1. Arroyo ED, Fiole D, Mantri SS, Huang C, Portera-Cailliau C. {{Dendritic Spines in Early Postnatal Fragile X Mice Are Insensitive to Novel Sensory Experience}}. {J Neurosci}. 2019; 39(3): 412-9.
Autism spectrum disorders are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in autism spectrum disorders could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic in vivo two-photon microscopy to image dendritic spines and axon « en passant » boutons of layer 2/3 pyramidal neurons in S1 of male and female WT and Fmr1 KO mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhance sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in Fmr1 KO mice. In contrast, axon « en passant » boutons dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of Fmr1 KO mice to modulate postsynaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS.SIGNIFICANCE STATEMENT Very few longitudinal in vivo imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience.
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2. Bartholomay KL, Lee CH, Bruno JL, Lightbody AA, Reiss AL. {{Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings}}. {Brain Sci}. 2019; 9(1).
Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population.
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3. Fleury VP, Trevors G, Kendeou P. {{Public Perception of Autism Treatments: The Role of Credibility and Evidence}}. {J Autism Dev Disord}. 2019.
We explored the influence of credibility and evidence on public perceptions of ASD treatments using survey methodology. Participants (N = 379) read texts about different ASD treatments. The text presentation was based on a 2 x 2 within-subjects factorial design with treatment status [evidence based practices (EBP) vs. non-EBP] and source credibility in the text (credible vs. non-credible) as the independent variables. An instructional manipulation condition served as a between subjects factor. Respondents were more familiar with non-EBPs than EBPs, but viewed EBPs as being more credible and were more likely to endorse them compared to pseudoscientific practices. Interactions between source credibility and instructional manipulation were found on ratings of credibility and recommendation of both EBP and non-EBP texts. Implications of these findings are discussed.
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4. Gouder L, Vitrac A, Goubran-Botros H, Danckaert A, Tinevez JY, Andre-Leroux G, Atanasova E, Lemiere N, Biton A, Leblond CS, Poulet A, Boland A, Deleuze JF, Benchoua A, Delorme R, Bourgeron T, Cloez-Tayarani I. {{Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations}}. {Sci Rep}. 2019; 9(1): 94.
The synaptic protein SHANK3 encodes a multidomain scaffold protein expressed at the postsynaptic density of neuronal excitatory synapses. We previously identified de novo SHANK3 mutations in patients with autism spectrum disorders (ASD) and showed that SHANK3 represents one of the major genes for ASD. Here, we analyzed the pyramidal cortical neurons derived from induced pluripotent stem cells from four patients with ASD carrying SHANK3 de novo truncating mutations. At 40-45 days after the differentiation of neural stem cells, dendritic spines from pyramidal neurons presented variable morphologies: filopodia, thin, stubby and muschroom, as measured in 3D using GFP labeling and immunofluorescence. As compared to three controls, we observed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) in correlation with a significant reduction in dendritic spine densities and whole spine and spine head volumes. These results, obtained through the analysis of de novo SHANK3 mutations in the patients’ genomic background, provide further support for the presence of synaptic abnormalities in a subset of patients with ASD.
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5. Kang E, Gadow KD, Lerner MD. {{Atypical Communication Characteristics, Differential Diagnosis, and the Autism Spectrum Disorder Phenotype in Youth}}. {J Clin Child Adolesc Psychol}. 2019: 1-13.
This study compared atypical communication characteristics (ACCs) in clinic-referred youth with and without autism spectrum disorder (ASD), identified subgroups based on different patterns of ACCs in youth with ASD, and determined if ACC subgroups result in meaningful clinical phenotypes in their relation to psychopathology and functional outcomes. Youth 6-18 years of age (N= 947; M age = 11.41; 72% male; 84% Caucasian) with and without ASD were assessed using Child and Adolescent Symptom Inventory-4R and the Parent Questionnaire, which included a checklist of ACCs. Prevalence of ACCs was examined and receiver operational characteristic analyses were used to estimate the diagnostic accuracy of number of ACCs for ASD. Latent class analysis was conducted to see if patterns of ACCs yielded clinically useful subgroups in youth with ASD. Youth with ASD exhibited higher rates of ACC than non-ASD psychiatry referrals, and a summary score of ACCs easily differentiated the two clinic-referred samples. Among youth with ASD, ACC subgroups exhibited differences in severity of psychiatric symptoms, ASD symptomatology, and functional outcomes. Our results suggest that ACCs are an important characteristic of the ASD clinical phenotype and may be a useful consideration for defining more precise ASD symptomatology, functional outcomes, and treatment targets.
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6. Kappel DB, Schuch JB, Rovaris DL, da Silva BS, Muller D, Breda V, Teche SP, R SR, Schuler-Faccini L, Rohde LA, Grevet EH, Bau CHD. {{ADGRL3 rs6551665 as a Common Vulnerability Factor Underlying Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder}}. {Neuromolecular medicine}. 2019.
Neurodevelopmental disorders are prevalent, frequently occur in comorbidity and share substantial genetic correlation. Previous evidence has suggested a role for the ADGRL3 gene in Attention-Deficit/Hyperactivity Disorder (ADHD) susceptibility in several samples. Considering ADGRL3 functionality in central nervous system development and its previous association with neurodevelopmental disorders, we aimed to assess ADGRL3 influence in early-onset ADHD (before 7 years of age) and Autism Spectrum Disorder (ASD). The sample comprises 187 men diagnosed with early-onset ADHD, 135 boys diagnosed with ASD and 468 male blood donors. We tested the association of an ADGRL3 variant (rs6551665) with both early-onset ADHD and ASD susceptibility. We observed significant associations between ADGRL3-rs6551665 on ADHD and ASD susceptibilities; we found that G-carriers were at increased risk of ADHD and ASD, in accordance with previous studies. The overall evidence from the literature, corroborated by our results, suggests that ADGRL3 might be involved in brain development, and genetic modifications related to it might be part of a shared vulnerability factor associated with the underlying neurobiology of neurodevelopmental disorders such as ADHD and ASD.
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7. King JB, Prigge MBD, King CK, Morgan J, Dean DC, 3rd, Freeman A, Villaruz JAM, Kane KL, Bigler ED, Alexander AL, Lange N, Zielinski BA, Lainhart JE, Anderson JS. {{Evaluation of Differences in Temporal Synchrony Between Brain Regions in Individuals With Autism and Typical Development}}. {JAMA network open}. 2018; 1(7): e184777.
Importance: Despite reports of widespread but heterogeneous atypicality of functional connectivity in individuals with autism, little is known regarding the temporal dynamics of functional brain connections and how they relate to autistic traits. Objective: To investigate differences in temporal synchrony between brain regions in individuals with autism and those with typical development. Design, Setting, and Participants: This cohort study, conducted at the University of Utah, included 90 adolescent and adult male participants. A larger sample from the multisite Autism Brain Imaging Data Exchange (ABIDE) was also used as a replication sample. The study includes data acquired between December 2016 and April 2018. Aggregate data included in the replication sample were released to the public in August 2012 (ABIDE I) and June 2016 (ABIDE II). Data analysis were conducted between January 2018 and April 2018. Exposures: Male individuals diagnosed as having autism (n = 52) and typically developing male individuals (n = 38). Main Outcomes and Measures: Long duration (30 minutes/individual) of multiband, multiecho functional magnetic resonance imaging was acquired to estimate functional connectivity between brain regions. Sustained connectivity, a measure of functional connectivity duration, as well as lagged temporal dynamics related to functional connectivity, were compared between groups for 361 gray matter regions of interest and a 17-network parcellation. Lagged findings were replicated in the larger ABIDE sample (n = 1402). Sustained connectivity findings were also associated with behavioral and cognitive variables. Results: In 52 males with autism (mean [SD] age, 27.73 [8.66] years) and 38 control males with typical development (mean [SD] age, 27.09 [7.49] years), increases in both sustained and functional connectivity at several lags were found in individuals with autism compared with the control group. Group differences in functional connectivity were replicated in the larger ABIDE data set at a 6-second lag. Measures of symptom severity in individuals with autism were positively associated with sustained connectivity values. In the control group, sustained connectivity was negatively associated with cognitive processing. A replication sample (n = 1402) composed of 579 individuals with autism (80 female and 499 male; mean [SD] age, 15.08 [6.89] years) and 823 in the control group (211 female and 612 male; mean [SD] age, 15.06 [6.79] years) from the ABIDE data set was also analyzed. Conclusions and Relevance: Whereas the magnitude of functional connectivity in autism is variable across brain regions, participant samples, and development, prolonged temporal synchrony of functional connections is reproducibly observed in autism, suggesting a potential mechanism for core symptoms.
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8. Lieder I, Adam V, Frenkel O, Jaffe-Dax S, Sahani M, Ahissar M. {{Perceptual bias reveals slow-updating in autism and fast-forgetting in dyslexia}}. {Nat Neurosci}. 2019.
Individuals with autism and individuals with dyslexia both show reduced use of previous sensory information (stimuli statistics) in perceptual tasks, even though these are very different neurodevelopmental disorders. To better understand how past sensory information influences the perceptual experience in these disorders, we first investigated the trial-by-trial performance of neurotypical participants in a serial discrimination task. Neurotypical participants overweighted recent stimuli, revealing fast updating of internal sensory models, which is adaptive in changing environments. They also weighted the detailed stimuli distribution inferred by longer-term accumulation of stimuli statistics, which is adaptive in stable environments. Compared to neurotypical participants, individuals with dyslexia weighted earlier stimuli less heavily, whereas individuals with autism spectrum disorder weighted recent stimuli less heavily. Investigating the dynamics of perceptual inference reveals that individuals with dyslexia rely more on information about the immediate past, whereas perception in individuals with autism is dominated by longer-term statistics.
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9. Lotan M. {{The cost of Rett syndrome}}. {Dev Med Child Neurol}. 2019.
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10. McDougle CJ. {{Another Step Toward Defining an Immune-Mediated Subtype of Autism Spectrum Disorder}}. {JAMA network open}. 2018; 1(2): e180280.
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11. Miyajima M, Omiya H, Yamashita K, Yambe K, Matsui M, Denda K. {{Therapeutic responses to a frontal/executive programme in autism spectrum disorder: Comparison with schizophrenia}}. {Hong Kong journal of occupational therapy : HKJOT}. 2018; 31(2): 69-75.
Introduction: Studies on autism spectrum disorder in recent years have controversially indicated similarities with schizophrenia. Cognitive dysfunction is present in both disorders, and while there is a rich array of interventions for cognitive dysfunction in schizophrenia, there are few such treatments for autism spectrum disorder. In this study, we have investigated a potentially useful approach in autism spectrum disorder by comparing autism spectrum disorder with schizophrenia in regard to the characteristics of cognitive dysfunction and therapeutic response to cognitive remediation therapy. Method: We studied seven patients with autism spectrum disorder and eight patients with schizophrenia, using a frontal/executive programme as the intervention. The characteristics of cognitive dysfunction in autism spectrum disorder before frontal/executive programme and the therapeutic response to frontal/executive programme in autism spectrum disorder patients were compared with those in schizophrenia patients, based on evaluation of cognitive function and social function. The changes in cognitive and social function after treatment in each patient group were compared using the Mann-Whitney’s U test. Results: The severity of cognitive dysfunction did not differ significantly between autism spectrum disorder and schizophrenia. Frontal/executive programme was effective in autism spectrum disorder, with subjects showing about the same therapeutic response as in schizophrenia. Conclusion: Frontal/executive programme appears to be useful for patients with autism spectrum disorder. Furthermore, the similarities in cognitive dysfunction and therapeutic response between autism spectrum disorder and schizophrenia are highly relevant to the recent debate concerning the similarity between these two disease concepts.
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12. Rai D, Heuvelman H, Dalman C, Culpin I, Lundberg M, Carpenter P, Magnusson C. {{Association Between Autism Spectrum Disorders With or Without Intellectual Disability and Depression in Young Adulthood}}. {JAMA network open}. 2018; 1(4): e181465.
Importance: Depression is a frequently occurring mental disorder and may be common in adults with autism spectrum disorders (ASD), but there is a lack of longitudinal population-based studies examining this association. Whether any increased risk of depression in ASD has a shared familial basis and whether it differs by co-occurring intellectual disability is not well known. Objectives: To examine whether individuals with ASD are more likely to be diagnosed as having depression in adulthood than the general population and their nonautistic siblings and to investigate whether these risks differ by the presence or absence of intellectual disability. Design, Setting, and Participants: Population-based cohort study with a nested sibling comparison. The Stockholm Youth Cohort is a total population record linkage study that includes all children and young people (age range, 0-17 years) who were ever resident in Stockholm County, Sweden, between January 2001 and December 2011 (n = 735096). Data analysis was conducted between January 5 and November 30, 2017, in Stockholm County, Sweden. Main Outcomes and Measures: Clinical diagnosis of depressive disorders was identified using the Stockholm County Adult Psychiatric Outpatient Register and the Swedish National Patient Register. Results: Participants were 223842 individuals followed up to age 27 years by 2011, of whom 4073 had diagnosed ASD (mean [SD] age, 21.5 [2.7] years; 65.9% male; 2927 without intellectual disability and 1146 with intellectual disability) and 219769 had no ASD (mean [SD] age, 22.1 [2.8] years; 50.9% male). By age 27 years, 19.8% (n = 808) of individuals diagnosed having ASD had a diagnosis of depression compared with 6.0% (n = 13114) of the general population (adjusted relative risk [RR], 3.64; 95% CI, 3.41-3.88). The risk of a depression diagnosis was higher in ASD without intellectual disability (adjusted RR, 4.28; 95% CI, 4.00-4.58) than in ASD with intellectual disability (adjusted RR, 1.81; 95% CI, 1.51-2.17). Nonautistic full-siblings (adjusted RR, 1.37; 95% CI, 1.23-1.53) and half-siblings (adjusted RR, 1.42; 95% CI, 1.23-1.64) of individuals with ASD also had a higher risk of depression than the general population. Compared with their nonautistic full-siblings, individuals with ASD had more than a 2-fold risk of a depression diagnosis (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27) in young adulthood. Conclusions and Relevance: According to this study’s results, ASD, particularly ASD without intellectual disability, is associated with depression by young adulthood compared with the general population. It appears that this association is unlikely to be explained by shared familial liability. Future research to identify modifiable pathways between ASD and depression may assist in the development of preventive interventions.
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13. Roux S, Bailly Y, Bossu JL. {{Regional and sex-dependent alterations in Purkinje cell density in the valproate mouse model of autism}}. {Neuroreport}. 2019; 30(2): 82-8.
Neuropathological and neuroimaging studies indicate a decrease in Purkinje cell (PC) density in the cerebellum of autistic patients and rodent models of autism. Autism is far more prevalent in males than females, and sex-specific properties of PCs have been reported recently. We investigated the differential sensitivity of PCs in the valproate acid (VPA) mouse model of autism by estimating the linear density of PCs immununolabelled with calbindin in the cerebellum of males and females. Whereas prenatal VPA treatment surprisingly increased PC linear density in both sexes 13 days after birth (P13), it significantly reduced the linear density of PCs in the cerebellum of 40-day-old (P40) males, but not females. In males, PC loss was more pronounced in the posterior part of the cerebellum and was significant in the VIth, VIIth, IXth and paramedian lobules. In females, PC loss was restricted to the paramedian lobule. These results suggest that this sex-specific sensitivity of PCs to VPA may contribute towards the motor disturbances and behavioural abnormalities observed in autism.
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14. Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M. {{Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder}}. {Neuron}. 2019; 101(2): 246-59.e6.
Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host’s gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.
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15. Xu G, Snetselaar LG, Jing J, Liu B, Strathearn L, Bao W. {{Association of Food Allergy and Other Allergic Conditions With Autism Spectrum Disorder in Children}}. {JAMA network open}. 2018; 1(2): e180279.
Importance: The prevalence of autism spectrum disorder (ASD) in US children has increased during the past decades. Immunologic dysfunction has recently emerged as a factor associated with ASD. Although children with ASD are more likely to have gastrointestinal disorders, little is known about the association between food allergy and ASD. Objective: To examine the association of food allergy and other allergic conditions with ASD in US children. Design, Setting, and Participants: This population-based, cross-sectional study used data from the National Health Interview Survey collected between 1997 and 2016. The data analysis was performed in 2018. All eligible children aged 3 to 17 years were included. Food allergy, respiratory allergy, and skin allergy were defined based on an affirmative response in the questionnaire by a parent or guardian. Main Outcomes and Measures: Reported ASD diagnosed by a physician or other health professional. Results: This analysis included 199520 children (unweighted mean [SD] age, 10.21 [4.41] years; 102690 boys [51.47%]; 55476 Hispanic [27.80%], 97200 non-Hispanic white [48.72%], 30760 non-Hispanic black [15.42%], and 16084 non-Hispanic other race [8.06%]). Among them, 8734 (weighted prevalence, 4.31%) had food allergy, 24555 (12.15%) had respiratory allergy, and 19399 (9.91%) had skin allergy. A diagnosis of ASD was reported in 1868 children (0.95%). The weighted prevalence of reported food, respiratory, and skin allergies was higher in children with ASD (11.25%, 18.73%, and 16.81%, respectively) compared with children without ASD (4.25%, 12.08%, and 9.84%, respectively). In analyses adjusting for age, sex, race/ethnicity, family highest education level, family income level, geographical region, and mutual adjustment for other allergic conditions, the associations between allergic conditions and ASD remained significant. The odds ratio (OR) of ASD increased in association with food allergy (OR, 2.29; 95% CI, 1.87-2.81), respiratory allergy (OR, 1.28; 95% CI, 1.10-1.50), and skin allergy (OR, 1.50; 95% CI, 1.28-1.77) when comparing children with these conditions and those without. Conclusions and Relevance: In a nationally representative sample of US children, a significant and positive association of common allergic conditions, in particular food allergy, with ASD was found. Further investigation is warranted to elucidate the causality and underlying mechanisms.
