Exploring the multifactorial nature of autism through computational systems biology: Calcium and the Rho GTPase RAC1 under the spotlight

Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication accompanied with repetitive behavioral patterns and unusual stereotyped interests. Autism is considered a highly heterogeneous disorder with diverse putative causes and associated factors giving rise to variable ranges of symptomatology. Incidence seems to be increasing with time, while the underlying pathophysiological mechanisms remain virtually uncharacterized (or unknown). By systematic review of the literature and a systems biology approach, our aims were to examine the multifactorial nature of autism with its broad range of severity, to ascertain the predominant biological processes, cellular components, and molecular functions integral to the disorder, and finally, to elucidate the most central contributions (genetic and/or environmental) in silico. With this goal, we developed an integrative network model for gene-environment interactions (GENVI model) where calcium (Ca2+) was shown to be its most relevant node. Moreover, considering the present data from our systems biology approach together with the results from the differential gene expression analysis of cerebellar samples from autistic patients, we believe that RAC1, in particular, and the RHO family of GTPases, in general, could play a critical role in the neuropathological events associated with autism. © 2013 Springer Science+Business Media New York.

Effects of Systematic Social Skill Training on the Social-Communication Behaviors of Young Children with Autism During Play Activities

A systematic social skills training intervention to teach reciprocal sharing was designed and implemented with triads of preschool-age children, including one child with an autism spectrum disorder (ASD) and two untrained classroom peers who had no delays or disabilities. A multiple-baseline research design was used to evaluate effects of the social skills training intervention on social-communication and sharing behaviors exhibited by the participants with ASD during interactive play activities with peers. Social-communication behaviors measured included contact and distal gestures, touching peers and speaking. Four sharing behaviors were also measured, including sharing toys and objects, receiving toys and objects, asking others to share, and giving requested items. Results indicated considerable gains in overall social-communication behaviors. The greatest improvements were observed in the participants’ use of contact gestures and speaking. Slightly increasing trends were noted and suggested that participants with ASD made modest gains in learning the sharing skills taught during social skills training lessons. Social validity data indicate that participants with ASD and peer participants found the intervention appropriate and acceptable, and staff perception ratings indicated significant changes in the social skills of participants with ASD. Study outcomes have practical implications for educational practitioners related to enhancing social-communication and social interactions of young children with ASD. Study limitations and future directions for research are discussed.

Social Cognition And Functional Brain Imaging: Extending The Broader Autism Phenotype

Evidence suggests that the social cognition deficits prevalent in autism spectrum disorders (ASDs) are widely distributed in first degree and extended relatives. This ¿broader autism phenotype¿ (BAP) can be extended into non-clinical populations and show wide distributions of social behaviors such as empathy and social responsiveness ¿ with ASDs exhibiting these behaviors on the lower ends of the distributions. Little evidence has previously shown relationships between self-report measures of social cognition and more objective tasks such as face perception in functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs). In this study, three specific hypotheses were addressed: a) increased social ability, as measured by an increased Empathy Quotient, decreased Social Responsiveness Scale (SRS-A) score, and increased Social Attribution Task score, will predict increased activation of the fusiform gyrus in response to faces as compared to houses; b) these same measures will predict N170 amplitude and latency showing decreased latency and increased amplitude for faces as compared to houses with increased social ability; c) increased amygdala volume will predict increased fusiform gyrus activation when viewing faces as compared to houses. Findings supported all of the hypotheses. Empathy scores significantly predicted both right FFG activation [F(1,20) = 4.811, p = .041, ß = .450, R2 = 0.20] and left FFG activation [F(1,20) = 7.70, p = .012, ß = .537, R2 = 0.29]. Based on ERP results increased right lateralization face-related N170 was significantly predicted by the EQ [F(1,54) = 6.94, p = .011, ß = .338, R2 = 0.11]. Finally, total amygdala volume significantly predicted right [F(1,20) = 7.217, p = .014, ß = .515, R2 = 0.27] and left [F(1,20) = 36.77, p < .001, ß = .805, R2 = 0.65] FFG activation. Consistent with the a priori hypotheses, traits attributed to the BAP can significantly predict neural responses to faces in a non-clinical population. This is consistent with the face processing deficits seen in ASDs. The findings presented here contribute to the extension of the BAP from unaffected relatives of individuals with ASDs to the general population. These findings also give continued evidence in support of a continuous distribution of traits found in psychiatric illnesses in place of a traditional, dichotomous ¿all-or-nothing¿ diagnostic framework of neurodevelopmental and neuropsychiatric disorders.

Complex syntax in autistic spectrum disorders: A study with relative clauses

Background The few studies that have evaluated syntax in autism spectrum disorder (ASD) have yielded conflicting findings: some suggest that once matched on mental age, ASD and typically developing controls do not differ for grammar, while others report that morphosyntactic deficits are independent of cognitive skills in ASD. There is a need for a better understanding of syntax in ASD and its relation to, or dissociation from, nonverbal abilities. Aims Syntax in ASD was assessed by evaluating subject and object relative clause comprehension in adolescents and adults diagnosed with ASD with a performance IQ within the normal range, and with or without a history of language delay. Methods & Procedures Twenty-eight participants with ASD (mean age 21.8) and 28 age-matched controls (mean age 22.07) were required to point to a character designated by relative clauses that varied in syntactic complexity. Outcomes & Results Scores indicate that participants with ASD regardless of the language development history perform significantly worse than age-matched controls with object relative clauses. In addition, participants with ASD with a history of language delay (diagnosed with high-functioning autism in the DSM-IV-TR) perform worse on subject relatives than ASD participants without language delay (diagnosed with Asperger syndrome in the DSM-IV-TR), suggesting that these two groups do not have equivalent linguistic abilities. Performance IQ has a positive impact on the success of the task for the population with ASD. Conclusions & Implications This study reveals subtle grammatical difficulties remaining in adult individuals with ASD within normal IQ range as compared with age-matched peers. Even in the absence of a history of language delay in childhood, the results suggest that a slight deficit may nevertheless be present and go undetected by standardized language assessments. Both groups with and without language delay have a similar global performance on relative clause comprehension; however, the study also indicates that the participants with reported language delay show more difficulty with subject relatives than the participants without language delay, suggesting the presence of differences in linguistic abilities between these subgroups of ASD.

Joint Attention in Young Children with Autism

Autism spectrum disorders (ASDs) are classified as pervasive developmental disorders characterized by social, communicative, and behavioral impairments. According to formal and informal reports, children with ASD present with receptive and expressive language delay. Joint attention (JA: the behavior that occurs when two individuals focus on the same object or event) has been identified as a possible marker of delayed language development in children with ASD. In this study, the JA behaviors in children with ASD were contrasted with initially language-matched typically developing (TYP) children across three visits. Measures of language, the frequency, duration, and source of initiation of JA episodes, and the choice of toy during those episodes, were coded. Across visits and groups, mothers initiated more JA episodes than children; however, typical children also initiated more JA episodes than ASD children at visits 1 and 2. Also, the total duration of typically developing children’s JA episodes was generally longer than that of the ASD children’s, significantly so at Visit 2. Significant associations emerged between children’s vocabulary and two measures of JA: frequency and number of maternal initiations. Teaching parents to incorporate JA training in their interactions with their children may likely help children with ASD acquire language.

CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM

Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. The proteins of these genes form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), which controls protein translation and cell growth. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. However, both disorders share cerebellar abnormalities. Therefore, we have characterized a novel mouse model in which the Tsc2 gene was selectively deleted from cerebellar Purkinje cells (Tsc2f/-;Cre). These mice exhibit progressive Purkinje cell degeneration. Since loss of Purkinje cells is a well-reported postmortem finding in patients with ASD, we conducted a series of behavior tests to assess if Tsc2f/-;Cre mice displayed autistic-like deficits. Using the three chambered social choice assay, we found that Tsc2f/-;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. Tsc2f/-;Cre mice also demonstrated increased repetitive behavior as assessed with marble burying activity. Altogether, these results demonstrate that loss of Tsc2 in Purkinje cells in a haploinsufficient background lead to behavioral deficits that are characteristic of human autism. Therefore, Purkinje cells loss and/or dysfunction may be an important link between TSC and ASD. Additionally, we have examined some of the cellular mechanisms resulting from mutations in Tsc2 leading to Purkinje cell death. Loss of Tsc2 led to upregulation of mTORC1 and increased cell size. As a consequence of increased protein synthesis, several cellular stress pathways were upregulated. Principally, these included altered calcium signaling, oxidative stress, and ER stress. Likely as a consequence of ER stress, there was also upregulation of ubiquitin and autophagy. Excitingly, treatment with an mTORC1 inhibitor, rapamycin attenuated mTORC1 activity and prevented Purkinje cell death by reducing of calcium signaling, the ER stress response, and ubiquitin. Remarkably, rapamycin treatment also reversed the social behavior deficits, thus providing a promising potential therapy for TSC-associated ASD.

Violence is Rare in Autism : When It Does Occur, Is It Sometimes Extreme?

Peer reviewed

The Development of an Intervention Tool to Address Challenges in the Medical Treatment of Children with Autism .

Challenges in treating children with an autism spectrum disorder (ASD) in medical settings are identified and discussed. Although research supports interventions for children with ASD including positive reinforcement, environmental modification, and visual supports and systems, limited research on the efficacy of these interventions in medical environments and with specific procedures exists. Based on the available intervention literature, this project proposes a picture schedule reinforcement system for use during blood draw procedures for ASD children with diabetes. Future efforts should include increased education for medical providers and health professionals as psychological interventions continue to inform best practices in care for children with ASD in medical settings.

Attitudes of the autism community to early autism research

Investigation into the earliest signs of autism in infants has become a significant sub-field of autism research. This work invokes specific ethical concerns such as use of 'at-risk' language, communicating study findings to parents and the future perspective of enrolled infants when they reach adulthood. This study aimed to ground this research field in an understanding of the perspectives of members of the autism community. Following focus groups to identify topics, an online survey was distributed to autistic adults, parents of children with autism and practitioners in health and education settings across 11 European countries. Survey respondents (n = 2317) were positively disposed towards early autism research, and there was significant overlap in their priorities for the field and preferred language to describe infant research participants. However, there were also differences including overall less favourable endorsement of early autism research by autistic adults relative to other groups and a dislike of the phrase 'at-risk' to describe infant participants, in all groups except healthcare practitioners. The findings overall indicate that the autism community in Europe is supportive of early autism research. Researchers should endeavour to maintain this by continuing to take community perspectives into account.

Utility of the Social Responsiveness Scale- Parent Report (SRS-Parent) as a Diagnostic Tool for Autism Identification

Thesis (Ph.D.)--University of Washington, 2016-06

Theory of mind and central coherence in adults with high-functioning autism or Asperger syndrome

The study investigated theory of mind and central coherence abilities in adults with high-functioning autism (HFA) or Asperger syndrome (AS) using naturalistic tasks. Twenty adults with HTA/AS correctly answered significantly fewer theory of mind questions than 20 controls on a forced-choice response task. On a narrative task, there were no differences in the proportion of mental state words between the two groups, although the participants with HFA/AS were less inclined to provide explanations for characters' mental states. No between-group differences existed on the central coherence questions of the forced-choice response task, and the participants with HTA/AS included an equivalent proportion of explanations for non-mental state phenomena in their narratives as did controls. These results support the theory of mind deficit account of autism spectrum disorders, and suggest that difficulties in mental state attribution cannot be exclusively attributed to weak central coherence.

Case study: auditory brain responses in a minimally verbal child with autism and cerebral palsy

An estimated 30% of individuals with autism spectrum disorders (ASD) remain minimally verbal into late childhood, but research on cognition and brain function in ASD focuses almost exclusively on those with good or only moderately impaired language. Here we present a case study investigating auditory processing of GM, a nonverbal child with ASD and cerebral palsy. At the age of 8 years, GM was tested using magnetoencephalography (MEG) whilst passively listening to speech sounds and complex tones. Where typically developing children and verbal autistic children all demonstrated similar brain responses to speech and nonspeech sounds, GM produced much stronger responses to nonspeech than speech, particularly in the 65–165 ms (M50/M100) time window post-stimulus onset. GM was retested aged 10 years using electroencephalography (EEG) whilst passively listening to pure tone stimuli. Consistent with her MEG response to complex tones, GM showed an unusually early and strong response to pure tones in her EEG responses. The consistency of the MEG and EEG data in this single case study demonstrate both the potential and the feasibility of these methods in the study of minimally verbal children with ASD. Further research is required to determine whether GM's atypical auditory responses are characteristic of other minimally verbal children with ASD or of other individuals with cerebral palsy.

The relationship between spoken language and speech and nonspeech processing in children with autism:a magnetic event-related field study

It has been proposed that language impairments in children with Autism Spectrum Disorders (ASD) stem from atypical neural processing of speech and/or nonspeech sounds. However, the strength of this proposal is compromised by the unreliable outcomes of previous studies of speech and nonspeech processing in ASD. The aim of this study was to determine whether there was an association between poor spoken language and atypical event-related field (ERF) responses to speech and nonspeech sounds in children with ASD (n = 14) and controls (n = 18). Data from this developmental population (ages 6-14) were analysed using a novel combination of methods to maximize the reliability of our findings while taking into consideration the heterogeneity of the ASD population. The results showed that poor spoken language scores were associated with atypical left hemisphere brain responses (200 to 400 ms) to both speech and nonspeech in the ASD group. These data support the idea that some children with ASD may have an immature auditory cortex that affects their ability to process both speech and nonspeech sounds. Their poor speech processing may impair their ability to process the speech of other people, and hence reduce their ability to learn the phonology, syntax, and semantics of their native language.

A Qualitative Study of Contextual Factors’ Impact on the Adaptation of a Caregiver-mediated Early Autism Intervention in South Africa

Background: Autism Spectrum Disorder (ASD) is a major global health challenge as the majority of individuals with ASD live in low- and middle-income countries (LMICs) and receive little to no services or support from health or social care systems. Despite this global crisis, the development and validation of ASD interventions has almost exclusively occurred in high-income countries, leaving many unanswered questions regarding what contextual factors would need to be considered to ensure the effectiveness of interventions in LMICs. This study sought to conduct explorative research on the contextual adaptation of a caregiver-mediated early ASD intervention for use in a low-resource setting in South Africa.

Methods: Participants included 22 caregivers of children with autism, including mothers (n=16), fathers (n=4), and grandmothers (n=2). Four focus groups discussions were conducted in Cape Town, South Africa with caregivers and lasted between 1.5-3.5 hours in length. Data was recorded, translated, and transcribed by research personnel. Data was then coded for emerging themes and analyzed using the NVivo qualitative data analysis software package.

Results: Nine contextual factors were reported to be important for the adaptation process including culture, language, location of treatment, cost of treatment, type of service provider, familial needs, length of treatment, support, and parenting practices. One contextual factor, evidence-based treatment, was reported to be both important and not important for adaptation by caregivers. The contextual factor of stigma was identified as an emerging theme and a specifically relevant challenge when developing an ASD intervention for use in a South African context.

Conclusions: Eleven contextual factors were discussed in detail by caregivers and examples were given regarding the challenges, sources, and preferences related to the contextual adaptation of a parent-mediated early ASD intervention in South Africa. Caregivers reported a preference for an affordable, in-home, individualized early ASD intervention, where they have an active voice in shaping treatment goals. Distrust of community-based nurses and health workers to deliver an early ASD intervention and challenges associated with ASD-based stigma were two unanticipated findings from this data set. Implications for practice and further research are discussed.

Staff training in autism: The one-eyed wo/man….

Having well-trained staff is key to ensuring good quality autism services, especially since people affected with autism generally tend to have higher support needs than other populations in terms of daily living as well as their mental and physical health. Poorly-trained staff can have detrimental effects on service provision and staff morale and can lead to staff burn-out as well as increased service user anxiety and stress. This paper reports on a survey with health, social care, and education staff who work within the statutory autism services sector in the UK that explored their knowledge and training with regards to autism. Interview data obtained from staff and service users offer qualitative illustrations of survey findings. Overall, the findings expose an acute lack of autism specific training that has detrimental impacts. At best this training was based on brief and very basic awareness raising rather than on in-depth understanding of issues related to autism or skills for evidence-based practice. Service users were concerned with the effects that lack of staff training had on the services they received. The paper concludes with a discussion of policy routes to achieving quality staff training based on international best practice. The focus is on improving the quality of life and mental health for services users and staff as well as making potentially significant cost-savings for governments.