargement that is commonly observed in this age range, the ASD-IgG group exhibited a more extreme 12.1% abnormal brain enlargement relative to the TD controls. In contrast, the remaining ASD children exhibited a smaller 4.4% abnormal brain enlargement relative to TD controls. Lobar and tissue type analyses revealed that the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected. These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement.     

Brief Report: Seeing the Man in the Moon: Do Children with Autism Perceive Pareidolic Faces? A Pilot Study

Faces are one of the most socially significant visual stimuli encountered in the environment, whereas pareidolias are illusions of faces arising from ambiguous stimuli in the environment. Autism spectrum disorder (ASD) is characterised by deficits in response to social stimuli. We found that children with ASD (n?=?60) identify significantly fewer pareidolic faces in a sequence of ambiguous stimuli than typically developing peers. The two groups did not differ in the number of objects identified, indicating that the children with ASD had a specific lack of attention to faces. Pareidolia have considerable potential as naturalistic and easy-to-create materials for the investigation of spontaneous attention to social stimuli in children with ASD.     

The effects of coping style,social support,and behavioral problems on the well-being of mothers of children with Autism Spectrum Disorders in Lebanon

The present study examined the effects of coping styles, social support, and child's behavioral symptoms on the well-being of 65 mothers of children with Autism Spectrum Disorders (ASD) in Lebanon. Comparisons to the well-being of 98 mothers of typically developing children were also drawn. Regression analyses showed that disengagement and distraction coping predicted poor well-being, whereas cognitive reframing showed a correlation with better well-being levels. A significant correlation was found between child's behavioral problems and maternal well-being. T-test analyses revealed that mothers of children with ASD differed in terms of coping styles used. Additionally, mothers of children with ASD showed lower levels of perceived social support. Well-being was significantly better for mothers of typically developing children. Study limitations and implications are discussed.     

Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression

The contribution of peripheral immunity to autism spectrum disorders (ASDs) risk is debated and poorly understood. Some mothers of children with ASD have autoantibodies that react to fetal brain proteins, raising the possibility that a subset of ASD cases may be associated with a maternal antibody response during gestation. The mechanism by which the maternal immune system breaks tolerance has not been addressed. We hypothesized that the mechanism may involve decreased expression of the MET receptor tyrosine kinase, an ASD risk gene that also serves as a key negative regulator of immune responsiveness. In a sample of 365 mothers, including 202 mothers of children with ASD, the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003). To determine the mechanism of this genetic association, we measured MET protein and cytokine production in freshly prepared peripheral blood mononuclear cells from 76 mothers of ASD and typically developing children. The MET rs1858830 C allele was significantly associated with MET protein expression (P=0.025). Moreover, decreased expression of the regulatory cytokine IL-10 was associated with both the MET gene C allele (P=0.001) and reduced MET protein levels (P=0.002). These results indicate genetic distinction among mothers who produce ASD-associated antibodies to fetal brain proteins, and suggest a potential mechanism for how a genetically determined decrease in MET protein production may lead to a reduction in immune regulation.     

Are Anxiety Disorders in Children and Adolescents Less Impairing Than ADHD and Autism Spectrum Disorders? Associations with Child Quality of Life and Parental Stress and Psychopathology

We compared clinically referred children with anxiety disorders (AD; n?=?63) to children with autism spectrum disorder (ASD; n?=?39), ADHD Combined (ADHD-C; n?=?62), ADHD Predominantly Inattentive (ADHD-I; n?=?64), and typically developing children (n?=?42) on child quality of life (QOL), paternal and maternal psychopathology and parental stress. Diagnoses were based on DSM-IV-TR criteria. Multilevel analyses showed that QOL in AD was higher on school and social functioning, compared to respectively ADHD and ASD, and lower compared to normal controls on all five domains. Fathers reported their AD children higher QOL than mothers. Also, AD appeared to be associated with less parental stress and parental psychopathology than other child psychopathology. Therefore, parental factors may need to be considered more in treatment of children with ADHD/ASD than AD.     

Cortisol Responsivity Differences in Children with Autism Spectrum Disorders During Free and Cooperative Play

Children with autism spectrum disorder (ASD) demonstrate significant heterogeneity in their profiles of social interaction and stress responsivity. We evaluated behavior and stress response in 52 male children ages 8–12 in a naturalistic playground interaction paradigm involving a child with ASD, a typically developing peer, and a same-age confederate. Younger children in the ASD group engaged in 5.8 times more approach behavior and showed a lower cortisol response than their older peers. Those that verbally initiated with their peers also showed a higher cortisol response. Older children with ASD exhibited the highest stress responsivity, while younger children with ASD showed more willingness to approach others without apparent stress. Intervening early and often may contribute to improvements in social engagement in youth with ASD.     

Television, Video Game and Social Media Use Among Children with ASD and Typically Developing Siblings

This study examined the nature of television, video game, and social media use in children (ages 8–18) with autism spectrum disorders (ASD, n = 202) compared to typically developing siblings (TD, n = 179), and relative to other activities. Parents completed measures assessing children’s screen-based and other extracurricular activities. Children with ASD spent approximately 62 % more time watching television and playing video games than in all non-screen activities combined. Compared with TD siblings, children with ASD spent more hours per day playing video games (2.4 vs. 1.6 for boys, and 1.8 vs. 0.8 for girls), and had higher levels of problematic video game use. In contrast, children with ASD spent little time using social media or socially interactive video games.     

Maternal infections and subsequent psychosis among offspring.

BACKGROUND: We tested the hypothesis that maternal infections during pregnancy are associated with the subsequent development of schizophrenia and other psychoses in adulthood. METHODS: We conducted a nested case-control study of 27 adults with schizophrenia and other psychotic illnesses and 54 matched unaffected control subjects (matched for sex, ethnicity, and date of birth) from the Providence, RI, cohort of the Collaborative Perinatal Project. We retrieved stored blood samples that had been obtained from these mothers at the end of pregnancy. These samples were analyzed for total class-specific immunoglobulins and for specific antibodies directed at recognized perinatal pathogens capable of affecting brain development. RESULTS: Maternal levels of IgG and IgM class immunoglobulins before the mothers were delivered of their neonates were significantly elevated among the case series (t = 3.06, P =.003; t = 2.93, P =.004, respectively, for IgG and IgM immunoglobulin-albumin ratios). Secondary analyses indicated a significant association between maternal antibodies to herpes simplex virus type 2 glycoprotein gG2 and subsequent psychotic illness (matched t test = 2.43, P =.02). We did not find significant differences between case and control mothers in the serum levels of IgA class immunoglobulins, or in specific IgG antibodies to herpes simplex virus type 1, cytomegalovirus, Toxoplasma gondii, rubella virus, human parvovirus B19, Chlamydia trachomatis, or human papillomavirus type 16. CONCLUSIONS: The offspring of mothers with elevated levels of total IgG and IgM immunoglobulins and antibodies to herpes simplex virus type 2 are at increased risk for the development of schizophrenia and other psychotic illnesses in adulthood.     

The role of family cohesion in the psychological adjustment of non-Hispanic White and Hispanic mothers of children with autism spectrum disorder

The current study utilizes a process-oriented approach to understand both personal and family factors influencing the development of depressive symptoms among non-Hispanic White and Hispanic mothers of children with ASD. Family cohesion was hypothesized to mediate the associations between the personal factors (optimism, benefit finding, social support) and depressive symptoms. Mothers of 117 children with ASD (Hispanic n = 73; non-Hispanic White n = 44) completed measures of depressive symptoms, family cohesion, social support, optimism, and benefit finding. Results from this study indicate that optimism, benefit finding, and social support are important predictors of positive maternal adjustment. Furthermore, these factors contribute to better family functioning, namely family cohesion. The mediation models containing optimism, benefit finding, partner and family support were significant for both Hispanic and non-Hispanic White mothers, suggesting a similar mediation process for both racial/ethnic groups. However, family cohesion was a significant mediator of the relationship between friend support and depressive symptoms for Hispanic mothers only. The results of this study complement and extend previous research examining family functioning among mothers of children with ASD and have implications for the development of interventions aimed at increasing maternal well-being.     

Temporal dynamics reveal atypical brain response to social exclusion in autism

Despite significant social difficulties, children with autism spectrum disorder (ASD) are vulnerable to the effects of social exclusion. We recorded EEG while children with ASD and typical peers played a computerized game involving peer rejection. Children with ASD reported ostracism-related distress comparable to typically developing children. Event-related potentials (ERPs) indicated a distinct pattern of temporal processing of rejection events in children with ASD. While typically developing children showed enhanced response to rejection at a late slow wave indexing emotional arousal and regulation, those with autism showed attenuation at an early component, suggesting reduced engagement of attentional resources in the aversive social context. Results emphasize the importance of studying the time course of social information processing in ASD; they suggest distinct mechanisms subserving similar overt behavior and yield insights relevant to development and implementation of targeted treatment approaches and objective measures of response to treatment.     

The effect of peer- and sibling-assisted aquatic program on interaction behaviors and aquatic skills of children with autism spectrum disorders and their peers/siblings

The purpose of this study was to assess the effect of peer- and sibling-assisted learning on interaction behaviors and aquatic skills in children with autism spectrum disorders (ASD). Outcome measures were also examined in their typically developing (TD) peers/siblings. Twenty-one children with ASD and 21 TD children were assigned in three groups: peer-assisted (PG), sibling-assisted (SG), and control (CG). All participated in 16-week aquatic settings under three instructional conditions (teacher-directed, peer/sibling-assisted, and voluntary support). The main findings were that (a) PG and SG of children with ASD showed significantly more improvement on physical and social interactions with their TD peers/siblings during peer/sibling-assisted condition as compared to CG (p < 0.01), (b) PG and SG of children with ASD showed significantly more improvement on physical interactions with their TD peers/siblings (p < 0.01) and social interactions with their teachers and other children with ASD (p < 0.01) during voluntary support condition as compared to CG, and (c) all children with ASD and their TD peers/siblings significantly increased their aquatic skills after the program. The benefit for children with ASD as well as TD peers/siblings makes the use of TD peer/sibling assisted learning an even more desirable instructional strategy.     

Death concerns and psychological well-being in mothers of children with autism spectrum disorder

PurposeUtilizing a terror management theory perspective, the present research examined whether having a child with autism spectrum disorder (ASD) is associated with underlying cognitions and explicit worries about death, and their roles in psychological well-being.Method147 mothers of children with ASD (n = 74) and typically developing children (n = 73) completed a fear of death scale, as well as measures of death-thought accessibility, positive and negative affect, depression, and anxiety.ResultsFollowing previous research, mothers of children with ASD reported worse psychological health. Additionally, they evidenced greater death-thought accessibility compared to mothers of typically developing children, but did not differ in explicit worries about mortality. Greater death-thought accessibility, in turn, mediated the influence of ASD diagnosis on negative affect, depression, and anxiety.ConclusionThe current study offers an initial understanding of the association between mortality concerns and psychological health for mothers of children with ASD. Further, it underscores the importance of health care providers’ efforts to attend to, and educate parents about, their thoughts of mortality, even if the parent does not acknowledge such concerns.What this paper addsThe present study examined the impact of both implicit and explicit worries about death in parents of children with Autism Spectrum Disorder (ASD). Specifically, we were able to demonstrate that increased death-thought accessibility among mothers of children with ASD was associated with worse psychological health. While it is possible for parents of children with ASD to report conscious worries about death, there were no observed differences on this measure. As far as we know, this work is the first to empirically examine the prevalence of mortality-related concerns in this population and the subsequent effects of death-thought accessibility on psychological health. This is an important avenue of research as parents of children with ASD may experience greater worries about leaving their children upon death with no one to care for them, or to leave their children in the care of individuals who may not understand their son or daughter's unique needs. Additionally, the current findings highlight the importance of addressing mortality-related concerns, even when they may not be explicitly recognized, among parents of children with ASD. Given the effectiveness of parent education programs for children with ASD, a primary avenue for intervention may be education. Training care providers in ways to better discuss thoughts of death may help to alleviate stress and foster greater psychological well-being.     

Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders

Autism spectrum disorders (ASDs) are characterized by impaired language and social skills, often with restricted interests and stereotyped behaviors. A previous investigation of blood plasma from children with ASDs (mean age = 5½ years) demonstrated that 21% of samples contained autoantibodies that reacted intensely with GABAergic Golgi neurons of the cerebellum while no samples from non-sibling, typically developing children showed similar staining (Wills et al., 2009). In order to characterize the clinical features of children positive for these autoantibodies, we analyzed plasma samples from children enrolled in the Autism Phenome Project, a multidisciplinary project aimed at identifying subtypes of ASD. Plasma from male and female children (mean age = 3.2 years) was analyzed immunohistochemically for the presence of autoantibodies using histological sections of macaque monkey brain. Immunoreactivity to cerebellar Golgi neurons and other presumed interneurons was observed for some samples but there was no difference in the rate of occurrence of these autoantibodies between children with ASD and their typically developing peers. Staining of neurons, punctate profiles in the molecular layer of the dentate gyrus, and neuronal nuclei were also observed. Taken together, 42% of controls and subjects with ASD demonstrated immunoreactivity to some neural element. Interestingly, children whose plasma reacted to brain tissue had scores on the Child Behavior Checklist (CBCL) that indicated increased behavioral and emotional problems. Children whose plasma was immunoreactive with neuronal cell bodies scored higher on multiple CBCL scales. These studies indicate that additional research into the genesis and prevalence of brain-directed autoantibodies is warranted.     

Sound before meaning: word learning in autistic disorders

Successful word learning depends on the integration of phonological and semantic information with social cues provided by interlocutors. How then, do children with autism spectrum disorders (ASDs) learn new words when social impairments pervade? We recorded the eye-movements of verbally-able children with ASD and their typical peers while completing a word learning task in a social context. We assessed learning of semantic and phonological features immediately after learning and again four weeks later. Eye-movement data revealed that both groups could follow social cues, but that typically developing children were more sensitive to the social informativeness of gaze cues. In contrast, children with ASD were more successful than peers at mapping phonological forms to novel referents; however, this advantage was not maintained over time. Typical children showed clear consolidation of learning both semantic and phonological information, children with ASD did not. These results provide unique evidence of qualitative differences in word learning and consolidation and elucidate the different mechanisms underlying the unusual nature of autistic language.     

Maternal androgens and autism spectrum disorder in the MARBLES prospective cohort study

BackgroundMaternal hormonal risk factors for autism spectrum disorder (ASD) in offspring could intersect genetic and environmental risk factors.ObjectivesThis analysis explored ASD risk in association with maternal testosterone, androstenedione, and dehydroepiandrosterone (DHEA) measured in first, second, and third trimesters of pregnancy.MethodsMARBLES is a prospective pregnancy cohort study based at the MIND Institute in Northern California that enrolls mothers who have at least one child previously diagnosed with ASD and are expecting, or planning to have another child. At 36 months the younger sibling is clinically classified as having ASD, or as non-typically developing (Non-TD), or typically developing (TD). Maternal androgens during pregnancy were measured in serum samples from 196 mothers. Multivariable logistic regression models estimated risk of ASD and Non-TD in offspring compared to TD, in relation to the log-transformed maternal androgen concentrations, at each trimester.ResultsNon-significant associations were observed, and borderline significant associations were only observed in some stratified unadjusted models. Second trimester maternal testosterone was non-significantly associated with ASD in female offspring, although not after adjustment, aRR 1.54 (95% CI 0.71, 3.33), and second trimester maternal DHEA was non-significantly associated with non-TD in male offspring, again not after adjustment, aRR 0.50 (95% CI 0.21, 1.21). Secondary analysis suggested that third trimester androgen concentrations in mothers with male offspring had significant or near significant associations with their child’s Social Responsiveness Scale score.ConclusionNo significant associations were found between maternal androgen concentrations and risk of ASD or Non-TD in the child.     

Brief Report: Antibodies Reacting to Brain Tissue in Basque Spanish Children with Autism Spectrum Disorder and Their Mothers

Previous investigations found that a subset of children with autism spectrum disorder (ASD) in California possessed plasma autoantibodies that reacted intensely with brain interneurons or other neural profiles. Moreover, for several cohorts of American women, maternal autoantibody reactivity to specific fetal brain proteins was highly specific to mothers of children with ASD. We sought to determine whether children and their mothers from a regionally specific cohort from the Basque Country of Spain demonstrated similar reactivity. Some children’s plasma reacted to interneurons, beaded axons or other neural profiles with no difference in the occurrence of these antibodies in children with or without ASD. Findings on the maternal antibodies confirmed previous research; plasma reactivity to fetal brain a combination of proteins at 37 and 73 kDa or 39 and 73 kDa was found exclusively in mothers of children with ASD.     

Types and experiences of bullying in adolescents with an autism spectrum disorder

Being victimized by one's peers is a major problem in adolescence, and research has suggested that individuals with autism spectrum disorders (ASD) may experience higher rates of bullying than their typically-developing (TD) peers. However, it is currently unclear whether adolescents with ASD are victimized more by their peers simply because they are ‘different’. This study was designed to examine percentage rates across different types of bullying behaviour in adolescents with an ASD (n = 24), in comparison to a group of special-needs adolescents without an ASD (n = 22), and a group of typically developing peers (n = 24), to determine whether simply being ‘different’ leads to higher rates of victimization. We also examined the agreement between parental and self-reports of bullying behaviour experienced by these groups. Overall, more adolescents with ASD reported victimization than adolescents in the other two groups. In addition, those with ASD reported more social bullying in comparison to the other two groups and more physical bullying than the TD group. No difference was found between parental and self-reports for the bullying experienced by the adolescents with ASD or special needs; however, TD adolescents reported higher levels of victimization than their parents reported for them. Contributing factors for the victimization experienced by adolescents with an ASD are discussed.     

Atypical spatiotemporal signatures of working memory brain processes in autism

Working memory (WM) impairments may contribute to the profound behavioural manifestations in children with autism spectrum disorder (ASD). However, previous behavioural results are discrepant as are the few functional magnetic resonance imaging (fMRI) results collected in adults and adolescents with ASD. Here we investigate the precise temporal dynamics of WM-related brain activity using magnetoencephalography (MEG) in 20 children with ASD and matched controls during an n-back WM task across different load levels (1-back vs 2-back). Although behavioural results were similar between ASD and typically developing (TD) children, the between-group comparison performed on functional brain activity showed atypical WM-related brain processes in children with ASD compared with TD children. These atypical responses were observed in the ASD group from 200 to 600 ms post stimulus in both the low- (1-back) and high- (2-back) memory load conditions. During the 1-back condition, children with ASD showed reduced WM-related activations in the right hippocampus and the cingulate gyrus compared with TD children who showed more activation in the left dorso-lateral prefrontal cortex and the insulae. In the 2-back condition, children with ASD showed less activity in the left insula and midcingulate gyrus and more activity in the left precuneus than TD children. In addition, reduced activity in the anterior cingulate cortex was correlated with symptom severity in children with ASD. Thus, this MEG study identified the precise timing and sources of atypical WM-related activity in frontal, temporal and parietal regions in children with ASD. The potential impacts of such atypicalities on social deficits of autism are discussed.     

Autism spectrum disorder and the student teacher relationship: A comparison study with peers with intellectual disability and typical development

This study examined relations among behavior problems, social skills, and student–teacher relationships within a sample of children (mean age 8) with autism spectrum disorders or ASD (n = 36) and comparison samples of children with typical development (n = 91) or with intellectual disability (n = 38.) Student–teacher relationships (STRs) for children with ASD appeared to be qualitatively different from those of similarly aged children with ID or typical development. The STRs for children with ASD were considerably poorer, with less closeness and more conflict, than in the two comparison groups. Within the group with ASD, teacher-reported child externalizing behavior and social skills accounted for significant variance in the total score on the Student Teacher Relationship Scale. Conflict was predicted only by externalizing behavior, whereas closeness was predicted by social skills; level of autistic mannerisms negatively related to the teacher's perception of closeness. Findings address the implications for transition to early schooling for children with ASD.