1. Arnett AB, Trinh S, Bernier RA. {{The state of research on the genetics of autism spectrum disorder: methodological, clinical and conceptual progress}}. {Current opinion in psychology}. 2018; 27: 1-5.
Autism spectrum disorder (ASD) is a behaviorally heterogeneous disorder with a strong genetic component, as evidenced by decades of twin and family studies. In recent years, enhanced methods of genomic sequencing have revealed that structural variation and mutations to both coding and non-coding regions of single, candidate genes may account for more than 30% of ASD cases. The current review highlights a genotype-first approach that builds upon these molecular findings to parse the heterogeneity of ASD. Advantages of this approach include strong potential for precision medicine diagnosis and treatment, as well as opportunity to advance basic science research on neurodevelopmental disorders. Psychosocial benefits of identifying genetic subtypes of ASD have already been realized through social networking, comprehensive clinical phenotyping, and increased awareness among providers of rare genetic mutations.
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2. Arnold Anteraper S, Guell X, D’Mello A, Joshi N, Whitfield-Gabrieli S, Joshi G. {{Disrupted Cerebrocerebellar Intrinsic Functional Connectivity in Young Adults with High-Functioning Autism Spectrum Disorder: A Data-Driven, Whole-Brain, High-Temporal Resolution Functional Magnetic Resonance Imaging Study}}. {Brain Connect}. 2018.
This study examines the resting-state functional-connectivity (RsFc) in young adults with high-functioning autism spectrum disorder (HF-ASD) using state-of-the-art fMRI data acquisition and analysis techniques. High temporal resolution fMRI using simultaneous multi-slice acquisition aided unbiased whole-brain connectome-wide multivariate pattern analysis (MVPA) techniques for assessing RsFc. MVPA revealed two clusters (Crus I/II and lobule IX) of abnormal connectivity in the cerebellum that are consistent with the notion of a triple representation of nonmotor processing in the cerebellum. Whole-brain seed-based RsFc analyses informed by these clusters showed significant under connectivity between the cerebellar and social, emotional, and language brain regions in the HF-ASD group compared to healthy controls. The results we report are coherent with existing structural, functional, and RsFc literature in autism, extend previous literature reporting cerebellar abnormalities in the neuropathology of autism, and highlight the cerebellum as a potential target for therapeutic, diagnostic, predictive, and prognostic developments in HF-ASD. The description of functional connectivity abnormalities reported in this study using whole-brain, data-driven analyses has the potential to crucially advance the development of ASD biomarkers, targets for therapeutic interventions, and neural predictors for measuring treatment response.
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3. Beacham C, Reid M, Bradshaw J, Lambha M, Evans L, Gillespie S, Klaiman C, Richardson SS. {{Screening for Autism Spectrum Disorder: Profiles of Children Who Are Missed}}. {J Dev Behav Pediatr}. 2018.
OBJECTIVE: To characterize children presenting with concerns for autism spectrum disorder (ASD) missed by parent-report screeners and to examine benefits of a combined screening approach with the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) and the Ages and Stages Questionnaire, Third Edition (ASQ-3). METHODS: Participants included were 154 children aged 16 to 42 months presenting for an evaluation at an autism center. Caregivers completed the M-CHAT-R, ASQ-3, and a demographic questionnaire. Children participated in an autism diagnostic evaluation consisting of the Mullen Scales of Early Learning (Mullen) and Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). RESULTS: A total of 124 children (81%) were diagnosed with ASD. The M-CHAT-R identified 85% (n = 105) of these children. Children with ASD missed by the M-CHAT-R had significantly higher scores on the Mullen and significantly lower scores on the ADOS-2. Of the ASQ-3 domains, the majority (n = 102, 82%) of children with ASD failed the communication domain; missed cases showed similar patterns of higher Mullen scores and lower ADOS-2 scores. When adopting a combined screening approach, using a failed screen from either the M-CHAT-R or ASQ-3 communication domain, 93% of children were identified. Parent-reported concerns on an open-ended questionnaire revealed ASD red flags for many missed cases. CONCLUSION: Children with ASD missed by screeners had higher scores on developmental testing and lower scores on the ADOS-2; however, children still performed below average on developmental tests. Our findings suggest that a combined screening approach was most effective for identifying children with ASD from a sample group referred for an ASD evaluation.
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4. Berding K, Donovan SM. {{Diet Can Impact Microbiota Composition in Children With Autism Spectrum Disorder}}. {Front Neurosci}. 2018; 12: 515.
Diet is one of the most influential environmental factors in determining the composition of the gastrointestinal microbiota. Microbial dysbiosis in children with Autism Spectrum Disorder (ASD) and the impact of some bacterial taxa on symptoms of ASD has been recognized. Children with ASD are often described as picky eaters with low intake of fiber-rich foods, including fruits and vegetables. However, the impact of diet on the microbiota composition in children with ASD is largely unknown. Herein, fecal samples, 3 day food diaries and the Youth and Adolescence Food Frequency questionnaire (YAQ) were collected from children with ASD (ASD; n = 26) and unaffected controls (CONT; n = 32). Children’s ASD symptoms were determined using the Pervasive Developmental Disorder Behavior Inventory Screening Version (PDDBI-SV). Differences in the microbiota composition at the phyla, order, family, and genus level between ASD and CONT were observed. Microbiota composition of children with ASD was investigated in relation to feeding behavior, nutrient and food group intake as well as dietary patterns derived from the YAQ. In children with ASD, two distinct dietary patterns (DP) were associated with unique microbial profiles. DP1, characterized by higher intakes of vegetables, legumes, nuts and seeds, fruit, refined carbohydrates, and starchy vegetables, but lower intakes of sweets, was associated with lower abundance of Enterobacteriaceae, Lactococcus, Roseburia, Leuconostoc, and Ruminococcus. DP2, characterized by low intakes of vegetables, legumes, nuts and seeds and starchy vegetables, was associated with higher Barnesiellaceae and Alistipes and lower Streptophyta, as well as higher levels of propionate, isobutyrate, valerate, and isovalerate. Peptostreptococcaceae and Faecalibacterium predicted social deficit scores in children with ASD as measured by the PDDBI-SV. Diet-associated microbial profiles were related to GI symptoms, but no significant interaction between nutrition and microbiota in predicting social deficit scores were observed. In conclusion, dietary patterns associated with fecal microbiota composition and VFA concentrations in children with ASD were identified. Future studies using a larger sample size and measuring other behaviors associated with ASD are needed to investigate whether dietary intake may be a modifiable moderator of ASD symptoms.
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5. Cassidy S, Bradley L, Shaw R, Baron-Cohen S. {{Risk markers for suicidality in autistic adults}}. {Mol Autism}. 2018; 9: 42.
Background: Research has shown high rates of suicidality in autism spectrum conditions (ASC), but there is lack of research into why this is the case. Many common experiences of autistic adults, such as depression or unemployment, overlap with known risk markers for suicide in the general population. However, it is unknown whether there are risk markers unique to ASC that require new tailored suicide prevention strategies. Methods: Through consultation with a steering group of autistic adults, a survey was developed aiming to identify unique risk markers for suicidality in this group. The survey measured suicidality (SBQ-R), non-suicidal self-injury (NSSI-AT), mental health problems, unmet support needs, employment, satisfaction with living arrangements, self-reported autistic traits (AQ), delay in ASC diagnosis, and ‘camouflaging’ ASC. One hundred sixty-four autistic adults (65 male, 99 female) and 169 general population adults (54 males, 115 females) completed the survey online. Results: A majority of autistic adults (72%) scored above the recommended psychiatric cut-off for suicide risk on the SBQ-R; significantly higher than general population (GP) adults (33%). After statistically controlling for a range of demographics and diagnoses, ASC diagnosis and self-reported autistic traits in the general population significantly predicted suicidality. In autistic adults, non-suicidal self-injury, camouflaging, and number of unmet support needs significantly predicted suicidality. Conclusions: Results confirm previously reported high rates of suicidality in ASC, and demonstrate that ASC diagnosis, and self-reported autistic traits in the general population are independent risk markers for suicidality. This suggests there are unique factors associated with autism and autistic traits that increase risk of suicidality. Camouflaging and unmet support needs appear to be risk markers for suicidality unique to ASC. Non-suicidal self-injury, employment, and mental health problems appear to be risk markers shared with the general population that are significantly more prevalent in the autistic community. Implications for understanding and prevention of suicide in ASC are discussed.
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6. Christensen SS, Bentz M, Clemmensen L, Strandberg-Larsen K, Olsen EM. {{Disordered eating behaviours and autistic traits-Are there any associations in nonclinical populations? A systematic review}}. {European eating disorders review : the journal of the Eating Disorders Association}. 2018.
OBJECTIVE: The objective of this study is to critically review existing literature concerning the possible association between autistic-like behaviours and problematic eating behaviours in nonclinical populations. METHOD: We performed a systematic literature search in three large databases. Studies were included if they assessed any association between a broad range of autistic-like behaviours and problematic eating behaviours in nonclinical samples. RESULTS: Sixteen eligible studies were found covering 3,595 participants in total, including five studies on children/adolescents (n = 685). All studies were cross-sectional, and thus, only concurrent associations could be evaluated. Several autistic-like behaviours were found to be associated with problematic eating behaviours, with the overall « autism spectrum quotient, » deficiencies in set-shifting, and theory of mind showing the strongest associations. CONCLUSIONS: The existing literature indicates concurrent associations between specific autistic-like behaviours and problematic eating behaviours in nonclinical samples across ages. Large prospective longitudinal studies are needed for insight into the temporal order of these associations.
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7. Fitzpatrick P, Frazier JA, Cochran D, Mitchell T, Coleman C, Schmidt RC. {{Relationship Between Theory of Mind, Emotion Recognition, and Social Synchrony in Adolescents With and Without Autism}}. {Front Psychol}. 2018; 9: 1337.
Difficulty in social communication and interaction is a primary diagnostic feature of ASD. Research has found that adolescents with ASD display various impairments in social behavior such as theory of mind (ToM), emotion recognition, and social synchrony. However, not much is known about the relationships among these dimensions of social behavior. Adolescents with and without ASD participated in the study. ToM ability was measured by viewing social animations of geometric shapes, recognition of facial emotions was measured by viewing pictures of faces, and synchrony ability was measured with a spontaneously arising interpersonal movement task completed with a caregiver and an intentional interpersonal task. Attention and social responsiveness were measured using parent reports. We then examined the relationship between ToM, emotion recognition, clinical measures of attention and social responsiveness, and social synchronization that arises either spontaneously or intentionally. Results indicate that spontaneous synchrony was related to ToM and intentional synchrony was related to clinical measures of attention and social responsiveness. Facial emotion recognition was not related to either ToM or social synchrony. Our findings highlight the importance of biological motion perception and production and attention for more fully understanding the social behavior characteristic of ASD. The findings suggest that the processes underlying difficulties in spontaneous synchrony in ASD are different than the processes underlying difficulties in intentional synchronization.
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8. Ford TC, Abu-Akel A, Crewther DP. {{The association of excitation and inhibition signaling with the relative symptom expression of autism and psychosis-proneness: Implications for psychopharmacology}}. {Prog Neuropsychopharmacol Biol Psychiatry}. 2018; 88: 235-42.
The underlying mechanisms of autism and schizophrenia are poorly understood, partly due to a lack of dimension-specific research. Aberrant excitatory and inhibitory neurotransmission are implicated in both conditions, particularly in social dysfunction. This study investigates the extent to which the degree of autistic tendency and psychosis-proneness exclusively and interactively predict excitatory and inhibitory neurotransmitter concentrations in the superior temporal cortex (STC). In 38 adults (18 male, 18-40years), we obtained autistic tendencies (Autism-Spectrum Quotient [AQ]) and psychosis-proneness scores (Schizotypal Personality Questionnaire [PP]); magnetic resonance spectroscopy (MRS) quantified glutamate and GABA+ concentrations from the STC. Results demonstrated a negative AQ/PP interaction with glutamate concentration for the left STC voxel, where PP increased with glutamate for average AQ, while AQ decreased with glutamate for average-high PP. There was a negative AQ/PP interaction with glutamate/GABA+ ratio for the right STC, AQ increasing with glutamate/GABA+ for low-average PP, while PP decreased with glutamate/GABA+ for high AQ. Consistent with animal studies, we also reveal that overall reduced glutamate/GABA+ ratio might be precipitated by increased right hemisphere GABA+ concentrations. These findings illustrate the importance of considering the concurrent effects of autism and psychosis dimensions on understanding the pathophysiological mechanisms implicated in either condition, and can advance psychopharmacological research into better treatment options for patients.
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9. Konkel L. {{Air Pollution and ASDs: A Deeper Dive into an Environmental Risk Factor}}. {Environmental health perspectives}. 2018; 126(7): 074001.
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10. Larson LR, Barger B, Ogletree S, Torquati J, Rosenberg S, Gaither CJ, Bartz JM, Gardner A, Moody E, Schutte A. {{Gray space and green space proximity associated with higher anxiety in youth with autism}}. {Health & place}. 2018; 53: 94-102.
This study used ZIP code level data on children’s health (National Survey of Children’s Health, 2012) and land cover (National Land Cover Database, 2011) from across the United States to investigate connections between proximity to green space (tree canopy), gray space (impervious surfaces), and expression of a critical co-morbid condition, anxiety, in three groups of youth: children diagnosed with autism spectrum disorder (ASD, n=1501), non-ASD children with special healthcare needs (CSHCN, n=15,776), and typically developing children (n=53,650). Both impervious surface coverage and tree canopy coverage increased the risk of severe anxiety in youth with autism, but not CSHCN or typical children. Children with ASD might experience the stress-reducing benefits of nature differently than their typically developing peers. More research using objective diagnostic metrics at finer spatial scales would help to illuminate complex relationships between green space, anxiety, and other co-morbid conditions in youth with ASD.
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11. Rosenberg A, Sunkara A. {{Does attenuated divisive normalization affect gaze processing in autism spectrum disorder? A commentary on Palmer et al. (2018)}}. {Cortex}. 2018.
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12. Singh J, Santosh P. {{Key issues in Rett syndrome: emotional, behavioural and autonomic dysregulation (EBAD) – a target for clinical trials}}. {Orphanet journal of rare diseases}. 2018; 13(1): 128.
Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.
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13. Szczurkowska J, Pischedda F, Pinto B, Manago F, Haas CA, Summa M, Bertorelli R, Papaleo F, Schafer MK, Piccoli G, Cancedda L. {{NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice}}. {Brain}. 2018.
Autism spectrum disorders are neurodevelopmental conditions with diverse aetiologies, all characterized by common core symptoms such as impaired social skills and communication, as well as repetitive behaviour. Cell adhesion molecules, receptor tyrosine kinases and associated downstream signalling have been strongly implicated in both neurodevelopment and autism spectrum disorders. We found that downregulation of the cell adhesion molecule NEGR1 or the receptor tyrosine kinase fibroblast growth factor receptor 2 (FGFR2) similarly affects neuronal migration and spine density during mouse cortical development in vivo and results in impaired core behaviours related to autism spectrum disorders. Mechanistically, NEGR1 physically interacts with FGFR2 and modulates FGFR2-dependent extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signalling by decreasing FGFR2 degradation from the plasma membrane. Accordingly, FGFR2 overexpression rescues all defects due to Negr1 knockdown in vivo. Negr1 knockout mice present phenotypes similar to Negr1-downregulated animals. These data indicate that NEGR1 and FGFR2 cooperatively regulate cortical development and suggest a role for defective NEGR1-FGFR2 complex and convergent downstream ERK and AKT signalling in autism spectrum disorders.
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14. Taylor SE, Taylor RD, Price J, Andreae LC. {{Single-molecule fluorescence in-situ hybridization reveals that human SHANK3 mRNA expression varies during development and in autism-associated SHANK3 heterozygosity}}. {Stem cell research & therapy}. 2018; 9(1): 206.
BACKGROUND: Deletions and mutations in the SHANK3 gene are strongly associated with autism spectrum disorder and underlie the autism-associated disorder Phelan-McDermid syndrome. SHANK3 is a scaffolding protein found at the post-synaptic membrane of excitatory neurons. METHODS: Single-molecule fluorescence in-situ hybridization (smFISH) allows the visualization of single mRNA transcripts in vitro. Here we perform and quantify smFISH in human inducible pluripotent stem cell (hiPSC)-derived cortical neurons, targeting the SHANK3 transcript. RESULTS: Both smFISH and conventional immunofluorescence staining demonstrated a developmental increase in SHANK3 mRNA and protein, respectively, in control human cortical neurons. Analysis of single SHANK3 mRNA molecules in neurons derived from an autistic individual heterozygous for SHANK3 indicated that while the number of SHANK3 mRNA transcripts remained comparable with control levels in the cell soma, there was a 50% reduction within neuronal processes, suggesting that local, dendritic targeting of SHANK3 mRNA may be specifically affected in SHANK3 haploinsufficiency. CONCLUSION: Human SHANK3 mRNA shows developmentally regulated dendritic localization in hiPSC-derived neurons, which is reduced in neurons generated from a haploinsufficient individual with autism. Although further replication is needed, given the importance of local mRNA translation in synaptic function, this could represent an important early abnormality.
