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1.
Nat Commun ; 11(1): 5140, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046712

RESUMO

Autism spectrum disorder (ASD) is thought to result from deviation from normal development of neural circuits and synaptic function. Many genes with mutation in ASD patients have been identified. Here we report that two molecules associated with ASD susceptibility, contactin associated protein-like 2 (CNTNAP2) and Abelson helper integration site-1 (AHI1), are required for synaptic function and ASD-related behavior in mice. Knockdown of CNTNAP2 or AHI1 in layer 2/3 pyramidal neurons of the developing mouse prefrontal cortex (PFC) reduced excitatory synaptic transmission, impaired social interaction and induced mild vocalization abnormality. Although the causes of reduced excitatory transmission were different, pharmacological enhancement of AMPA receptor function effectively restored impaired social behavior in both CNTNAP2- and AHI1-knockdown mice. We conclude that reduced excitatory synaptic transmission in layer 2/3 pyramidal neurons of the PFC leads to impaired social interaction and mild vocalization abnormality in mice.


Assuntos
Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/psicologia , Córtex Pré-Frontal/metabolismo , Células Piramidais/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Modelos Animais de Doenças , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Transmissão Sináptica
2.
Nat Commun ; 11(1): 5272, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077750

RESUMO

16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Encéfalo/fisiopatologia , Esquizofrenia/genética , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Cognição , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Duplicação Gênica , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Adulto Jovem
3.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32900877

RESUMO

BACKGROUND: Children born preterm are at high risk for autism spectrum disorder (ASD). However, there is still a lack of appropriate developmental markers. In this study, we aim to examine whether early mental performance trajectory is related to ASD outcome in the preterm population. METHODS: The population-based cohort included 414 very preterm survivors born between 2008 and 2014. After excluding children with severe neurosensory impairment, 319 children with available records of developmental quotients before age 2 years were enrolled. The trajectory of mental performance evaluated by using the Bayley Scales of Infant Development across 6, 12, and 24 months of age was analyzed with group-based trajectory modeling. At 5 years of age, the ASD diagnosis was established by using the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. RESULTS: There were 29 children with ASD and 290 children without ASD. The mental performances from age 6 to 24 months could be classified into 3 trajectory patterns: low declining, high declining, and high stable, which corresponded to ASD prevalence at age 5 years of 35%, 9%, and 3%, respectively. ASD odds was 15 times higher in the low-declining group than in the high-stable group (odds ratio 15; 95% confidence interval 3.8-59; P < .001). Through the analysis of multinomial logistic regression, we found that male infants with longer exposure to oxygen therapy whose mothers had lower maternal education levels tended to follow the low-declining trajectory. CONCLUSIONS: The early-life mental trajectory patterns, by using the Bayley Scales of Infant Development, may lead to identification of vulnerable children born preterm for early ASD diagnosis and targeted intervention.


Assuntos
Transtorno do Espectro Autista , Desenvolvimento Infantil , Lactente Extremamente Prematuro , Fatores Etários , Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Intervalos de Confiança , Diagnóstico Precoce , Escolaridade , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Razão de Chances , Oxigênio/uso terapêutico , Prevalência , Fatores Sexuais
4.
Nat Protoc ; 15(10): 3464-3477, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895524

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and other behavioral abnormalities. The three-chamber social preference test is often used to assess social deficits in mouse models of ASD. However, varying and often contradicting phenotypic descriptions of ASD mouse models can be found in the scientific literature, and the substantial variability in the methods used by researchers to assess social deficits in mice could be a contributing factor. Here we describe a standardized three-chamber social preference protocol, which is sensitive and reliable at detecting social preference deficits in several mouse models of ASD. This protocol comprises three phases that can all be completed within 1 d. The test mouse is first habituated to the apparatus containing two empty cups in the side chambers, followed by the pre-test phase in which the mouse can interact with two identical inanimate objects placed in the cups. During the test phase, the mouse is allowed to interact with a social stimulus (an unfamiliar wild-type (WT) mouse) contained in one cup and a novel non-social stimulus contained in the other cup. The protocol is thus designed to assess preference between social and non-social stimuli under conditions of equal salience. The broad implementation of the three-chamber social preference protocol presented here should improve the accuracy and consistency of assessments for social preference deficits associated with ASD and other psychiatric disorders.


Assuntos
Análise do Comportamento Aplicada/métodos , Transtorno Autístico/psicologia , Modelos Animais de Doenças , Animais , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/fisiopatologia , Comportamento Animal/fisiologia , Camundongos , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Comportamento Social , Transtornos do Comportamento Social/fisiopatologia
5.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(4): 508-513, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32985165

RESUMO

More and more evidences support that the abnormality of GABAergic interneurons is associated with autism spectrum disorders (ASD), epilepsy, schizophrenia and other neurodevelopmental disorders. In recent years, numerous drugs have been developed to regulate ion channels and receptors in GABAergic interneurons, including sodium channels and N-methyl-D-aspartate (NMDA) receptors. The activators of Na+ channel can enhance the action potential of GABAergic interneurons by reducing the inactivation of Na+ channel. NMDA receptor, as a potential therapeutic target of ASD, can restore the NMDA function of GABAergic interneurons, which would be used to treat behavioral defects. In addition, there are many ion channels and receptors on GABAergic interneurons related to ASD. This article reviews GABAergic interneurons in the pathogenesis of ASD and the related interventions.


Assuntos
Transtorno do Espectro Autista , Neurônios GABAérgicos , Interneurônios , Neurologia , Potenciais de Ação , Transtorno do Espectro Autista/fisiopatologia , Neurônios GABAérgicos/patologia , Humanos , Interneurônios/patologia , Neurologia/tendências , Receptores de N-Metil-D-Aspartato/metabolismo
6.
Nat Neurosci ; 23(9): 1090-1101, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661394

RESUMO

While the neuronal underpinnings of autism spectrum disorder (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. We discover that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction results in impaired cerebral angiogenesis at postnatal day 14, and in altered neurovascular coupling and cerebrovascular reactivity at postnatal day 50. Moreover, we show that there is defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in induced-pluripotent-stem-cell-derived endothelial cells from human carriers of the 16p11.2 deletion. Finally, we find that mice with an endothelium-specific 16p11.2 deletion (16p11.2ΔEC) partially recapitulate some of the behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Células Endoteliais/patologia , Acoplamento Neurovascular/fisiologia , Animais , Transtorno Autístico , Circulação Cerebrovascular/fisiologia , Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 16 , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Deficiência Intelectual , Masculino , Camundongos , Neovascularização Fisiológica/genética
7.
Nat Neurosci ; 23(9): 1102-1110, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661395

RESUMO

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Cerebelo/fisiopatologia , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Masculino , Camundongos , Camundongos Mutantes
8.
PLoS One ; 15(7): e0235552, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645114

RESUMO

The aim of the study is to compare the spatial working memory and visual perception between children with autism spectrum disorder (ASD) and typically developing control (TDC). Furthermore, this study validated whether this impairment was a feature of autism in general population with different autism-like traits (ALTs). This study contains two parts: case-control study and community population study. The ASD group and the control group were enlisted voluntarily (ASD group, n = 52; control group, n = 32). In the population study, we recruited 2994 children. Based on the scores of Autism Spectrum Quotient (AQ), children were divided into two groups (higher ALTs n = 122, lower ALTs n = 122). The participants completed the cognition tasks focusing on spatial working memory, visual-motor integration, and Intelligence. Analysis of covariance (ANCOVA) was conducted, with potential confounders IQ, age, and gender were controlled. Pearson correlations were computed by controlling the IQ and age as covariate to better understand the relations between visual perception, spatial working memory, and autism-like traits. In the case-control study, the results of cognition tasks focusing on the spatial working memory and visual perception indicated underperformance in children with ASD. In the community population study, we found that individuals with higher ALTs performed worse than children with lower ALTs in spatial working memory. Pearson correlation analysis suggested that a correlation between SWM total errors and visual perception was identified both in the children with ASD and in community population (ASD group, r = -0.592, p<0.001; general population, r = -0.201, p = 0.003). It suggested that spatial working memory deficit was a characteristic of autism, and may be distributed across the general population. Furthermore, we speculated a correlation between spatial working memory and visual perception in children with ASD and in general population.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Memória de Curto Prazo , Memória Espacial , Percepção Visual , Adolescente , Transtorno do Espectro Autista/psicologia , Criança , Feminino , Humanos , Inteligência , Masculino , Desempenho Psicomotor
10.
PLoS One ; 15(6): e0224186, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497045

RESUMO

Recent discussions in the literature, along with the revision of the Diagnostic and Statistical Manual (DSM) (American Psychiatric Association 2013), suggest aetiological commonalities between the highly comorbid Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). Addressing this discussion requires studying these disorders together by comparing constructs typical to each of them. In the present study, we investigate global processing, known to be difficult for participants with ASD, and Intra-Subject Variability (ISV), known to be consistently increased in participants with ADHD, in groups, aged 10-13 years, with ADHD (n = 25), ASD without comorbid ADHD (ASD-) (n = 13) and ASD with ADHD (ASD+) (n = 18) in comparison with a typically developing group (n = 22). A Copying task, typically requiring global processing and in this case particularly designed using equally complex stimuli to also measure ISV across trials, was selected. Oculomotor measures in this task proved to be particularly sensitive to group differences. While increased ISV was not observed in the present task in participants with ADHD, both ASD groups looked longer on the figure to be drawn, indicating that global processing takes longer in ASD. However, the ASD+ group fixated on the figure only between drawing movements, whereas the ASD- group did this throughout the drawing process. The present study provides evidence towards ASD and ADHD being separate, not-overlapping, disorders. Since the pure ASD- group was affected more by central coherence problems than the ASD+ group, it may suggest that neuropsychological constructs interact differently in different clinical groups and sub-groups.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Movimento , Desempenho Psicomotor , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Espectro Autista/diagnóstico , Criança , Feminino , Humanos , Masculino
11.
Stud Health Technol Inform ; 270: 287-291, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32570392

RESUMO

Eye tracking studies have demonstrated deficits in attention in individuals with Autism Spectrum Disorder (ASD) for a range of different social attention-based tasks. Here we examined social attention skills in a large sample of ASD participants (n = 120), using eye tracking data from a social information processing task, and compared them with a typically developing (TD) group (n = 35). Assuming eye movement parameters are random variables generated by an underlying stochastic process, we modeled the fixation sequences of participants in ASD and TD groups with a Hidden Markov Model. The Regions of Interests (ROIs), modeled as hidden states, corresponded to the true ROIs with a prediction accuracy of >90% for each group. The transition between ROIs revealed bias towards a specific area in the scene in ASD group, which deviated from the TD group. Objective time-dynamic measures of gaze patterns can potentially serve as useful endpoints in ASD diagnosis. Clinical Trial Registration: NCT02299700.


Assuntos
Atenção/fisiologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Movimentos Oculares/fisiologia , Fixação Ocular/fisiologia , Aprendizagem/fisiologia , Estudos de Casos e Controles , Humanos , Cadeias de Markov , Comportamento Social , Habilidades Sociais , Processos Estocásticos
12.
Am J Psychiatry ; 177(9): 834-843, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32539527

RESUMO

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data. METHODS: Structural T1-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures). RESULTS: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood. CONCLUSIONS: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Cérebro , Neuroimagem/métodos , Transtorno Obsessivo-Compulsivo , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Cérebro/diagnóstico por imagem , Cérebro/patologia , Cérebro/fisiopatologia , Criança , Feminino , Desenvolvimento Humano/fisiologia , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/psicologia , Tamanho do Órgão , Psicopatologia , Relatório de Pesquisa , Análise de Sistemas
14.
Proc Natl Acad Sci U S A ; 117(20): 11158-11166, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32358192

RESUMO

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disturbance afflicting a variety of functions. The recent computational focus suggesting aberrant Bayesian inference in ASD has yielded promising but conflicting results in attempting to explain a wide variety of phenotypes by canonical computations. Here, we used a naturalistic visual path integration task that combines continuous action with active sensing and allows tracking of subjects' dynamic belief states. Both groups showed a previously documented bias pattern by overshooting the radial distance and angular eccentricity of targets. For both control and ASD groups, these errors were driven by misestimated velocity signals due to a nonuniform speed prior rather than imperfect integration. We tracked participants' beliefs and found no difference in the speed prior, but there was heightened variability in the ASD group. Both end point variance and trajectory irregularities correlated with ASD symptom severity. With feedback, variance was reduced, and ASD performance approached that of controls. These findings highlight the need for both more naturalistic tasks and a broader computational perspective to understand the ASD phenotype and pathology.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Adolescente , Teorema de Bayes , Criança , Humanos , Modelos Neurológicos , Percepção de Movimento/fisiologia , Estimulação Luminosa
15.
Sci Rep ; 10(1): 7834, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398858

RESUMO

Inhibitory interneurons are essential for proper brain development and function. Dysfunction of interneurons is implicated in several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID). We have previously shown that Arid1b haploinsufficiency interferes with interneuron development and leads to social, cognitive, and emotional impairments consistent with ASD and ID. It is unclear, however, whether interneurons play a major role for the behavioral deficits in Arid1b haploinsufficiency. Furthermore, it is critical to determine which interneuron subtypes contribute to distinct behavioral phenotypes. In the present study, we generated Arid1b haploinsufficient mice in which a copy of the Arid1b gene is deleted in either parvalbumin (PV) or somatostatin (SST) interneurons, and examined their ASD- and ID-like behaviors. We found that Arid1b haploinsufficiency in PV or SST interneurons resulted in distinct features that do not overlap with one another. Arid1b haploinsufficiency in PV neurons contributed to social and emotional impairments, while the gene deletion in the SST population caused stereotypies as well as learning and memory dysfunction. These findings demonstrate a critical role of interneurons in Arid1b haploinsufficient pathology and suggest that PV and SST interneurons may have distinct roles in modulating neurological phenotypes in Arid1b haploinsufficiency-induced ASD and ID.


Assuntos
Transtorno do Espectro Autista/genética , Haploinsuficiência , Deficiência Intelectual/genética , Interneurônios/metabolismo , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Fatores de Transcrição/genética , Animais , Ansiedade/complicações , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Depressão/complicações , Regulação da Expressão Gênica , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Interneurônios/patologia , Memória , Fenótipo , Comportamento Social , Aprendizagem Espacial
16.
Dev Cogn Neurosci ; 42: 100754, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32452464

RESUMO

Heterogeneity in cognitive and academic abilities is a prominent feature of autism spectrum disorder (ASD), yet little is known about its underlying causes. Here we combine functional brain imaging during numerical problem-solving with hierarchical drift-diffusion models of behavior and standardized measures of numerical abilities to investigate neural mechanisms underlying cognitive variability in children with ASD, and their IQ-matched Typically Developing (TD) peers. Although the two groups showed similar levels of brain activation, the relation to individual abilities differed markedly in ventral temporal-occipital, parietal and prefrontal regions important for numerical cognition: children with ASD showed a positive correlation between functional brain activation and numerical abilities, whereas TD children showed the opposite pattern. Despite similar accuracy and response times, decision thresholds were significantly higher in the ASD group, suggesting greater evidence required for problem-solving. Critically, the relationship between individual abilities and engagement of prefrontal control systems anchored in the anterior insula was differentially moderated by decision threshold in subgroups of children with ASD. Our findings uncover novel cognitive and neural sources of variability in academically-relevant cognitive skills in ASD and suggest that multilevel measures and latent decision-making dynamics can aid in characterization of cognitive variability and heterogeneity in neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Mapeamento Encefálico/métodos , Encéfalo/fisiopatologia , Cognição/fisiologia , Tomada de Decisões/fisiologia , Criança , Feminino , Humanos , Masculino
17.
J Neurosci ; 40(19): 3815-3826, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253362

RESUMO

Autism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, reflected in exaggerated and variable responses to sensory stimuli. Attentional engagement is known to be regulated by the locus ceruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether, under different attentional task demands, individuals with ASD exhibit a different profile of LC activity compared with typically developing controls. Males and females with ASD and age- and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses, an established correlate for LC activity, were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared with controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed specifically in response to task-relevant events, providing confirmation that the group differences most likely were specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.SIGNIFICANCE STATEMENT Individuals with autism spectrum disorder (ASD) exhibit atypical attentional behaviors, including altered sensory responses and atypical fixedness, but the neural mechanism underlying these behaviors remains elusive. One candidate mechanism is atypical locus ceruleus (LC) activity, as the LC plays a critical role in attentional modulation. Specifically, LC activity is involved in regulating the trade-off between environmental exploration and focused attention. This study shows that, under tightly controlled conditions, task-evoked pupil responses, an LC activity proxy, are lower in individuals with ASD than in controls, but only in the presence of task-irrelevant stimuli. This suggests that individuals with ASD evince atypical modulation of LC activity in accordance with changes in attentional demands, offering a mechanistic account for attentional atypicalities in ASD.


Assuntos
Atenção/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Locus Cerúleo/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Reflexo Pupilar/fisiologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-32260520

RESUMO

Depression and anxiety are associated with unemployment and disability pension, while autism spectrum disorder (ASD) is less studied. We aimed to first identify unemployment trajectories among young adults with and without ASD, and then to examine their social determinants. Finally, we used the trajectories as determinants for subsequent disability pension. We used a population-based cohort, including 814 people who were 19-35 years old, not on disability pension, and who had their ASD diagnosis between 2001 and 2009. A matched reference population included 22,013 people with no record of mental disorders. Unemployment follow-up was the inclusion year and four years after. Disability pension follow-up started after the unemployment follow-up and continued through 2013. We identified three distinctive trajectories of unemployment during the follow-up: (1) low, then sharply increasing (9%,) (2) low (reference, 67%), and (3) high then slowly decreasing (24%). People with ASD had higher odds of belonging belong to the trajectory groups 1 (OR 2.53, 95% CI 2.02-3.18) and 3 (OR 3.60, 95% CI 3.08-4.19). However, the mean number of unemployment days was relatively low in all groups. A disability pension was a rare event in the cohort, although memberships to groups 1 and 3 were associated with the risk of a future disability pension. More knowledge is needed about factors facilitating participation in paid employment among people with ASD.


Assuntos
Transtorno do Espectro Autista , Pessoas com Deficiência , Determinantes Sociais da Saúde , Desemprego , Adolescente , Adulto , Transtorno do Espectro Autista/fisiopatologia , Feminino , Humanos , Masculino , Pensões , Fatores de Risco , Suécia , Adulto Jovem
19.
J Neurosci ; 40(19): 3799-3814, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32269107

RESUMO

MECP2 gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene-circuit-behavior analyses including MECP2 coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5 MECP2 overexpressed monkeys (Macaca fascicularis; 3 females) and 20 wild-type monkeys (Macaca fascicularis; 11 females). Whole-genome expression analysis revealed MECP2 coexpressed genes significantly enriched in GABA-related signaling pathways, whereby reduced ß-synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile, MECP2-induced hyperconnectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 patients with autism and 72 healthy controls of 1112 subjects using functional connectivity patterns, and identified dysconnectivity profiles similar to those in monkeys. By establishing a circuit-based construct link between genetically defined models and stratified patients, these results pave new avenues to deconstruct clinical heterogeneity and advance accurate diagnosis in psychiatric disorders.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a complex disorder with co-occurring symptoms caused by multiple genetic variations and brain circuit abnormalities. To dissect the gene-circuit-behavior causal chain underlying ASD, animal models are established by manipulating causative genes such as MECP2 However, it is unknown whether such models have captured any circuit-level pathology in ASD patients, as demonstrated by human brain imaging studies. Here, we use transgenic macaques to examine the causal effect of MECP2 overexpression on gene coexpression, brain circuits, and behaviors. For the first time, we demonstrate that the circuit abnormalities linked to MECP2 and autism-like traits in the monkeys can be mapped to a homogeneous ASD subgroup, thereby offering a new strategy to deconstruct clinical heterogeneity in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Encéfalo/fisiologia , Locomoção/genética , Proteína 2 de Ligação a Metil-CpG/genética , Vias Neurais/fisiopatologia , Animais , Animais Geneticamente Modificados , Mapeamento Encefálico/métodos , Modelos Animais de Doenças , Eletroencefalografia , Feminino , Neurônios GABAérgicos/fisiologia , Duplicação Gênica , Humanos , Macaca fascicularis , Imagem por Ressonância Magnética , Masculino
20.
Psychol Bull ; 146(5): 377-410, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32191044

RESUMO

To address inconsistencies in the literature on memory in autism spectrum disorder (ASD), we report the first ever meta-analysis of short-term memory (STM) and episodic long-term memory (LTM) in ASD, evaluating the effects of type of material, type of retrieval and the role of interitem relations. Analysis of 64 studies comparing individuals with ASD and typical development (TD) showed greater difficulties in ASD compared with TD individuals in STM (Hedges' g = -0.53, 95% CI [-0.90, -0.16], p = .005, I² = 96%) compared with LTM (g = -0.30, 95% CI [-0.42, -0.17], p < .00001, I² = 24%), a small difficulty in verbal LTM (g = -0.21, p = .01), contrasting with a medium difficulty for visual LTM (g = -0.41, p = .0002) in ASD compared with TD individuals. We also found a general diminution in free recall compared with cued recall and recognition (LTM, free recall: g = -0.38, p < .00001, cued recall: g = -0.08, p = .58, recognition: g = -0.15, p = .16; STM, free recall: g = -0.59, p = .004, recognition: g = -0.33, p = .07). We discuss these results in terms of their relation to semantic memory. The limited diminution in verbal LTM and preserved overall recognition and cued recall (supported retrieval) may result from a greater overlap of these tasks with semantic long-term representations which are overall preserved in ASD. By contrast, difficulties in STM or free recall may result from less overlap with the semantic system or may involve additional cognitive operations and executive demands. These findings highlight the need to support STM functioning in ASD and acknowledge the potential benefit of using verbal materials at encoding and broader forms of memory support at retrieval to enhance performance. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Rememoração Mental/fisiologia , Reconhecimento Psicológico/fisiologia , Transtorno do Espectro Autista/complicações , Disfunção Cognitiva/etiologia , Humanos
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