Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms / Eric COURCHESNE in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 22p. Titre : Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms Type de document : texte imprimé Auteurs : Eric COURCHESNE, Auteur ; Vani TALUJA, Auteur ; Sanaz NAZARI, Auteur ; Caitlin M. AAMODT, Auteur ; Karen PIERCE, Auteur ; Kuaikuai DUAN, Auteur ; Sunny STOPHAEROS, Auteur ; Linda LOPEZ, Auteur ; Cynthia CARTER BARNES, Auteur ; Jaden TROXEL, Auteur ; Kathleen CAMPBELL, Auteur ; Tianyun WANG, Auteur ; Kendra HOEKZEMA, Auteur ; Evan E. EICHLER, Auteur ; Joao V. NANI, Auteur ; Wirla PONTES, Auteur ; Sandra S. SANCHEZ, Auteur ; Michael V. LOMBARDO, Auteur ; Janaina S. DE SOUZA, Auteur ; Mirian A.F. HAYASHI, Auteur ; Alysson R. MUOTRI, Auteur Article en page(s) : 22p. Langues : Anglais (eng) Mots-clés : Humans  Autism Spectrum Disorder/pathology/physiopathology  Organoids/pathology  Male  Female  Child, Preschool  Cerebral Cortex/pathology  Social Behavior  Organ Size  Infant  Severity of Illness Index  Brain/pathology Index. décimale : PER Périodiques Résumé : BACKGROUND: Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with "profound" autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known. METHODS: Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we  tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions. RESULTS: At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences. LIMITATIONS: Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes. CONCLUSIONS: By embryogenesis, the biological bases of two subtypes of ASD social and brain development-profound autism and mild autism-are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler's social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions. En ligne : https://dx.doi.org/10.1186/s13229-024-00602-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms [texte imprimé] / Eric COURCHESNE, Auteur ; Vani TALUJA, Auteur ; Sanaz NAZARI, Auteur ; Caitlin M. AAMODT, Auteur ; Karen PIERCE, Auteur ; Kuaikuai DUAN, Auteur ; Sunny STOPHAEROS, Auteur ; Linda LOPEZ, Auteur ; Cynthia CARTER BARNES, Auteur ; Jaden TROXEL, Auteur ; Kathleen CAMPBELL, Auteur ; Tianyun WANG, Auteur ; Kendra HOEKZEMA, Auteur ; Evan E. EICHLER, Auteur ; Joao V. NANI, Auteur ; Wirla PONTES, Auteur ; Sandra S. SANCHEZ, Auteur ; Michael V. LOMBARDO, Auteur ; Janaina S. DE SOUZA, Auteur ; Mirian A.F. HAYASHI, Auteur ; Alysson R. MUOTRI, Auteur . - 22p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 22p. Mots-clés : Humans  Autism Spectrum Disorder/pathology/physiopathology  Organoids/pathology  Male  Female  Child, Preschool  Cerebral Cortex/pathology  Social Behavior  Organ Size  Infant  Severity of Illness Index  Brain/pathology Index. décimale : PER Périodiques Résumé : BACKGROUND: Social affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with "profound" autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known. METHODS: Because ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we  tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions. RESULTS: At the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences. LIMITATIONS: Larger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes. CONCLUSIONS: By embryogenesis, the biological bases of two subtypes of ASD social and brain development-profound autism and mild autism-are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler's social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions. En ligne : https://dx.doi.org/10.1186/s13229-024-00602-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Impaired downregulation of visual cortex during auditory processing is associated with autism symptomatology in children and adolescents with autism spectrum disorder / R. Joanne JAO KEEHN in Autism Research, 10-1 (January 2017)  

Public ISBD [article]  inAutism Research > 10-1 (January 2017) . - p.130-143 Titre : Impaired downregulation of visual cortex during auditory processing is associated with autism symptomatology in children and adolescents with autism spectrum disorder Type de document : texte imprimé Auteurs : R. Joanne JAO KEEHN, Auteur ; Sandra S. SANCHEZ, Auteur ; Claire R. STEWART, Auteur ; Weiqi ZHAO, Auteur ; Emily L. GRENESKO-STEVENS, Auteur ; Brandon KEEHN, Auteur ; Ralph-Axel MULLER, Auteur Article en page(s) : p.130-143 Langues : Anglais (eng) Mots-clés : autism spectrum disorders  development  visual  auditory  functional magnetic resonance imaging Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are pervasive developmental disorders characterized by impairments in language development and social interaction, along with restricted and stereotyped behaviors. These behaviors often include atypical responses to sensory stimuli; some children with ASD are easily overwhelmed by sensory stimuli, while others may seem unaware of their environment. Vision and audition are two sensory modalities important for social interactions and language, and are differentially affected in ASD. In the present study, 16 children and adolescents with ASD and 16 typically developing (TD) participants matched for age, gender, nonverbal IQ, and handedness were tested using a mixed event-related/blocked functional magnetic resonance imaging paradigm to examine basic perceptual processes that may form the foundation for later-developing cognitive abilities. Auditory (high or low pitch) and visual conditions (dot located high or low in the display) were presented, and participants indicated whether the stimuli were “high” or “low.” Results for the auditory condition showed downregulated activity of the visual cortex in the TD group, but upregulation in the ASD group. This atypical activity in visual cortex was associated with autism symptomatology. These findings suggest atypical crossmodal (auditory-visual) modulation linked to sociocommunicative deficits in ASD, in agreement with the general hypothesis of low-level sensorimotor impairments affecting core symptomatology. En ligne : http://dx.doi.org/10.1002/aur.1636 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=303 [article] Impaired downregulation of visual cortex during auditory processing is associated with autism symptomatology in children and adolescents with autism spectrum disorder [texte imprimé] / R. Joanne JAO KEEHN, Auteur ; Sandra S. SANCHEZ, Auteur ; Claire R. STEWART, Auteur ; Weiqi ZHAO, Auteur ; Emily L. GRENESKO-STEVENS, Auteur ; Brandon KEEHN, Auteur ; Ralph-Axel MULLER, Auteur . - p.130-143. Langues : Anglais (eng) in Autism Research > 10-1 (January 2017) . - p.130-143 Mots-clés : autism spectrum disorders  development  visual  auditory  functional magnetic resonance imaging Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are pervasive developmental disorders characterized by impairments in language development and social interaction, along with restricted and stereotyped behaviors. These behaviors often include atypical responses to sensory stimuli; some children with ASD are easily overwhelmed by sensory stimuli, while others may seem unaware of their environment. Vision and audition are two sensory modalities important for social interactions and language, and are differentially affected in ASD. In the present study, 16 children and adolescents with ASD and 16 typically developing (TD) participants matched for age, gender, nonverbal IQ, and handedness were tested using a mixed event-related/blocked functional magnetic resonance imaging paradigm to examine basic perceptual processes that may form the foundation for later-developing cognitive abilities. Auditory (high or low pitch) and visual conditions (dot located high or low in the display) were presented, and participants indicated whether the stimuli were “high” or “low.” Results for the auditory condition showed downregulated activity of the visual cortex in the TD group, but upregulation in the ASD group. This atypical activity in visual cortex was associated with autism symptomatology. These findings suggest atypical crossmodal (auditory-visual) modulation linked to sociocommunicative deficits in ASD, in agreement with the general hypothesis of low-level sensorimotor impairments affecting core symptomatology. En ligne : http://dx.doi.org/10.1002/aur.1636 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=303

Sensory Symptoms and Processing of Nonverbal Auditory and Visual Stimuli in Children with Autism Spectrum Disorder / Claire R. STEWART in Journal of Autism and Developmental Disorders, 46-5 (May 2016)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 46-5 (May 2016) . - p.1590-1601 Titre : Sensory Symptoms and Processing of Nonverbal Auditory and Visual Stimuli in Children with Autism Spectrum Disorder Type de document : texte imprimé Auteurs : Claire R. STEWART, Auteur ; Sandra S. SANCHEZ, Auteur ; Emily L. GRENESKO, Auteur ; Christine M. BROWN, Auteur ; Colleen P. CHEN, Auteur ; Brandon KEEHN, Auteur ; Francisco VELASQUEZ, Auteur ; Alan J. LINCOLN, Auteur ; Ralph-Axel MULLER, Auteur Article en page(s) : p.1590-1601 Langues : Anglais (eng) Mots-clés : Autism  Visual  Auditory  Sensory integration  Bisensory facilitation  Sensory profile Index. décimale : PER Périodiques Résumé : Atypical sensory responses are common in autism spectrum disorder (ASD). While evidence suggests impaired auditory–visual integration for verbal information, findings for nonverbal stimuli are inconsistent. We tested for sensory symptoms in children with ASD (using the Adolescent/Adult Sensory Profile) and examined unisensory and bisensory processing with a nonverbal auditory–visual paradigm, for which neurotypical adults show bisensory facilitation. ASD participants reported more atypical sensory symptoms overall, most prominently in the auditory modality. On the experimental task, reduced response times for bisensory compared to unisensory trials were seen in both ASD and control groups, but neither group showed significant race model violation (evidence of intermodal integration). Findings do not support impaired bisensory processing for simple nonverbal stimuli in high-functioning children with ASD. En ligne : http://dx.doi.org/10.1007/s10803-015-2367-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=288 [article] Sensory Symptoms and Processing of Nonverbal Auditory and Visual Stimuli in Children with Autism Spectrum Disorder [texte imprimé] / Claire R. STEWART, Auteur ; Sandra S. SANCHEZ, Auteur ; Emily L. GRENESKO, Auteur ; Christine M. BROWN, Auteur ; Colleen P. CHEN, Auteur ; Brandon KEEHN, Auteur ; Francisco VELASQUEZ, Auteur ; Alan J. LINCOLN, Auteur ; Ralph-Axel MULLER, Auteur . - p.1590-1601. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 46-5 (May 2016) . - p.1590-1601 Mots-clés : Autism  Visual  Auditory  Sensory integration  Bisensory facilitation  Sensory profile Index. décimale : PER Périodiques Résumé : Atypical sensory responses are common in autism spectrum disorder (ASD). While evidence suggests impaired auditory–visual integration for verbal information, findings for nonverbal stimuli are inconsistent. We tested for sensory symptoms in children with ASD (using the Adolescent/Adult Sensory Profile) and examined unisensory and bisensory processing with a nonverbal auditory–visual paradigm, for which neurotypical adults show bisensory facilitation. ASD participants reported more atypical sensory symptoms overall, most prominently in the auditory modality. On the experimental task, reduced response times for bisensory compared to unisensory trials were seen in both ASD and control groups, but neither group showed significant race model violation (evidence of intermodal integration). Findings do not support impaired bisensory processing for simple nonverbal stimuli in high-functioning children with ASD. En ligne : http://dx.doi.org/10.1007/s10803-015-2367-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=288

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