Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging / J. ELLEGOOD in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 24p. Titre : Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging Type de document : Texte imprimé et/ou numérique Auteurs : J. ELLEGOOD, Auteur ; Y. YEE, Auteur ; T. M. KERR, Auteur ; C. L. MULLER, Auteur ; R. D. BLAKELY, Auteur ; R. M. HENKELMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; J. P. LERCH, Auteur Article en page(s) : 24p. Langues : Anglais (eng) Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Analysis of neuroanatomical differences in mice with genetically modified serotonin transporters assessed by structural magnetic resonance imaging [Texte imprimé et/ou numérique] / J. ELLEGOOD, Auteur ; Y. YEE, Auteur ; T. M. KERR, Auteur ; C. L. MULLER, Auteur ; R. D. BLAKELY, Auteur ; R. M. HENKELMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; J. P. LERCH, Auteur . - 24p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 24p. Mots-clés : Animals  Brain/diagnostic imaging/metabolism  Female  Magnetic Resonance Imaging  Male  Mice  Mice, Inbred C57BL  Mutation  Neurons/metabolism  Serotonin/metabolism  Serotonin Plasma Membrane Transport Proteins/genetics/metabolism  5-ht  5htt  Brain  Dorsal raphe  Magnetic resonance imaging  Neurodevelopment  Serotonin  Slc6a4 Index. décimale : PER Périodiques Résumé : Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4, has been extensively studied. Methods: Using a 7-T MRI and deformation-based morphometry, we assessed neuroanatomical differences in an Slc6a4 knockout mouse on a C57BL/6 genetic background, along with an Slc6a4 Ala56 knockin mouse on two different genetic backgrounds (129S and C57BL/6). Results: Individually (same sex, same background, same genotype), the only differences found were in the female Slc6a4 knockout mouse; all the others had no significant differences. However, an analysis of variance across the whole study sample revealed a significant effect of Slc6a4 on the amygdala, thalamus, dorsal raphe nucleus, and lateral and frontal cortices. Conclusions: This work shows that an increase or decrease in SERT function has a significant effect on the neuroanatomy in 5-HT relevant regions, particularly the raphe nuclei. Notably, the Slc6a4 Ala56 knockin alone appears to have an insignificant, but suggestive, effect compared to the KO, which is consistent with Slc6a4 function. Despite the small number of 5-HT neurons and their localization to the brainstem, it is clear that 5-HT plays an important role in neuroanatomical organization. En ligne : https://dx.doi.org/10.1186/s13229-018-0210-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder / K. G. MARGOLIS in Journal of Autism and Developmental Disorders, 49-1 (January 2019)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 49-1 (January 2019) . - p.349-362 Titre : Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder Type de document : Texte imprimé et/ou numérique Auteurs : K. G. MARGOLIS, Auteur ; Timothy M. BUIE, Auteur ; J. Blake TURNER, Auteur ; A. E. SILBERMAN, Auteur ; J. F. FELDMAN, Auteur ; K. F. MURRAY, Auteur ; M. MCSWIGGAN-HARDIN, Auteur ; J. LEVY, Auteur ; M. L. BAUMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; A. H. WHITAKER, Auteur ; Harland S. WINTER, Auteur Article en page(s) : p.349-362 Langues : Anglais (eng) Mots-clés : Autism  Behavior  Comorbidities  Gi  Gastrointestinal  Screen Index. décimale : PER Périodiques Résumé : Gastrointestinal dysfunction in children with autism spectrum disorder (ASD) is common and associated with problem behaviors. This study describes the development of a brief, parent-report screen that relies minimally upon the child's ability to report or localize pain for identifying children with ASD at risk for one of three common gastrointestinal disorders (functional constipation, functional diarrhea, and gastroesophageal reflux disease). In a clinical sample of children with ASD, this 17-item screen identified children having one or more of these disorders with a sensitivity of 84%, specificity of 43%, and a positive predictive value of 67%. If found to be valid in an independent sample of children with ASD, the screen will be useful in both clinical practice and research. En ligne : http://dx.doi.org/10.1007/s10803-018-3767-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=377 [article] Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder [Texte imprimé et/ou numérique] / K. G. MARGOLIS, Auteur ; Timothy M. BUIE, Auteur ; J. Blake TURNER, Auteur ; A. E. SILBERMAN, Auteur ; J. F. FELDMAN, Auteur ; K. F. MURRAY, Auteur ; M. MCSWIGGAN-HARDIN, Auteur ; J. LEVY, Auteur ; M. L. BAUMAN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; A. H. WHITAKER, Auteur ; Harland S. WINTER, Auteur . - p.349-362. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 49-1 (January 2019) . - p.349-362 Mots-clés : Autism  Behavior  Comorbidities  Gi  Gastrointestinal  Screen Index. décimale : PER Périodiques Résumé : Gastrointestinal dysfunction in children with autism spectrum disorder (ASD) is common and associated with problem behaviors. This study describes the development of a brief, parent-report screen that relies minimally upon the child's ability to report or localize pain for identifying children with ASD at risk for one of three common gastrointestinal disorders (functional constipation, functional diarrhea, and gastroesophageal reflux disease). In a clinical sample of children with ASD, this 17-item screen identified children having one or more of these disorders with a sensitivity of 84%, specificity of 43%, and a positive predictive value of 67%. If found to be valid in an independent sample of children with ASD, the screen will be useful in both clinical practice and research. En ligne : http://dx.doi.org/10.1007/s10803-018-3767-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=377

Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome / T. D. ROGERS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 30p. Titre : Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur Article en page(s) : 30p. Langues : Anglais (eng) Mots-clés : Amygdala  Autism spectrum disorder  Fragile X syndrome  Prefrontal cortex  RNA sequencing  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome [Texte imprimé et/ou numérique] / T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur . - 30p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 30p. Mots-clés : Amygdala  Autism spectrum disorder  Fragile X syndrome  Prefrontal cortex  RNA sequencing  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice / A. M. J. ANACKER in Autism Research, 12-5 (May 2019)  

Public ISBD [article]  inAutism Research > 12-5 (May 2019) . - p.732-743 Titre : Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice Type de document : Texte imprimé et/ou numérique Auteurs : A. M. J. ANACKER, Auteur ; J. T. MORAN, Auteur ; S. SANTARELLI, Auteur ; C. G. FORSBERG, Auteur ; T. D. ROGERS, Auteur ; G. D. STANWOOD, Auteur ; B. J. HALL, Auteur ; E. DELPIRE, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; M. D. SAXE, Auteur Article en page(s) : p.732-743 Langues : Anglais (eng) Mots-clés : Gaba  autism  dominance  excitatory  inhibitory  social Index. décimale : PER Périodiques Résumé : The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2(+/-) mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2(+/-) mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2(+/-) mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes. Autism Research 2019, 12: 732-743. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors. En ligne : http://dx.doi.org/10.1002/aur.2098 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=397 [article] Enhanced Social Dominance and Altered Neuronal Excitability in the Prefrontal Cortex of Male KCC2b Mutant Mice [Texte imprimé et/ou numérique] / A. M. J. ANACKER, Auteur ; J. T. MORAN, Auteur ; S. SANTARELLI, Auteur ; C. G. FORSBERG, Auteur ; T. D. ROGERS, Auteur ; G. D. STANWOOD, Auteur ; B. J. HALL, Auteur ; E. DELPIRE, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; M. D. SAXE, Auteur . - p.732-743. Langues : Anglais (eng) in Autism Research > 12-5 (May 2019) . - p.732-743 Mots-clés : Gaba  autism  dominance  excitatory  inhibitory  social Index. décimale : PER Périodiques Résumé : The K-Cl cotransporter KCC2 is essential in the development of the "GABA switch" that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild-type littermates, KCC2(+/-) mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety-like behaviors. However, KCC2(+/-) mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild-type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2(+/-) mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism-like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism-related behavioral phenotypes. Autism Research 2019, 12: 732-743. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism-related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism-like behaviors. En ligne : http://dx.doi.org/10.1002/aur.2098 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=397

Inpatient Psychiatric Treatment of Serious Behavioral Problems in Children with Autism Spectrum Disorder (ASD): Specialized Versus General Inpatient Units / B. J. TAYLOR in Journal of Autism and Developmental Disorders, 49-3 (March 2019)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 49-3 (March 2019) . - p.1242-1249 Titre : Inpatient Psychiatric Treatment of Serious Behavioral Problems in Children with Autism Spectrum Disorder (ASD): Specialized Versus General Inpatient Units Type de document : Texte imprimé et/ou numérique Auteurs : B. J. TAYLOR, Auteur ; K. B. SANDERS, Auteur ; M. KYLE, Auteur ; K. A. PEDERSEN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; M. SIEGEL, Auteur Article en page(s) : p.1242-1249 Langues : Anglais (eng) Mots-clés : Autism  Inpatient  Psychiatric hospitalization  Specialized unit Index. décimale : PER Périodiques Résumé : Psychiatric hospitalization of children with autism spectrum disorder (ASD) is common, but there is little comparative information available on different psychiatric hospital treatment models. Children with ASD ages 4-20 were enrolled upon admission to either a specialized (N = 53) or a general child psychiatric unit (N = 27). Caregivers completed the Aberrant Behavioral Checklist-Irritability Sub-scale (ABC-I) at admission, discharge, and 2 months post-discharge and reported information on crisis service utilization 2 months post-discharge. Children treated in the specialized unit had lower ABC-I scores at discharge and 2 months post-discharge (F = 8.98, p = 0.003) and were significantly less likely to experience an ER visit within 2 months post-discharge (X(2) = 5.51, p = 0.019). Specialized inpatient units may be more effective for children with ASD in need of psychiatric hospitalization. En ligne : http://dx.doi.org/10.1007/s10803-018-3816-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386 [article] Inpatient Psychiatric Treatment of Serious Behavioral Problems in Children with Autism Spectrum Disorder (ASD): Specialized Versus General Inpatient Units [Texte imprimé et/ou numérique] / B. J. TAYLOR, Auteur ; K. B. SANDERS, Auteur ; M. KYLE, Auteur ; K. A. PEDERSEN, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur ; M. SIEGEL, Auteur . - p.1242-1249. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 49-3 (March 2019) . - p.1242-1249 Mots-clés : Autism  Inpatient  Psychiatric hospitalization  Specialized unit Index. décimale : PER Périodiques Résumé : Psychiatric hospitalization of children with autism spectrum disorder (ASD) is common, but there is little comparative information available on different psychiatric hospital treatment models. Children with ASD ages 4-20 were enrolled upon admission to either a specialized (N = 53) or a general child psychiatric unit (N = 27). Caregivers completed the Aberrant Behavioral Checklist-Irritability Sub-scale (ABC-I) at admission, discharge, and 2 months post-discharge and reported information on crisis service utilization 2 months post-discharge. Children treated in the specialized unit had lower ABC-I scores at discharge and 2 months post-discharge (F = 8.98, p = 0.003) and were significantly less likely to experience an ER visit within 2 months post-discharge (X(2) = 5.51, p = 0.019). Specialized inpatient units may be more effective for children with ASD in need of psychiatric hospitalization. En ligne : http://dx.doi.org/10.1007/s10803-018-3816-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386

Modeling rare gene variation to gain insight into the oldest biomarker in autism: construction of the serotonin transporter Gly56Ala knock-in mouse / J. VEENSTRA-VANDERWEELE in Journal of Neurodevelopmental Disorders, 1-2 (June 2009)  

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Translation in fragile X: no home runs in the first at-bat / J. VEENSTRA-VANDERWEELE in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

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Whole Blood Serotonin Levels and Platelet 5-HT2A Binding in Autism Spectrum Disorder / E. AARON in Journal of Autism and Developmental Disorders, 49-6 (June 2019)  

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