ABSTRACT
A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.
Subject(s)
Autistic Disorder , Biomedical Research , Humans , Biomedical Research/ethics , Behavior , Community-Based Participatory ResearchABSTRACT
Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Follow-Up Studies , Neuroanatomy , Cross-Sectional StudiesABSTRACT
BACKGROUND: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. AIMS: Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD. METHOD: Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.6 years of age) and 181 typically developing participants (7.6-30.8 years of age). RESULTS: Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD. CONCLUSIONS: Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Autism Spectrum Disorder , Autistic Disorder , Humans , Autism Spectrum Disorder/diagnostic imaging , Brain/diagnostic imaging , Brain Mapping , Reward , Magnetic Resonance Imaging/methodsABSTRACT
Flexible behavior is critical for everyday decision-making and has been implicated in restricted, repetitive behaviors (RRB) in autism spectrum disorder (ASD). However, how flexible behavior changes developmentally in ASD remains largely unknown. Here, we used a developmental approach and examined flexible behavior on a probabilistic reversal learning task in 572 children, adolescents, and adults (ASD N = 321; typical development [TD] N = 251). Using computational modeling, we quantified latent variables that index mechanisms underlying perseveration and feedback sensitivity. We then assessed these variables in relation to diagnosis, developmental stage, core autism symptomatology, and associated psychiatric symptoms. Autistic individuals showed on average more perseveration and less feedback sensitivity than TD individuals, and, across cases and controls, older age groups showed more feedback sensitivity than younger age groups. Computational modeling revealed that dominant learning mechanisms underpinning flexible behavior differed across developmental stages and reduced flexible behavior in ASD was driven by less optimal learning on average within each age group. In autistic children, perseverative errors were positively related to anxiety symptoms, and in autistic adults, perseveration (indexed by both task errors and model parameter estimates) was positively related to RRB. These findings provide novel insights into reduced flexible behavior in relation to clinical symptoms in ASD.
Subject(s)
Aging/physiology , Autistic Disorder/physiopathology , Behavior , Learning/physiology , Models, Biological , Adolescent , Adult , Age Factors , Child , Female , Humans , Intelligence Tests , Male , Reproducibility of Results , Task Performance and Analysis , Young AdultABSTRACT
BACKGROUND: Alexithymia (difficulties in identifying and describing emotion) is a transdiagnostic trait implicated in social-emotional and mental health problems in the general population. Many autistic individuals experience significant social-communication difficulties and elevated anxiety/depression and alexithymia. Nevertheless, the role of alexithymia in explaining individual variability in the quality/severity of social-communication difficulties and/or anxiety and depression symptoms in autism remains poorly understood. METHODS: In total, 337 adolescents and adults (autism N = 179) were assessed for alexithymia on the Toronto Alexithymia Scale and for social-communication difficulties, anxiety and depression symptoms. A total of 135 individuals (autism N = 76) were followed up 12-24 months later. We used regression models to establish cross-sectional and longitudinal associations between alexithymia, social-communication difficulties, anxiety and depression symptoms. RESULTS: Autistic individuals reported significantly higher alexithymia than comparison individuals (p < 0.001, r effect size = 0.48), with 47.3% of autistic females and 21.0% of autistic males meeting cut-off for clinically relevant alexithymia (score ⩾61). Difficulties in describing feelings were particularly associated with current self-reported social-communication difficulties [p < 0.001, ß = 0.57, 95% confidence interval (CI) 0.44-0.67] and predicted later social-communication difficulties (p = 0.02, ß = 0.43, 95% CI 0.07-0.82). Difficulties in identifying feelings were particularly associated with current anxiety symptom severity (p < 0.001, ß = 0.54, 95% CI 0.41-0.77) and predicted later anxiety (p = 0.01; ß = 0.31, 95% CI 0.08-0.62). CONCLUSIONS: Our findings suggest that difficulties in identifying v. describing emotion are associated with differential clinical outcomes in autism. Psychological therapies targeting emotional awareness may improve social-communication and anxiety symptoms in autism, potentially conferring long-term benefits.
Subject(s)
Affective Symptoms , Autistic Disorder , Adolescent , Adult , Affective Symptoms/epidemiology , Anxiety/epidemiology , Communication , Cross-Sectional Studies , Depression/epidemiology , Female , Humans , MaleABSTRACT
Over the past decade, biomarker discovery has become a key goal in psychiatry to aid in the more reliable diagnosis and prognosis of heterogeneous psychiatric conditions and the development of tailored therapies. Nevertheless, the prevailing statistical approach is still the mean group comparison between "cases" and "controls," which tends to ignore within-group variability. In this educational article, we used empirical data simulations to investigate how effect size, sample size, and the shape of distributions impact the interpretation of mean group differences for biomarker discovery. We then applied these statistical criteria to evaluate biomarker discovery in one area of psychiatric research-autism research. Across the most influential areas of autism research, effect size estimates ranged from small (d = 0.21, anatomical structure) to medium (d = 0.36 electrophysiology, d = 0.5, eye-tracking) to large (d = 1.1 theory of mind). We show that in normal distributions, this translates to approximately 45% to 63% of cases performing within 1 standard deviation (SD) of the typical range, i.e., they do not have a deficit/atypicality in a statistical sense. For a measure to have diagnostic utility as defined by 80% sensitivity and 80% specificity, Cohen's d of 1.66 is required, with still 40% of cases falling within 1 SD. However, in both normal and nonnormal distributions, 1 (skewness) or 2 (platykurtic, bimodal) biologically plausible subgroups may exist despite small or even nonsignificant mean group differences. This conclusion drastically contrasts the way mean group differences are frequently reported. Over 95% of studies omitted the "on average" when summarising their findings in their abstracts ("autistic people have deficits in X"), which can be misleading as it implies that the group-level difference applies to all individuals in that group. We outline practical approaches and steps for researchers to explore mean group comparisons for the discovery of stratification biomarkers.
Subject(s)
Biomarkers/analysis , Computational Biology/education , Autistic Disorder/diagnosis , Case-Control Studies , Computational Biology/statistics & numerical data , Computer Simulation , Humans , Individuality , Mental Disorders/diagnosis , Neurodevelopmental Disorders/diagnosis , Neuropsychiatry/statistics & numerical data , Neuropsychology/statistics & numerical data , Normal Distribution , Sample SizeABSTRACT
Individuals with autism experience substantially higher rates of mood problems compared to the general population, which contribute to reduced quality of life and increased mortality through suicide. Here, we reviewed evidence for the clinical presentation, aetiology and therapeutic approaches for mood problems in autism. We identified a lack of validated tools for accurately identifying mood problems in individuals with autism, who may present with 'atypical' features (e.g. severe irritability). Risk factors for mood problems in autism appear to be largely overlapping with those identified in the general population, including shared genetic, environmental, cognitive, physiological/neurobiological mechanisms. However, these mechanisms are exacerbated directly/indirectly by lived experiences of autism, including increased vulnerability for chronic stress - often related to social-communication difficulties(/bullying) and sensory sensitivities. Lastly, current therapeutic approaches are based on recommendations for primary mood disorders, with little reference to the neurobiological/cognitive differences associated with autism. Thus, we recommend: 1) the development and validation of (objective) tools to identify mood problems in autism and measure therapeutic efficacy; 2) an interactive approach to investigating aetiologies in large-scale longitudinal studies, integrating different levels of analysis (e.g. cognitive, neurobiological) and lived experience; 3) testing potential treatments through high-quality (e.g. sufficiently powered, blinded) clinical trials, specifically for individuals with autism.
Subject(s)
Autistic Disorder , Mood Disorders , Autistic Disorder/mortality , Autistic Disorder/psychology , Autistic Disorder/therapy , Bullying , Humans , Mood Disorders/mortality , Mood Disorders/psychology , Mood Disorders/therapy , Quality of Life , SuicideABSTRACT
BACKGROUND: Autism is a heterogeneous neurodevelopmental condition accompanied by differences in brain connectivity. Structural connectivity in autism has mainly been investigated within the white matter. However, many genetic variants associated with autism highlight genes related to synaptogenesis and axonal guidance, thus also implicating differences in intrinsic (i.e., gray matter) connections in autism. Intrinsic connections may be assessed in vivo via so-called intrinsic global and local wiring costs. METHODS: Here, we examined intrinsic global and local wiring costs in the brain of 359 individuals with autism and 279 healthy control participants ages 6 to 30 years from the EU-AIMS LEAP (Longitudinal European Autism Project). FreeSurfer was used to derive surface mesh representations to compute the estimated length of connections required to wire the brain within the gray matter. Vertexwise between-group differences were assessed using a general linear model. A gene expression decoding analysis based on the Allen Human Brain Atlas was performed to link neuroanatomical differences to putative underpinnings. RESULTS: Group differences in global and local wiring costs were predominantly observed in medial and lateral prefrontal brain regions, in inferior temporal regions, and at the left temporoparietal junction. The resulting neuroanatomical patterns were enriched for genes that had been previously implicated in the etiology of autism at genetic and transcriptomic levels. CONCLUSIONS: Based on intrinsic gray matter connectivity, the current study investigated the complex neuroanatomy of autism and linked between-group differences to putative genomic and/or molecular mechanisms to parse the heterogeneity of autism and provide targets for future subgrouping approaches.
Subject(s)
Autism Spectrum Disorder , White Matter , Humans , Gray Matter/diagnostic imaging , Autism Spectrum Disorder/diagnostic imaging , Autism Spectrum Disorder/genetics , Magnetic Resonance Imaging/methods , Cerebral Cortex , Brain/diagnostic imaging , White Matter/diagnostic imaging , GenomicsABSTRACT
INTRODUCTION: Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles. METHODS AND ANALYSIS: EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms. ETHICS AND DISSEMINATION: To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).
Subject(s)
Autistic Disorder , Genomics , Registries , Whole Genome Sequencing , Child , Humans , Male , Autistic Disorder/genetics , Cohort Studies , Europe , Multicenter Studies as Topic , Research DesignABSTRACT
Mental health difficulties commonly co-occur with autism, especially in autistic people accessing clinic services, impacting substantially on quality-of-life. Alexithymia (difficulty describing/identifying feelings) and sensory processing differences are prevalent traits in autism that have been associated with depression/anxiety in autistic community samples. However, it is important to better understand interrelationships between these traits in clinical populations to improve identification of service-user needs. In this study, 190 autistic adults (65.3% male), seen in a tertiary autism clinic, completed self-report measures of alexithymia (20-item Toronto Alexithymia Scale), sensory processing differences (Adolescent/Adult Sensory Profile) and depression/anxiety (Hospital Anxiety and Depression Scale). Multiple linear regression models and mediation analyses were used to examine associations between alexithymia, sensory processing differences, and depression/anxiety severity. Across the sample, 66.3% of individuals (N = 126) were classified as alexithymic (score ≥ 61). Total alexithymia and difficulty describing/identifying feelings were significantly associated with depression severity (ß = 0.30-0.38, highest p < 0.002), and difficulty identifying feelings was significantly associated with anxiety severity (ß = 0.36, p < 0.001). Sensory processing differences were also significantly associated with depression severity (ß = 0.29, p = 0.002) and anxiety severity across all models (ß = 0.34-0.48, highest p < 0.001) Finally, difficulty describing/identifying feelings partially mediated the relationships between sensory processing differences and both depression/anxiety severity. Overall, these results highlight that interventions adapted for and targeting emotional awareness and sensory-related uncertainty may improve mental health outcomes in autistic service-users.
ABSTRACT
Up to 50% of autistic people experience co-occurring anxiety, which significantly impacts their quality of life. Consequently, developing new interventions (and/ or adapting existing ones) that improve anxiety has been indicated as a priority for clinical research and practice by the autistic community. Despite this, there are very few effective, evidence-based therapies available to autistic people that target anxiety; and those that are available (e.g., autism adapted Cognitive Behavioural Therapy; CBT) can be challenging to access. Thus, the current study will provide an early-stage proof of concept for the feasibility and acceptability of a novel app-based therapeutic approach that has been developed with, and adapted for, autistic people to support them in managing anxiety using UK National Institute for Health and Care Excellence (NICE) recommended adapted CBT approaches. This paper describes the design and methodology of an ethically approved (22/LO/0291) ongoing non-randomised pilot trial that aims to enrol approximately 100 participants aged ≥16-years with an existing autism diagnosis and mild-to-severe self-reported anxiety symptoms (trial registration NCT05302167). Participants will be invited to engage with a self-guided app-based intervention-'Molehill Mountain'. Primary (Generalised Anxiety Disorder Assessment, Hospital Anxiety and Depression Scale) and secondary outcomes (medication/ service use and Goal Attainment Scaling) will be assessed at baseline (Week 2 +/- 2), endpoint (Week 15 +/- 2) and three follow-ups (Weeks 24, 32 and 41 +/- 4). Participants will also be invited to complete an app acceptability survey/ interview at the study endpoint. Analyses will address: 1) app acceptability/ useability and feasibility (via survey/ interview and app usage data); and 2) target population, performance of outcome measures and ideal timing/ duration of intervention (via primary/ secondary outcome measures and survey/ interview)-with both objectives further informed by a dedicated stakeholder advisory group. The evidence from this study will inform the future optimisation and implementation of Molehill Mountain in a randomised-controlled trial, to provide a novel tool that can be accessed easily by autistic adults and may improve mental health outcomes.
Subject(s)
Autistic Disorder , Mobile Applications , Adult , Humans , Anxiety/psychology , Anxiety Disorders/therapy , Autistic Disorder/therapy , Feasibility Studies , Pilot Projects , Quality of Life , Treatment OutcomeABSTRACT
BACKGROUND: Many autistic children experience difficulties in their communication and language skills development, with consequences for social development into adulthood, often resulting in challenges over the life-course and high economic impacts for individuals, families, and society. The Preschool Autism Communication Trial (PACT) intervention is effective in terms of improved social communication and some secondary outcomes. A previously published within-trial economic analysis found that results at 13 months did not support its cost-effectiveness. We modeled cost-effectiveness over 6 years and across four European countries. METHODS: Using simulation modeling, we built on economic analyses in the original trial, exploring longer-term cost-effectiveness at 6 years (in England). We adapted our model to undertake an economic analysis of PACT in Ireland, Italy, and Spain. Data on resource use were taken from the original trial and a more recent Irish observational study. RESULTS: PACT is cost-saving over time from a societal perspective, even though we confirmed that, at 13 months post-delivery, PACT is more expensive than usual treatment (across all countries) when given to preschool autistic children. After 6 years, we found that PACT has lower costs than usual treatment in terms of unpaid care provided by parents (in all countries). Also, if we consider only out-of-pocket expenses from an Irish study, PACT costs less than usual treatment. DISCUSSION: PACT may be recommended as a cost-saving early intervention for families with an autistic child.
Subject(s)
Autistic Disorder , Child, Preschool , Child , Humans , Autistic Disorder/therapy , Ireland , Spain , England , Communication , Cost-Benefit AnalysisABSTRACT
We examine the cost-effectiveness of treating epilepsy with anti-epileptic medicines in autistic children, looking at impacts on healthcare providers (in England, Ireland, Italy and Spain) and children's families (in Ireland). We find carbamazepine to be the most cost-effective drug to try first in children with newly diagnosed focal seizures. For England and Spain, oxcarbazepine is the most cost-effective treatment when taken as additional treatment for those children whose response to monotherapy is suboptimal. In Ireland and Italy, gabapentin is the most cost-effective option. Our additional scenario analysis presents the aggregate cost to families with autistic children who are being treated for epilepsy: this cost is considerably higher than healthcare provider expenditure.
ABSTRACT
BACKGROUND: Autism and epilepsy often occur together. Epilepsy and other associated conditions have a substantial impact on the well-being of autistic people and their families, reduce quality of life, and increase premature mortality. Despite this, there is a lack of studies investigating the care pathway of autistic children with co-occurring epilepsy in Europe. METHODS: We analyzed the care pathway for autistic children with associated epilepsy in Italy, Spain, and the United Kingdom from the perspective of caregivers (using a survey aimed at caregivers of autistic children 0-18 years old), the autistic community, and professionals, in order to identify major barriers preventing caregivers and autistic children from receiving timely screening and treatment of possible co-occurring epilepsy. RESULTS: Across all three countries, an analysis of the current care pathway showed a lack of systematic screening of epilepsy in all autistic children, lack of treatment of co-occurring epilepsy, and inappropriate use of antiepileptic drugs. A major challenge is the lack of evidence-based harmonized guidelines for autism with co-occurring epilepsy in these countries. CONCLUSIONS: Our findings show both heterogeneity and major gaps in the care pathway for autism with associated epilepsy and the great efforts that caregivers must make for timely screening, diagnosis, and adequate management of epilepsy in autistic children. We call for policy harmonization in Europe in order to improve the experiences and quality of life of autistic people and their families.
Subject(s)
Autistic Disorder , Critical Pathways , Epilepsy , Autistic Disorder/complications , Autistic Disorder/diagnosis , Epilepsy/complications , Epilepsy/diagnosis , Epilepsy/therapy , Quality of Life , Italy , Spain , United Kingdom , Caregivers , Anticonvulsants/therapeutic use , Evidence-Based Medicine , Humans , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Electroencephalography , Intellectual Disability/complications , Male , FemaleABSTRACT
BACKGROUND: Although many studies have explored atypicalities in gray matter (GM) and white matter (WM) morphology of autism, most of them relied on unimodal analyses that did not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish brain patterns of modalities that differentiate between individuals with and without autism and explore associations between these brain patterns and clinical measures in the autism group. METHODS: We studied 183 individuals with autism and 157 nonautistic individuals (age range, 6-30 years) in a large, deeply phenotyped autism dataset (EU-AIMS LEAP [European Autism Interventions-A Multicentre Study for Developing New Medications Longitudinal European Autism Project]). Linked independent component analysis was used to link all participants' GM volume and WM diffusion tensor images, and group comparisons of modality shared variances were examined. Subsequently, we performed univariate and multivariate brain-behavior correlation analyses to separately explore the relationships between brain patterns and clinical profiles. RESULTS: One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM volume in bilateral insula and frontal, precentral and postcentral, cingulate, and caudate areas and co-occurred with altered WM features in the superior longitudinal fasciculus. The brain-behavior correlation analyses showed a significant multivariate association primarily between brain patterns that involved variation of WM and symptoms of restricted and repetitive behavior in the autism group. CONCLUSIONS: Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism and show that the complex clinical autism phenotype can be interpreted by brain covariation patterns that are spread across the brain involving both cortical and subcortical areas.
Subject(s)
Autistic Disorder , White Matter , Humans , Child , Adolescent , Young Adult , Adult , White Matter/diagnostic imaging , Magnetic Resonance Imaging/methods , Brain , Gray Matter/diagnostic imagingABSTRACT
BACKGROUND: Autism is a lifelong complex neurodevelopmental condition that affects brain development and behaviour with significant consequences for everyday life. Despite its personal, familial, and societal impact, Europe-wide harmonised guidelines are still lacking for early detection, diagnosis, and intervention, leading to an overall unsatisfactory autistic person and carer journey. METHODS: The care pathway for autistic children and adolescents was analysed in Italy, Spain and the UK from the perspective of carers (using a survey aimed at caregivers of autistic children 0-18 years old), the autistic community, and professionals in order to identify major barriers (treatment gaps) preventing carers from receiving information, support, and timely screening/diagnosis and intervention. RESULTS: Across all three countries, analysis of the current care pathway showed: long waits from the time carers raised their first concerns about a child's development and/or behaviour until screening and confirmed diagnosis; delayed or no access to intervention once a diagnosis was confirmed; limited information about autism and how to access early detection services; and deficient support for families throughout the journey. CONCLUSIONS: These findings call for policy harmonisation in Europe to shorten long wait times for diagnosis and intervention and therefore, improve autistic people and their families' journey experience and quality of life.
Subject(s)
Autistic Disorder , Child , Adolescent , Humans , Infant, Newborn , Infant , Child, Preschool , Autistic Disorder/diagnosis , Autistic Disorder/therapy , Quality of Life , Critical Pathways , Europe , CaregiversABSTRACT
BACKGROUND: Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings. METHODS: We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings. RESULTS: In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD-but not for ADHD-related genes. LIMITATIONS: Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting. CONCLUSION: Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Autism Spectrum Disorder , Autistic Disorder , Humans , Autistic Disorder/diagnostic imaging , Autistic Disorder/genetics , Autistic Disorder/complications , Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/complications , Neuroanatomy , Brain/diagnostic imaging , Autism Spectrum Disorder/diagnostic imaging , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/complications , GenomicsABSTRACT
LAY ABSTRACT: Autistic individuals are more likely than non-autistic individuals to experience a mental health condition in their lifetime, and this includes externalising and internalising symptoms. We know very little about how different environments and family conditions impact these symptoms for autistic individuals. Improving our understanding of these relationships is important so that we can identify individuals who may be in greater need of support. In this article, we seek to improve our understanding of how environmental and family conditions impact externalising and internalising symptoms in autistic and non-autistic people. To do this, we conducted analyses with two cohorts in very different settings - in Europe and South Africa - to ensure our findings are globally representative. We used advanced statistical methods to establish environmental and family conditions that were similar to each other, and which could be combined into specific 'factors'. We found that four similar 'factors' could be identified in the two cohorts. These were distinguished by personal characteristics and environmental conditions of individuals, and were named Person Characteristics, Family System, Parental and Material Resources. Interestingly, just 'Family System' was associated with internalising and externalising symptoms, and this was the same in both cohorts. We also found that having high traits of autism impacted this relationship between Family System and mental health conditions with opposite directions in the two settings. These results show that characteristics in the Family System are associated with internalising and externalising symptoms, and autistic persons are particularly impacted, reinforcing the notion that family stressors are important to consider when implementing policy and practice related to improving the mental health of autistic people.
ABSTRACT
Sensory atypicalities are particularly common in autism spectrum disorders (ASD). Nevertheless, our knowledge about the divergent functioning of the underlying somatosensory region and its association with ASD phenotype features is limited. We applied a data-driven approach to map the fine-grained variations in functional connectivity of the primary somatosensory cortex (S1) to the rest of the brain in 240 autistic and 164 neurotypical individuals from the EU-AIMS LEAP dataset, aged between 7 and 30. We estimated the S1 connection topography ('connectopy') at rest and during the emotional face-matching (Hariri) task, an established measure of emotion reactivity, and accessed its association with a set of clinical and behavioral variables. We first demonstrated that the S1 connectopy is organized along a dorsoventral axis, mapping onto the S1 somatotopic organization. We then found that its spatial characteristics were linked to the individuals' adaptive functioning skills, as measured by the Vineland Adaptive Behavior Scales, across the whole sample. Higher functional differentiation characterized the S1 connectopies of individuals with higher daily life adaptive skills. Notably, we detected significant differences between rest and the Hariri task in the S1 connectopies, as well as their projection maps onto the rest of the brain suggesting a task-modulating effect on S1 due to emotion processing. All in all, variation of adaptive skills appears to be reflected in the brain's mesoscale neural circuitry, as shown by the S1 connectivity profile, which is also differentially modulated during rest and emotional processing.
Subject(s)
Autism Spectrum Disorder , Somatosensory Cortex , Humans , Somatosensory Cortex/diagnostic imaging , Brain , Emotions , Brain Mapping , Phenotype , Magnetic Resonance ImagingABSTRACT
Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA-DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes.