Showing papers in "Molecular Autism in 2020"

Coping, fostering resilience, and driving care innovation for autistic people and their families during the COVID-19 pandemic and beyond.

Abstract: The new coronavirus disease (COVID-19) pandemic is changing how society operates. Environmental changes, disrupted routines, and reduced access to services and social networks will have a unique impact on autistic individuals and their families and will contribute to significant deterioration in some. Access to support is crucial to address vulnerability factors, guide adjustments in home environments, and apply mitigation strategies to improve coping. The current crisis highlights that our regular care systems are not sufficient to meet the needs of the autism communities. In many parts of the world, people have shifted to online school and increased use of remote delivery of healthcare and autism supports. Access to these services needs to be increased to mitigate the negative impact of COVID-19 and future epidemics/pandemics. The rapid expansion in the use of telehealth platforms can have a positive impact on both care and research. It can help to address key priorities for the autism communities including long waitlists for assessment and care, access to services in remote locations, and restricted hours of service. However, system-level changes are urgently needed to ensure equitable access and flexible care models, especially for families and individuals who are socioeconomically disadvantaged. COVID-19 mandates the use of technology to support a broader range of care options and better meet the diverse needs of autistic people and their families. It behooves us to use this crisis as an opportunity to foster resilience not only for a given individual or their family, but also the system: to drive enduring and autism-friendly changes in healthcare, social systems, and the broader socio-ecological contexts.

Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology

Abstract: The complex pathophysiology of autism spectrum disorder encompasses interactions between genetic and environmental factors. On the one hand, hundreds of genes, converging at the functional level on selective biological domains such as epigenetic regulation and synaptic function, have been identified to be either causative or risk factors of autism. On the other hand, exposure to chemicals that are widespread in the environment, such as endocrine disruptors, has been associated with adverse effects on human health, including neurodevelopmental disorders. Interestingly, experimental results suggest an overlap in the regulatory pathways perturbed by genetic mutations and environmental factors, depicting convergences and complex interplays between genetic susceptibility and toxic insults. The pervasive nature of chemical exposure poses pivotal challenges for neurotoxicological studies, regulatory agencies, and policy makers. This highlights an emerging need of developing new integrative models, including biomonitoring, epidemiology, experimental, and computational tools, able to capture real-life scenarios encompassing the interaction between chronic exposure to mixture of substances and individuals’ genetic backgrounds. In this review, we address the intertwined roles of genetic lesions and environmental insults. Specifically, we outline the transformative potential of stem cell models, coupled with omics analytical approaches at increasingly single cell resolution, as converging tools to experimentally dissect the pathogenic mechanisms underlying neurodevelopmental disorders, as well as to improve developmental neurotoxicology risk assessment.

Quantifying compensatory strategies in adults with and without diagnosed autism

Abstract: There is growing recognition that some autistic people engage in ‘compensation’, showing few behavioural symptoms (e.g. neurotypical social skills), despite continuing to experience autism-related cognitive difficulties (e.g. difficulties in social cognition). One way this might be achieved is by individuals consciously employing ‘compensatory strategies’ during everyday social interaction. However, very little is currently known about the broad range of these strategies, their mechanisms and consequences for clinical presentation and diagnosis. We aimed to measure compensatory strategies in autism for the first time. Using a novel checklist, we quantified self-reported social compensatory strategies in 117 adults (58 with autism, 59 without autism) and explored the relationships between compensation scores and autism diagnostic status, autistic traits, education level, sex and age at diagnosis. Higher compensation scores—representing a greater repertoire of compensatory strategies—were associated with having an autism diagnosis, more autistic traits and a higher education level. The link between autism diagnostic status and compensation scores was, however, explained by autistic traits and education level. Compensation scores were unrelated to sex or age at diagnosis. Our sample was self-selected and predominantly comprised of intellectually able females; therefore, our findings may not generalise to the wider autistic population. Together, our findings suggest that many intellectually able adults, with and without a clinical diagnosis of autism, report using compensatory strategies to modify their social behaviour. We discuss the clinical utility of measuring self-reported compensation (e.g., using our checklist), with important implications for the accurate diagnosis and management of autism and related conditions.

Prevalence and cumulative incidence of autism spectrum disorders and the patterns of co-occurring neurodevelopmental disorders in a total population sample of 5-year-old children.

Abstract: Whether there is a true increase in autism spectrum disorder (ASD) frequency or not remains unclear. Additionally, the rates of co-existing neurodevelopmental disorders (NDD) in a total population sample has not been fully examined before. Therefore, using a total population sample in Japan, we aimed to estimate the prevalence and cumulative incidence of autism spectrum disorder (ASD) annually, to determine whether there is a true increase in ASD prevalence by estimating the cumulative incidence of ASD annually, and to examine the rates of co-existing neurodevelopmental disorders (NDD). In this cross-sectional sequential design study, all 5-year-old children in the catchment area underwent the screening annually from the year 2013–2016. Screen-positive children were invited to participate in a comprehensive assessment, including child and parent interview, behavioral observation, and cognitive and motor function testing. All cases were reviewed by a multidisciplinary research team. Caregivers of 3954 children returned the screening, among which 559 children underwent the assessment with 87 children receiving an ASD diagnosis. Adjusted ASD prevalence was 3.22% (95% confidence interval (CI) 2.66–3.76%). The male to female ratio of the crude prevalence was 2.2:1. The cumulative incidence of ASD up to 5 years of age for the total study years was 1.31% (95% CI 1.00–1.62%). A generalized linear model revealed no significant linear trends in 5-year cumulative incidence over the study years. Only 11.5% of children had ASD alone; the remaining 88.5% were found to have at least one co-existing NDD. Modest sample size for a total population study. Our findings demonstrate the stability of the 5-year cumulative incidence of ASD, implying no true rise in ASD incident cases over the 4-year study period in the study catchment area. High rates of co-existing NDDs reflect the importance of investigating broad developmental challenges in children with ASD.

Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up

Abstract: Intranasal administration of the “prosocial” neuropeptide oxytocin is increasingly explored as a potential treatment for targeting the core characteristics of autism spectrum disorder (ASD). However, long-term follow-up studies, evaluating the possibility of long-lasting retention effects, are currently lacking. Using a double-blind, randomized, placebo-controlled, parallel design, this pilot clinical trial explored the possibility of long-lasting behavioral effects of 4 weeks of intranasal oxytocin treatment (24 International Units once daily in the morning) in 40 adult men with ASD. To do so, self-report and informant-based questionnaires assessing core autism symptoms and characterizations of attachment were administered at baseline, immediately after 4 weeks of treatment (approximately 24 h after the last nasal spray administration), and at two follow-up sessions, 4 weeks and 1 year post-treatment. No treatment-specific effects were identified in the primary outcome assessing social symptoms (Social Responsiveness Scale, self- and informant-rated). In particular, with respect to self-reported social responsiveness, improvements were evident both in the oxytocin and in the placebo group, yielding no significant between-group difference (p = .37). Also informant-rated improvements in social responsiveness were not significantly larger in the oxytocin, compared to the placebo group (between-group difference: p = .19). Among the secondary outcome measures, treatment-specific improvements were identified in the Repetitive Behavior Scale and State Adult Attachment Measure, indicating reductions in self-reported repetitive behaviors (p = .04) and reduced feelings of avoidance toward others (p = .03) in the oxytocin group compared to the placebo group, up to 1 month and even 1 year post-treatment. Treatment-specific effects were also revealed in screenings of mood states (Profile of Mood States), indicating higher reports of “vigor” (feeling energetic, active, lively) in the oxytocin, compared to the placebo group (p = .03). While no treatment-specific improvements were evident in terms of core social symptoms, the current observations of long-term beneficial effects on repetitive behaviors and feelings of avoidance are promising and suggestive of a therapeutic potential of oxytocin treatment for ASD. However, given the exploratory nature of this pilot study, future studies are warranted to evaluate the long-term effects of OT administration further. The trial was registered with the European Clinical Trial Registry (Eudract 2014-000586-45) on January 22, 2014 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000586-45/BE).

A comparative study of autistic and non-autistic women’s experience of motherhood

Abstract: Autism is a lifelong neurodevelopmental difference and disability, yet there is limited research examining parenting in autistic mothers. To explore autistic mothers’ experience of the perinatal period and parenthood. This includes pregnancy, childbirth, the postpartum period, self-perception of parenting strengths and weaknesses, communication with professionals in relation to one’s child, mental health difficulties and the social experience of motherhood. It also includes disclosing one’s diagnosis of autism in parenting contexts. We used a community-based participatory research model, and recruited an advisory panel, with whom we co-developed an anonymous, online survey for autistic mothers. The online survey was completed by autistic and non-autistic mothers, and we compared their responses using Chi-squared analysis. Autistic mothers (n = 355), and non-autistic mothers (n = 132), each of whom had at least one autistic child, were included in our final analysis. There were differences in education, gender identity and age of mother at birth of first child. Autistic mothers were more likely to have experienced additional psychiatric conditions, including pre- or post-partum depression, and reported greater difficulties in areas such as multi-tasking, coping with domestic responsibilities and creating social opportunities for their child. They were also more likely to report feeling misunderstood by professionals, and reported greater anxiety, higher rates of selective mutism, and not knowing which details were appropriate to share with professionals. They were also more likely to find motherhood an isolating experience, to worry about others judging their parenting, or feel unable to turn to others for support in parenting. However, despite these challenges, autistic mothers were able to act in the best interest of their child, putting their child’s needs first. Autistic mothers face unique challenges and the stigma associated with autism may further exacerbate communication difficulties. Greater understanding and acceptance amongst individuals who interact with autistic mothers is needed, and autistic mothers would benefit from additional and better-tailored support.

Reduced nonverbal interpersonal synchrony in autism spectrum disorder independent of partner diagnosis: a motion energy study

Abstract: One of the main diagnostic features of individuals with autism spectrum disorders is nonverbal behaviour difficulties during naturalistic social interactions. The ‘Interactional Heterogeneity Hypothesis’ of ASD proposes that the degree to which individuals share a common ground substantially influences their ability to achieve smooth social interactions. To test this hypothesis, we filmed 29 autistic and 29 matched typically developed adults engaged in several conversational tasks. Windowed cross-lagged correlations were computed using the time series of motion energy of both individuals in a dyad. These coefficients were then compared across the three dyad types that were homo- or heterogenous with respect to diagnosis: pairs of two autistic individuals, two typically developed individuals or pairs of one autistic and one typically developed person. We found that all dyad types achieved above-chance interpersonal synchrony, but that synchrony was more expressed in typical dyads compared to both autistic and mixed dyads. The method presented here provides only one, albeit objective and robust, approach to explore synchrony. The methodological choices as well as the lack of consideration for other communication modalities may limit our interpretation of the findings. Moreover, the sample size is small with respect to exploring associations between synchrony and various outcome and social skill measures. The present results do not provide support for the Interactional Heterogeneity Hypothesis given that autistic individuals do not coordinate better when interacting with another autistic individual, compared to when interacting with a typical individual.

Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project

Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the “social brain,” a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition.

Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study.

Abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of γ-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC. Participants were treated with bumetanide (2dd 0.5–1.0 mg) for 13 weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91 days of treatment and after a 28-day wash-out period. Fifteen patients (8–21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency. The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures. Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers.

Abstract: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis. Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation. We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22–2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring. Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.

Reduced auditory steady state responses in autism spectrum disorder.

Abstract: Auditory steady state responses (ASSRs) are elicited by clicktrains or amplitude-modulated tones, which entrain auditory cortex at their specific modulation rate. Previous research has reported reductions in ASSRs at 40 Hz for autism spectrum disorder (ASD) participants and first-degree relatives of people diagnosed with ASD (Mol Autism. 2011;2:11, Biol Psychiatry. 2007;62:192–197). Using a 1.5 s-long auditory clicktrain stimulus, designed to elicit an ASSR at 40 Hz, this study attempted to replicate and extend these findings. Magnetencephalography (MEG) data were collected from 18 adolescent ASD participants and 18 typically developing controls. The ASSR localised to bilateral primary auditory regions. Regions of interest were thus defined in left and right primary auditory cortex (A1). While the transient gamma-band response (tGBR) from 0-0.1 s following presentation of the clicktrain stimulus was not different between groups, for either left or right A1, the ASD group had reduced oscillatory power at 40 Hz from 0.5 to 1.5 s post-stimulus onset, for both left and right A1. Additionally, the ASD group had reduced inter-trial coherence (phase consistency over trials) at 40 Hz from 0.64-0.82 s for right A1 and 1.04-1.22 s for left A1. In this study, we did not conduct a clinical autism assessment (e.g. the ADOS), and therefore, it remains unclear whether ASSR power and/or ITC are associated with the clinical symptoms of ASD. Overall, our results support a specific reduction in ASSR oscillatory power and inter-trial coherence in ASD, rather than a generalised deficit in gamma-band responses. We argue that this could reflect a developmentally relevant reduction in non-linear neural processing.

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

Abstract: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8–12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = − 0.32, 95% CI [− 0.39, − 0.25], in repetitive behaviors − 0.23[− 0.32, − 0.15] and in scales measuring overall core symptoms − 0.36 [− 0.46, − 0.26]. Overall, 19%, 95% CI [16–22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

Abstract: There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 L-type Ca2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13–17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca2+-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca2+-channel blocker isradipine by 3–4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca2+-channel blockers.

Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD

Abstract: Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance. The development of induced pluripotent stem cell (iPSC) technology and recent advances in neuronal differentiation techniques provide a unique opportunity to model complex neuronal connectivity and to test the E/I hypothesis of ASD in human-based models. Here, we aim to review the latest advances in studying the different cellular and molecular mechanisms contributing to E/I balance using iPSC-based in vitro models of ASD.

Differential mirror neuron system (MNS) activation during action observation with and without social-emotional components in autism: a meta-analysis of neuroimaging studies

Abstract: Impaired imitation has been found to be an important factor contributing to social communication deficits in individuals with autism spectrum disorder (ASD). It has been hypothesized that the neural correlate of imitation, the mirror neuron system (MNS), is dysfunctional in ASD, resulting in imitation impairment as one of the key behavioral manifestations in ASD. Previous MNS studies produced inconsistent results, leaving the debate of whether “broken” mirror neurons in ASD are unresolved. This meta-analysis aimed to explore the differences in MNS activation patterns between typically developing (TD) and ASD individuals when they observe biological motions with or without social-emotional components. Effect size signed differential mapping (ES-SDM) was adopted to synthesize the available fMRI data. ES-SDM analysis revealed hyperactivation in the right inferior frontal gyrus and left supplementary motor area in ASD during observation of biological motions. Subgroup analysis of experiments involving the observation of stimuli with or without emotional component revealed hyperactivation in the left inferior parietal lobule and left supplementary motor during action observation without emotional components, whereas hyperactivation of the right inferior frontal gyrus was found during action observation with emotional components in ASD. Subgroup analyses of age showed hyperactivation of the bilateral inferior frontal gyrus in ASD adolescents, while hyperactivation in the right inferior frontal gyrus was noted in ASD adults. Meta-regression within ASD individuals indicated that the right cerebellum crus I activation increased with age, while the left inferior temporal gyrus activation decreased with age. This meta-analysis is limited in its generalization of the findings to individuals with ASD by the restricted age range, heterogeneous study sample, and the large within-group variation in MNS activation patterns during object observation. Furthermore, we only included action observation studies which might limit the generalization of our results to the imitation deficits in ASD. In addition, the relatively small sample size for individual studies might also potentially overestimate the effect sizes. The MNS is impaired in ASD. The abnormal activation patterns were found to be modulated by the nature of stimuli and age, which might explain the contradictory results from earlier studies on the “broken mirror neuron” debate.

Gender identity, sexual orientation and adverse sexual experiences in autistic females

Abstract: There is growing recognition that autistic females present with more diverse gender and sexual identities than their non-autistic counterparts. Likewise, autistic females are also at an increased risk of adverse sexual experiences. As higher rates of sexual victimisation are observed in individuals with diverse sexual identities in the broader population, rates of negative sexual experiences among autistic females remain unclear. This study aimed to investigate the representation of gender and sexual diversity within autistic females and examine their rates of regretted, and unwanted, sexual encounters among females with a transgender gender identity and non-heterosexual sexual orientation. Two hundred and ninety-five females completed the Sexual Behaviour Scale-III (SBS-III) online. Self-reported gender identity and sexual orientation were compared between 134 autistic (Mage= 26.2 years, SD = 8.7) and 161 non-autistic females (Mage = 22.0 years, SD = 4.6). Differences in the prevalence of negative sexual experiences were compared across diagnosis and each gender identity and sexual orientation label. Autistic females were more likely to identify with a transgender gender identity (p < .05) and non-heterosexual sexual orientation (p < .007) compared to non-autistic females. Autistic homosexual females were more likely to have experienced a range of negative sexual experiences than autistic heterosexual females (OR ≥ 3.29; p < .01) and were more likely to have experienced unwanted sexual experiences than non-autistic females regardless of sexual orientation (OR ≥ 2.38; p < .05). There were no differences in rates of negative sexual experiences between autistic bisexual and both autistic heterosexual and non-autistic bisexual females. Non-autistic bisexual females (OR = 0.24; p = .018) presented with a reduced risk of regretted sexual experiences than non-autistic heterosexual peers. There were no differences in negative sexual experiences across gender identity in the autistic sample. The use of fixed format response items may have restricted participants’ abilities to provide rich responses pertaining to their sexual identities and nature of negative sexual experiences. The small number of participants who identified as transgender (n = 40) limits the reliability of results pertaining to sexual experiences across gender identity. Moreover, although multiple recruitment methods were used in this study, non-representative may bias estimates of prevalence rates. Thus, the data may not be representative of the broader population. Results indicate that autistic females present with greater diversity in their sexual identities than individuals without autism, with those with a homosexual sexual orientation being at greater risk of experiencing adverse sexual encounters. Findings suggest the importance of increased clinical attention to this diversity and the need to provide support to facilitate the development of a healthy sexual identity and reduce the risks identified in this study.

Face individual identity recognition: a potential endophenotype in autism

Abstract: Face individual identity recognition skill is heritable and independent of intellectual ability Difficulties in face individual identity recognition are present in autistic individuals and their family members and are possibly linked to oxytocin polymorphisms in families with an autistic child While it is reported that developmental prosopagnosia (ie, impaired face identity recognition) occurs in 2–3% of the general population, no prosopagnosia prevalence estimate is available for autism Furthermore, an autism within-group approach has not been reported towards characterizing impaired face memory and to investigate its possible links to social and communication difficulties The present study estimated the prevalence of prosopagnosia in 80 autistic adults with no intellectual disability, investigated its cognitive characteristics and links to autism symptoms’ severity, personality traits, and mental state understanding from the eye region by using standardized tests and questionnaires More than one third of autistic participants showed prosopagnosia Their face memory skill was not associated with their symptom’s severity, empathy, alexithymia, or general intelligence Face identity recognition was instead linked to mental state recognition from the eye region only in autistic individuals who had prosopagnosia, and this relationship did not depend on participants’ basic face perception skills Importantly, we found that autistic participants were not aware of their face memory skills We did not test an epidemiological sample, and additional work is necessary to establish whether these results generalize to the entire autism spectrum Impaired face individual identity recognition meets the criteria to be a potential endophenotype in autism In the future, testing for face memory could be used to stratify autistic individuals into genetically meaningful subgroups and be translatable to autism animal models

TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling

Abstract: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with frequent occurrence of epilepsy, autism spectrum disorder (ASD), intellectual disability (ID), and tumors in multiple organs. The aberrant activation of mTORC1 in TSC has led to treatment with mTORC1 inhibitor rapamycin as a lifelong therapy for tumors, but TSC-associated neurocognitive manifestations remain unaffected by rapamycin. Here, we generated patient-specific, induced pluripotent stem cells (iPSCs) from a TSC patient with a heterozygous, germline, nonsense mutation in exon 15 of TSC1 and established an isogenic set of heterozygous (Het), null and corrected wildtype (Corr-WT) iPSCs using CRISPR/Cas9-mediated gene editing. We differentiated these iPSCs into neural progenitor cells (NPCs) and examined neurodevelopmental phenotypes, signaling and changes in gene expression by RNA-seq. Differentiated NPCs revealed enlarged cell size in TSC1-Het and Null NPCs, consistent with mTORC1 activation. TSC1-Het and Null NPCs also revealed enhanced proliferation and altered neurite outgrowth in a genotype-dependent manner, which was not reversed by rapamycin. Transcriptome analyses of TSC1-NPCs revealed differentially expressed genes that display a genotype-dependent linear response, i.e., genes upregulated/downregulated in Het were further increased/decreased in Null. In particular, genes linked to ASD, epilepsy, and ID were significantly upregulated or downregulated warranting further investigation. In TSC1-Het and Null NPCs, we also observed basal activation of ERK1/2, which was further activated upon rapamycin treatment. Rapamycin also increased MNK1/2-eIF4E signaling in TSC1-deficient NPCs. MEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental events such as NPC proliferation and initial process formation, such as neurite number and length that occur prior to neuronal differentiation, represent primary events in neurogenesis critical to disease pathogenesis of neurodevelopmental disorders such as ASD.

Dissecting the phenotypic heterogeneity in sensory features in autism spectrum disorder: a factor mixture modelling approach.

Abstract: Heterogeneity in the phenotypic presentation of autism spectrum disorder (ASD) is apparent in the profile and the severity of sensory features. Here, we applied factor mixture modelling (FMM) to test a multidimensional factor model of sensory processing in ASD. We aimed to identify homogeneous sensory subgroups in ASD that differ intrinsically in their severity along continuous factor scores. We also investigated sensory subgroups in relation to clinical variables: sex, age, IQ, social-communication symptoms, restricted and repetitive behaviours, adaptive functioning and symptoms of anxiety and attention-deficit/hyperactivity disorder. Three hundred thirty-two children and adults with ASD between the ages of 6 and 30 years with IQs varying between 40 and 148 were included. First, three different confirmatory factor models were fit to the 38 items of the Short Sensory Profile (SSP). Then, latent class models (with two-to-six subgroups) were evaluated. The best performing factor model, the 7-factor structure, was subsequently used in two FMMs that varied in the number of subgroups: a two-subgroup, seven-factor model and a three-subgroup and seven-factor model. The ‘three-subgroup/seven-factor’ FMM was superior to all other models based on different fit criteria. Identified subgroups differed in sensory severity from severe, moderate to low. Accounting for the potential confounding effects of age and IQ, participants in these sensory subgroups had different levels of social-communicative symptoms, restricted and repetitive behaviours, adaptive functioning skills and symptoms of inattention and anxiety. Results were derived using a single parent-report measure of sensory features, the SSP, which limits the generalisability of findings. Sensory features can be best described by three homogeneous sensory subgroups that differ in sensory severity gradients along seven continuous factor scores. Identified sensory subgroups were further differentiated by the severity of core and co-occurring symptoms, and level of adaptive functioning, providing novel evidence on the associated clinical correlates of sensory subgroups. These sensory subgroups provide a platform to further interrogate the neurobiological and genetic correlates of altered sensory processing in ASD.

Sex differences in brain structure: a twin study on restricted and repetitive behaviors in twin pairs with and without autism

Abstract: Females with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors. In 75 twin pairs (n = 150, 62 females, 88 males) enriched for autism spectrum disorder (n = 32), and other neurodevelopmental disorders (n = 32), we explored the association of restricted and repetitive behaviors and interests—operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)—with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks. Co-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum. However, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution. Our findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males.

Cerebral organoids as tools to identify the developmental roots of autism.

Abstract: Some autism spectrum disorders (ASD) likely arise as a result of abnormalities during early embryonic development of the brain. Studying human embryonic brain development directly is challenging, mainly due to ethical and practical constraints. However, the recent development of cerebral organoids provides a powerful tool for studying both normal human embryonic brain development and, potentially, the origins of neurodevelopmental disorders including ASD. Substantial evidence now indicates that cerebral organoids can mimic normal embryonic brain development and neural cells found in organoids closely resemble their in vivo counterparts. However, with prolonged culture, significant differences begin to arise. We suggest that cerebral organoids, in their current form, are most suitable to model earlier neurodevelopmental events and processes such as neurogenesis and cortical lamination. Processes implicated in ASDs which occur at later stages of development, such as synaptogenesis and neural circuit formation, may also be modeled using organoids. The accuracy of such models will benefit from continuous improvements to protocols for organoid differentiation.

Inattention and hyperactive/impulsive component scores do not differentiate between autism spectrum disorder and attention-deficit/hyperactivity disorder in a clinical sample.

Abstract: Although there is high co-occurrence between ASD and ADHD, the nature of this co-occurrence remains unclear. Our study aimed to examine the underlying relationship between ASD and ADHD symptoms in a combined sample of children with a primary clinical diagnosis of ASD or ADHD. Participants included children and youth (aged 3-20 years) with a clinical diagnosis of ASD (n = 303) or ADHD (n = 319) for a total of 622 participants. Parents of these children completed the social communication questionnaire (SCQ), a measure of autism symptoms, and the strengths and weaknesses of ADHD and normal behavior (SWAN) questionnaire, a measure of ADHD symptoms. A principal component analysis (PCA) was performed on combined SCQ and SWAN items, followed by a profile analysis comparing normalized component scores between diagnostic groups and gender. PCA revealed a four-component solution (inattention, hyperactivity/impulsivity, social-communication, and restricted, repetitive, behaviors, and interests (RRBI)), with no overlap between SCQ and SWAN items in the components. Children with ASD had higher component scores in social-communication and RRBI than children with ADHD, while there was no difference in inattentive and hyperactive/impulsive scores between diagnostic groups. Males had higher scores than females in social-communication, RRBI, and hyperactivity/impulsivity components in each diagnostic group. We did not formally assess children with ASD for ADHD using our research-criteria for ADHD, and vice versa. High rates of co-occurring ADHD in ASD, for example, may have inflated component scores in inattention and hyperactivity/impulsivity. A disadvantage with using single informant-based reports (i.e., parent-rated questionnaires) is that ASD and ADHD symptoms may be difficult to distinguish by parents, and may be interpreted differently between parents and clinicians. ASD and ADHD items loaded on separate components in our sample, suggesting that the measurement structure cannot explain the covariation between the two disorders in clinical samples. High levels of inattention and hyperactivity/impulsivity were seen in both ASD and ADHD in our clinical sample. This supports the need for a dimensional framework that examines neurodevelopmental domains across traditional diagnostic boundaries. Females also had lower component scores across social-communication, RRBI, and hyperactivity/impulsivity than males, suggesting that there may be gender-specific phenotypes related to the two conditions.

Links between self-injury and suicidality in autism

Abstract: Autistic individuals without intellectual disability are at heightened risk of self-injury, and appear to engage in it for similar reasons as non-autistic people. A wide divergence of autistic perspectives on self-injury, including those who frame it as a helpful coping mechanism, motivate investigating the link between self-injury, suicide ideation, and attempts which has been reported in typically developing individuals. One hundred three autistic participants completed the Non-Suicidal Self-Injury Assessment Tool (NSSI-AT), the Suicide Behaviors Questionnaire (SBQ-R), and the Interpersonal Social Evaluation List (ISEL-12) across two online studies. Logistic regression was conducted to predict self-harming status via responses to questions on suicidality, and to predict whether certain self-injurious behaviors, including cutting, were especially associated with suicide ideation and attempts. Non-parametric correlation analysis examined relationships between suicide ideation/attempts and other variables that might characterize self-harmers especially at risk of suicidality. These included perceived access to social support, purposes or reasons for self-injury, the number of different self-injurious behaviors engaged in, the duration and lifetime incidence of self-injury, and the individual’s feelings about their self-injury. While self-injuring status was significantly predicted by responses to a question on suicide ideation and attempts, there was no relationship between suicide ideation/attempts and a participant’s personal feelings about their self-injury. The method of cutting was also predicted by suicide ideation and attempts, though other methods common in autistic people were at borderline significance. Use of self-injury for the regulation of low-energy emotional states like depression, for self-punishment or deterrence from suicide, and for sensory stimulation, was associated with suicide ideation and attempts, as was the number of self-injurious behaviors engaged in. There was no significant relationship between suicide ideation/attempts and the duration and lifetime incidence of self-injury or social support. These preliminary data suggest that while individuals might frame their self-injury as a positive or neutral thing, there remains a concerning relationship between self-injury and suicidality which exists regardless of individual feelings on self-injury. This is consistent with the theoretical perspective that self-injury can be a “gateway” through which individuals acquire capability for lethal suicidal behaviors. The data highlight that particular methods (cutting) and reasons for self-injury may be of significant concern, but this information, which might be of extreme value for clinicians, requires further investigation and validation.

Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan-McDermid syndrome and autism

Abstract: Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability, and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions. We developed human-induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n = 7) and their unaffected siblings (n = 6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (hiPSC-NPCs; n = 39) and induced forebrain neurons (hiPSC-neurons; n = 41). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings. Transcriptome analyses identified 391 differentially expressed genes (DEGs) in hiPSC-NPCs and 82 DEGs in hiPSC-neurons, when comparing cells from PMS probands and unaffected siblings (FDR < 5%). Genes under-expressed in PMS were implicated in Wnt signaling, embryonic development, and protein translation, while over-expressed genes were enriched for pre- and postsynaptic density genes, regulation of synaptic plasticity, and G-protein-gated potassium channel activity. Gene co-expression network analysis identified two modules in hiPSC-neurons that were over-expressed in PMS, implicating postsynaptic signaling and GDP binding, and both modules harbored a significant enrichment of genetic risk loci for developmental delay and intellectual disability. Finally, PMS-associated genes were integrated with other ASD hiPSC transcriptome findings and several points of convergence were identified, indicating altered Wnt signaling and extracellular matrix. Given the rarity of the condition, we could not carry out experimental validation in independent biological samples. In addition, functional and morphological phenotypes caused by loss of SHANK3 were not characterized here. This is the largest human neural sample analyzed in PMS. Genome-wide RNA-sequencing in hiPSC-derived neural cells from individuals with PMS revealed both shared and distinct transcriptional signatures across hiPSC-NPCs and hiPSC-neurons, including many genes implicated in risk for ASD, as well as specific neurobiological pathways, including the Wnt pathway.

Children with autism spectrum disorder produce more ambiguous and less socially meaningful facial expressions: an experimental study using random forest classifiers.

Abstract: Computer vision combined with human annotation could offer a novel method for exploring facial expression (FE) dynamics in children with autism spectrum disorder (ASD). We recruited 157 children with typical development (TD) and 36 children with ASD in Paris and Nice to perform two experimental tasks to produce FEs with emotional valence. FEs were explored by judging ratings and by random forest (RF) classifiers. To do so, we located a set of 49 facial landmarks in the task videos, we generated a set of geometric and appearance features and we used RF classifiers to explore how children with ASD differed from TD children when producing FEs. Using multivariate models including other factors known to predict FEs (age, gender, intellectual quotient, emotion subtype, cultural background), ratings from expert raters showed that children with ASD had more difficulty producing FEs than TD children. In addition, when we explored how RF classifiers performed, we found that classification tasks, except for those for sadness, were highly accurate and that RF classifiers needed more facial landmarks to achieve the best classification for children with ASD. Confusion matrices showed that when RF classifiers were tested in children with ASD, anger was often confounded with happiness. The sample size of the group of children with ASD was lower than that of the group of TD children. By using several control calculations, we tried to compensate for this limitation. Children with ASD have more difficulty producing socially meaningful FEs. The computer vision methods we used to explore FE dynamics also highlight that the production of FEs in children with ASD carries more ambiguity.

Developmental changes in attention to social information from childhood to adolescence in autism spectrum disorders: a comparative study

Abstract: Elucidating developmental changes in the symptoms of autism spectrum disorder (ASD) is important to support individuals with ASD. However, no report has clarified the developmental changes in attention to social information for a broad age range. The aim of this study was to investigate the developmental changes in attention to social information from early childhood to adolescence in individuals with ASD and typically developed (TD) children. We recruited children with ASD (n = 83) and TD participants (n = 307) between 2 and 18 years of age. Using the all-in-one-eye-tracking system, Gazefinder, we measured the percentage fixation time allocated to areas of interest (AoIs) depicted in movies (the eyes and mouth in movies of a human face with/without mouth motion, upright and inverted biological motion in movies showing these stimuli simultaneously, people and geometry in preference paradigm movies showing these stimuli simultaneously, and objects with/without finger-pointing in a movie showing a woman pointing toward an object). We conducted a three-way analysis of variance, 2 (diagnosis: ASD and TD) by 2 (sex: male and female) by 3 (age group: 0–5, 6–11, and 12–18 years) and locally weighted the scatterplot smoothing (LOESS) regression curve on each AoI. In the face stimuli, the percentage fixation time to the eye region for the TD group increased with age, whereas the one for the ASD group did not. In the ASD group, the LOESS curves of the gaze ratios at the eye region increased up to approximately 10 years of age and thereafter tended to decrease. For the percentage fixation time to the people region in the preference paradigm, the ASD group gazed more briefly at people than did the TD group. It is possible that due to the cross-sectional design, the degree of severity and of social interest might have differed according to the subjects’ age. There may be qualitative differences in abnormal eye contact in ASD between individuals in early childhood and those older than 10 years.

Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation

Abstract: Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory–excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1.

Common and unique multimodal covarying patterns in autism spectrum disorder subtypes.

Abstract: The heterogeneity inherent in autism spectrum disorder (ASD) presents a substantial challenge to diagnosis and precision treatment. Heterogeneity across biological etiologies, genetics, neural systems, neurocognitive attributes and clinical subtypes or phenotypes has been observed across individuals with ASD. In this study, we aim to investigate the heterogeneity in ASD from a multimodal brain imaging perspective. The Autism Diagnostic Observation Schedule (ADOS) was used as a reference to guide functional and structural MRI fusion. DSM-IV-TR diagnosed Asperger’s disorder (n = 79), pervasive developmental disorder-not otherwise specified [PDD-NOS] (n = 58) and Autistic disorder (n = 92) from ABIDE II were used as discovery cohort, and ABIDE I (n = 400) was used for replication. Dorsolateral prefrontal cortex and superior/middle temporal cortex are the primary common functional–structural covarying cortical brain areas shared among Asperger’s, PDD-NOS and Autistic subgroups. Key differences among the three subtypes are negative functional features within subcortical brain areas, including negative putamen–parahippocampus fractional amplitude of low-frequency fluctuations (fALFF) unique to the Asperger’s subtype; negative fALFF in anterior cingulate cortex unique to PDD-NOS subtype; and negative thalamus–amygdala–caudate fALFF unique to the Autistic subtype. Furthermore, each subtype-specific brain pattern is correlated with different ADOS subdomains, with social interaction as the common subdomain. The identified subtype-specific patterns are only predictive for ASD symptoms manifested in the corresponding subtypes, but not the other subtypes. Although ASD has a common neural basis with core deficits linked to social interaction, each ASD subtype is strongly linked to unique brain systems and subdomain symptoms, which may help to better understand the underlying mechanisms of ASD heterogeneity from a multimodal neuroimaging perspective. This study is male based, which cannot be generalized to the female or the general ASD population.

Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm.

Abstract: Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes. We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS. Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case–control status. The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited. Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B.

Abstract: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan–McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. Exosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 107 particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates. Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.