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1.
Neurology ; 93(20): e1900-e1905, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31604793

RESUMO

OBJECTIVE: To examine changing features of cortical morphology in middle-aged adults with autism spectrum disorders (ASDs) vs typical comparison (TC) participants, hypothesizing regionally decreased local gyrification index (lGI), given our previous findings of accelerated lGI decline during adolescence. METHODS: After quality assurance, T1-weighted MRI sequences from 20 participants with ASD and 21 TC participants (40-61 years) matched on age were analyzed. lGI, cortical thickness (CT), and surface area (SA) were measured with FreeSurfer version 5.3. Statistical analyses used a general linear model including age, nonverbal IQ, and total brain volume as covariates. Clusters of significant group effects were used as regions of interest for behavioral analyses. RESULTS: Clusters of decreased lGI were observed bilaterally in the ASD group with large effect sizes in insular and anterior cingulate (ACC), left postcentral, and middle frontal and right orbitofrontal and supramarginal regions. lGI was also shown to decline with age across groups in bilateral precentral and right supramarginal clusters. No significant group, age, or group-by-age interaction effects were observed for CT or SA in this age group. lGI showed a significant correlation with Social Responsiveness Scale total scores in a right caudal ACC cluster in the TC group only, while several correlations were found in the ASD group between executive function scores and clusters in the bilateral insula and right orbitofrontal cortex. CONCLUSION: The pattern of regionally decreased lGI observed here in middle-aged adults with ASDs is consistent with an abnormal trajectory of cortical folding changes across different stages of life in ASDs, as shown in previous studies.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Adulto , Fatores Etários , Estudos de Casos e Controles , Córtex Cerebral/patologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/patologia , Humanos , Modelos Lineares , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tamanho do Órgão , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologia
2.
Nat Commun ; 10(1): 4188, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519897

RESUMO

An aim of autism spectrum disorder (ASD) research is to identify early biomarkers that inform ASD pathophysiology and expedite detection. Brain oscillations captured in electroencephalography (EEG) are thought to be disrupted as core ASD pathophysiology. We leverage longitudinal EEG power measurements from 3 to 36 months of age in infants at low- and high-risk for ASD to test how and when power distinguishes ASD risk and diagnosis by age 3-years. Power trajectories across the first year, second year, or first three years postnatally were submitted to data-driven modeling to differentiate ASD outcomes. Power dynamics during the first postnatal year best differentiate ASD diagnoses. Delta and gamma frequency power trajectories consistently distinguish infants with ASD diagnoses from others. There is also a developmental shift across timescales towards including higher-frequency power to differentiate outcomes. These findings reveal the importance of developmental timing and trajectory in understanding pathophysiology and classifying ASD outcomes.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Transtorno Autístico/fisiopatologia , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno Autístico/diagnóstico por imagem , Biomarcadores , Encéfalo/fisiologia , Criança , Pré-Escolar , Neurociência Cognitiva , Eletroencefalografia , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Adulto Jovem
3.
J Autism Dev Disord ; 49(12): 4751-4760, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31444629

RESUMO

Evidence on neurophysiological correlates of coexisting autism spectrum disorders (ASD) and overweight/obesity may elucidate mechanisms leading to the observed greater risk of obesity in children with ASD. An exploratory secondary data analysis was performed on resting state functional magnetic resonance imaging (rs-fMRI) data of children downloaded from the ABIDE Preprocessed database (n = 81). Children with isolated ASD showed hypo-connectivity between anterior and posterior default mode network (DMN) (p = 0.003; FWER). Children with coexisting ASD and overweight/obesity showed hyper-connectivity between anterior and posterior DMN (p = 0.015; FWER). More evidence is needed to confirm these contrasting rs-fMRI connectivity profiles and to explicate causal inferences regarding neurophysiological mechanisms associated with coexisting ASD and overweight/obesity.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Obesidade Pediátrica/diagnóstico por imagem , Adolescente , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Criança , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Rede Nervosa/fisiopatologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Sobrepeso/diagnóstico por imagem , Sobrepeso/epidemiologia , Sobrepeso/fisiopatologia , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/fisiopatologia
4.
Nat Commun ; 10(1): 3454, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371726

RESUMO

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/metabolismo , Animais , Transtorno do Espectro Autista/diagnóstico por imagem , Axônios , Comportamento Animal , Encéfalo/diagnóstico por imagem , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Estudos de Associação Genética , Haploinsuficiência , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Sistema Nervoso/metabolismo , Fenômenos Fisiológicos do Sistema Nervoso/genética , Fenótipo , Desempenho Psicomotor , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Filtro Sensorial , Substância Branca
5.
Brain Stimul ; 12(6): 1410-1420, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31324604

RESUMO

BACKGROUND: Social deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders. OBJECTIVE: We first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid-exposed ASD rat offspring model. METHODS: Brain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model. RESULTS: The DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits. CONCLUSIONS: Applying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/terapia , Estimulação Encefálica Profunda/métodos , Imagem por Ressonância Magnética/métodos , Núcleo Mediodorsal do Tálamo/diagnóstico por imagem , Núcleo Mediodorsal do Tálamo/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Mapeamento Encefálico/métodos , Relações Interpessoais , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo
7.
Dev Cogn Neurosci ; 38: 100668, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31174061

RESUMO

Recent work has suggested atypical neural reward responses in individuals with Autism Spectrum Disorder (ASD), particularly for social reinforcers. Less is known about neural responses to restricted interests and few studies have investigated response to rewards in a learning context. We investigated neurophysiological differences in reinforcement learning between adolescents with ASD and typically developing (TD) adolescents (27 ASD, 31 TD). FMRI was acquired during a learning task in which participants chose one of two doors to reveal an image outcome. Doors differed in their probability of showing liked and not-liked images, which were individualized for each participant. Participants chose the door paired with liked images, but not the door paired with not-liked images, significantly above chance and choice allocation did not differ between groups. Interestingly, participants with ASD made choices less consistent with their initial door preferences. We found a neural prediction-error response at the time of outcome in the ventromedial prefrontal and posterior cingulate cortices that did not differ between groups. Together, behavioural and neural findings suggest that learning with individual interest outcomes is not different between individuals with and without ASD, adding to our understanding of motivational aspects of ASD.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Individualidade , Aprendizagem , Imagem por Ressonância Magnética/métodos , Córtex Pré-Frontal/diagnóstico por imagem , Adolescente , Transtorno do Espectro Autista/psicologia , Emoções/fisiologia , Feminino , Giro do Cíngulo/fisiologia , Humanos , Aprendizagem/fisiologia , Masculino , Motivação/fisiologia , Estimulação Luminosa/métodos , Córtex Pré-Frontal/fisiologia , Tempo de Reação/fisiologia , Recompensa , Adulto Jovem
8.
Neuroimage ; 199: 651-662, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220576

RESUMO

The specificity and sensitivity of resting state functional MRI (rs-fMRI) measurements depend on preprocessing choices, such as the parcellation scheme used to define regions of interest (ROIs). In this study, we critically evaluate the effect of brain parcellations on machine learning models applied to rs-fMRI data. Our experiments reveal an intriguing trend: On average, models with stochastic parcellations consistently perform as well as models with widely used atlases at the same spatial scale. We thus propose an ensemble learning strategy to combine the predictions from models trained on connectivity data extracted using different (e.g., stochastic) parcellations. We further present an implementation of our ensemble learning strategy with a novel 3D Convolutional Neural Network (CNN) approach. The proposed CNN approach takes advantage of the full-resolution 3D spatial structure of rs-fMRI data and fits non-linear predictive models. Our ensemble CNN framework overcomes the limitations of traditional machine learning models for connectomes that often rely on region-based summary statistics and/or linear models. We showcase our approach on a classification (autism patients versus healthy controls) and a regression problem (prediction of subject's age), and report promising results.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Conectoma/métodos , Interpretação de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Imagem por Ressonância Magnética/métodos , Adolescente , Adulto , Atlas como Assunto , Encéfalo/fisiopatologia , Criança , Estudos de Coortes , Conectoma/normas , Humanos , Interpretação de Imagem Assistida por Computador/normas , Imagem por Ressonância Magnética/normas , Masculino , Adulto Jovem
9.
Brain Lang ; 194: 109-120, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31133435

RESUMO

Young humans are typically sensitive to evolutionarily important aspects of information in the surrounding environment in a way that makes us thrive. Seeking to probe the putative disruptions of this process in infancy, I examined the statistical character of head movements in 52 9-10 mo-old infants, half at high familial risk (HR) for Autism Spectrum Disorders (ASD), who underwent an fMRI scan while listening to words spoken with alternating stress patterns on syllables. Relative to low risk (LR) infants, HR infants, in particular those showing the least rapid receptive language progress, had significantly lower noise-to-signal levels and increased symmetry. A comparison of patterns during a native language and a sleep scan revealed the most atypical ordering of signatures on the 3 tasks in a subset of HR infants, suggesting that the biological mechanism of language development is least acquisitive in those HR infants who go on to develop ASD in toddlerhood.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Desenvolvimento da Linguagem , Transtorno do Espectro Autista/diagnóstico por imagem , Movimentos da Cabeça , Humanos , Lactente , Imagem por Ressonância Magnética , Sono , Percepção da Fala
10.
Biol Psychol ; 145: 174-184, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31051206

RESUMO

From an early age, individuals with autism spectrum disorder (ASD) spend less time engaged in social interaction compared to typically developing peers (TD). One reason behind this behavior may be that the brains of children diagnosed with ASD do not attribute enough value to potential social exchanges as compared to the brains of typically developing children; thus, potential social exchanges are avoided because other environmental stimuli are more highly valued by default. Neurobiological investigations into the mechanisms underlying value-based decision-making has shown that the ventral medial prefrontal cortex (vmPFC) is critical for encoding the expected outcome value of different actions corresponding to distinct environmental cues. Here, we tested the hypothesis that the responsiveness of the vmPFC in children diagnosed with ASD (compared to TD controls) is diminished for visual cues that represent highly valued social interaction. Using a passive picture viewing task and functional magnetic resonance imaging (fMRI) we measured the response of an a priori defined region of interest in the vmPFC in children diagnosed with ASD and an age-matched TD cohort. We show that the average response of the vmPFC is significantly diminished in the ASD group. Further, we demonstrate that a single-stimulus and less than 30 s of fMRI data are sufficient to differentiate the ASD and TD cohorts. These findings are consistent with the hypothesis that the brains of children with ASD do not encode the value of social exchange in the same manner as TD children. The latter finding suggests the possibility of utilizing single-stimulus fMRI as a potential biologically based diagnostic tool to augment traditional clinical approaches.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/fisiopatologia , Relações Interpessoais , Imagem por Ressonância Magnética , Comportamento Social , Transtorno do Espectro Autista/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Criança , Desenvolvimento Infantil , Feminino , Humanos , Masculino , Estimulação Luminosa , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia
11.
J Autism Dev Disord ; 49(7): 3036-3044, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004246

RESUMO

Imaging technologies such as positron emission tomography (PET) and magnetic resonance imaging (MRI) present unparalleled opportunities to investigate the neural basis of autism spectrum disorder (ASD). However, challenges such as deficits in social interaction, anxiety around new experiences, impaired language abilities, and hypersensitivity to sensory stimuli make participating in neuroimaging studies challenging for individuals with ASD. In this commentary, we describe the existent training protocols for preparing individuals with ASD for PET/MRI scans and our own experience developing a training protocol to facilitate the inclusion of low-functioning adults with ASD in PET-MRI studies. We hope to raise awareness of the need for more information exchange between research groups about lessons learned in this context in order to include the entire disease spectrum in neuroimaging studies.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Adulto , Humanos , Masculino , Neuroimagem
12.
J Autism Dev Disord ; 49(6): 2612-2617, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30969385

RESUMO

Determining a patient's dental age is essential from the dental standpoint but can also have connotations of a forensic, anthropological and medicolegal nature. In this study, we assessed the correspondence between dental age and chronological age in a group of 50 children with autism spectrum disorders, with a chronological age range of 3-17 years. The dental age was calculated using panoramic radiography images, applying linear regression models derived from the classical indices by Nolla and Demirjian. In 2 of every 3 boys, the dental age was ahead of the chronological age, and in almost 1 of every 3 cases, the difference was ≥ 12 months. In the girls, conversely, we found no significant differences between dental age and chronological age.


Assuntos
Determinação da Idade pelos Dentes , Transtorno do Espectro Autista/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Radiografia Panorâmica , Dente
13.
Medicine (Baltimore) ; 98(14): e15058, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30946352

RESUMO

BACKGROUND: Impaired language function is frequently observed as an initial sign in people with autism spectrum disorder (ASD). However, clinically, the early stages of ASD are difficult to distinguish from those of developmental language disorder (DLD). OBJECTIVE: To evaluate the ability of diffusion tensor imaging (DTI) parameters for language-related white matter tracts (arcuate fasciculus) to differentiate ASD from DLD among toddlers. MATERIALS AND METHODS: We included 16 ASD toddlers with language delay and 18 DLD toddlers in this study. Magnetic resonance imaging sequences included T2-weighted imaging (T2WI), T1 3-dimensional magnetization-prepared rapid acquisition gradient-echo (3D MP-RAGE), and DTI. Tractography was performed using Neuro 3D in the Siemens Syngo Workstation, and fractional anisotropy (FA), average fiber length (AFL), tract volume (TV), and number of voxels (NV) were automatically calculated. Data were then analyzed using IBM SPSS Statistics 22. RESULTS: The ASD group exhibited significantly lower FA values, as well as significantly higher TV and NV values compared with the DLD group. With age as the covariate, analysis of covariance revealed different significances in TV and NV. Analysis of variance for AFL revealed no significant differences between the 2 groups. CONCLUSION: DTI parameters of arcuate fasciculus were useful for differentiating ASD with language delay from DLD among toddlers. DTI has the potential to provide an objective and effective method for aiding early diagnosis, early intervention and improving long-term outcomes of ASD.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Transtornos do Desenvolvimento da Linguagem/diagnóstico por imagem , Análise de Variância , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Imageamento Tridimensional , Lactente , Masculino , Testes Psicológicos , Substância Branca/diagnóstico por imagem
14.
Brain Connect ; 9(5): 425-436, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30900464

RESUMO

Studies suggest that individuals with autism spectrum disorder (ASD) exhibit altered electrophysiological alpha to gamma phase-amplitude coupling (PAC). Preliminary reports with small samples report conflicting findings regarding the directionality of the alpha to gamma PAC alterations in ASD. The present study examined resting-state activity throughout the brain in a relatively large sample of 119 children with ASD and 47 typically developing children. Children with ASD demonstrated regionally specific abnormalities in alpha to low-gamma PAC, with increased alpha to low-gamma PAC for a central midline source and decreased PAC at lateral sources. Group differences in local gamma-band power did not account for the regional group differences in alpha to low-gamma PAC. Moreover, local alpha power did not significantly modulate alpha to low-gamma PAC estimates. Finally, PAC estimates were correlated with Social Responsiveness Scale (SRS) indicating clinical relevance of the PAC metric. In conclusion, alpha to low-gamma PAC alterations in ASD demonstrate a heterogeneous spatial profile consistent with previous studies and were related to symptom severity.


Assuntos
Ritmo alfa/fisiologia , Transtorno do Espectro Autista/diagnóstico por imagem , Ritmo Gama/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Criança , Fenômenos Eletrofisiológicos/fisiologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Magnetoencefalografia/métodos , Masculino , Vias Neurais/fisiologia , Descanso/fisiologia
15.
Neuron ; 101(6): 1070-1088, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897358

RESUMO

Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders.


Assuntos
Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Plasticidade Neuronal , RNA Mensageiro/metabolismo , Sinapses/metabolismo , Animais , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Espinhas Dendríticas , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Camundongos , Processamento Pós-Transcricional do RNA , Transdução de Sinais , Transmissão Sináptica
16.
Mol Autism ; 10: 8, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858964

RESUMO

Background: Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2α knockout (KO) model. Methods: Fixed brains of Nrxn2α KO mice underwent DTI using 9.4 T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. Results: DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2α KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Conclusions: Our findings demonstrate that deleting a single neurexin gene (Nrxn2α) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.


Assuntos
Transtorno do Espectro Autista/genética , Encéfalo/diagnóstico por imagem , Proteínas do Tecido Nervoso/genética , Animais , Transtorno do Espectro Autista/diagnóstico por imagem , Imagem de Tensor de Difusão , Deleção de Genes , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Transl Psychiatry ; 9(1): 72, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718456

RESUMO

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal-parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to <0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Córtex Cerebral/patologia , Sistema Límbico/patologia , Transtorno de Comunicação Social/patologia , Transtorno de Comunicação Social/fisiopatologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Criança , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/patologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno de Comunicação Social/diagnóstico por imagem , Transtorno de Comunicação Social/etiologia
18.
Transl Psychiatry ; 9(1): 86, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755585

RESUMO

Structural neuroimaging studies suggest altered brain maturation in autism spectrum disorder (ASD) compared with typically developing controls (TDC). However, the prognostic value of whole-brain structural connectivity analysis in ASD has not been established. Diffusion magnetic imaging data were acquired in 27 high-functioning young ASD participants (2 females) and 29 age-matched TDC (12 females; age 8-18 years) at baseline and again following 3-7 years. Whole-brain structural connectomes were reconstructed from these data and analyzed using a longitudinal statistical model. We identified distinct patterns of widespread brain connections that exhibited either significant increases or decreases in connectivity over time (p < 0.001). There was a significant interaction between diagnosis and time in brain development (p < 0.001). This was expressed by a decrease in structural connectivity within the frontoparietal network-and its broader connectivity-in ASD during adolescence and early adulthood. Conversely, these connections increased with time in TDC. Crucially, stronger baseline connectivity in this subnetwork predicted a lower symptom load at follow-up (p = 0.048), independent of the expression of symptoms at baseline. Our findings suggest a clinically meaningful relationship between the atypical development of frontoparietal structural connections and the dynamics of the autism phenotype through early adulthood. These results highlight a potential marker of future outcome.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Adolescente , Adulto , Encéfalo/crescimento & desenvolvimento , Mapeamento Encefálico , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/fisiopatologia , Reprodutibilidade dos Testes , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-30777604

RESUMO

BACKGROUND: Children with autism spectrum disorder (ASD) and co-occurring attention-deficit/hyperactivity disorder (ADHD) symptoms have worse functional outcomes and treatment response than those without ADHD symptoms. There is limited knowledge of the neurobiology of ADHD symptoms in ASD. Here, we test the hypothesis that aberrant functional connectivity of two large-scale executive brain networks implicated in ADHD-the frontoparietal and salience/ventral attention networks-also play a role in ADHD symptoms in ASD. METHODS: We compared resting-state functional connectivity of the two executive brain networks in children with ASD (n = 77) and typically developing control children (n = 82). These two executive brain networks comprise five subnetworks (three frontoparietal, two salience/ventral attention). After identifying aberrant functional connections among subnetworks, we examined dimensional associations with parent-reported ADHD symptoms. RESULTS: Weaker functional connectivity in ASD was present within and between the frontoparietal and salience/ventral attention subnetworks. Decreased functional connectivity within a single salience/ventral attention subnetwork, as well as between two frontoparietal subnetworks, significantly correlated with ADHD symptoms. Furthermore, follow-up linear regressions demonstrated that the salience/ventral attention and frontoparietal subnetworks explain unique variance in ADHD symptoms. These executive brain network-ADHD symptom relationships remained significant after controlling for ASD symptoms. Finally, specificity was also demonstrated through the use of a control brain network (visual) and a control co-occurring symptom domain (anxiety). CONCLUSIONS: The present findings provide novel evidence that both frontoparietal and salience/ventral attention networks' weaker connectivities are linked to ADHD symptoms in ASD. Moreover, co-occurring ADHD in the context of ASD is a source of meaningful neural heterogeneity in ASD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Córtex Cerebral/fisiopatologia , Conectoma , Função Executiva/fisiologia , Rede Nervosa/fisiopatologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Espectro Autista/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem
20.
Biol Psychiatry ; 85(7): 584-595, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711191

RESUMO

BACKGROUND: Our aim was to assess resting cerebral blood flow (rCBF) in children and adults with autism spectrum disorder (ASD). METHODS: We acquired pulsed arterial spin labeling magnetic resonance imaging data in 44 generally high-functioning participants with ASD simplex and 66 typically developing control subjects with comparable mean full-scale IQs. We compared rCBF values voxelwise across diagnostic groups and assessed correlations with symptom scores. We also assessed the moderating influences of participant age, sex, and IQ on our findings and the correlations of rCBF with N-acetylaspartate metabolite levels. RESULTS: We detected significantly higher rCBF values throughout frontal white matter and subcortical gray matter in participants with ASD. rCBF correlated positively with socialization deficits in participants with ASD in regions where hyperperfusion was greatest. rCBF declined with increasing IQ in the typically developing group, a correlation that was absent in participants with ASD, whose rCBF values were elevated across all IQ levels. rCBF in the ASD group correlated inversely with N-acetylaspartate metabolite levels throughout the frontal white matter, with greater rCBF accompanying lower and increasingly abnormal N-acetylaspartate levels relative to those of typically developing control subjects. CONCLUSIONS: These findings taken together suggest the presence of altered metabolism, likely of mitochondrial origin, and dysfunctional maintenance processes that support axonal functioning in ASD. These disturbances in turn likely reduce neural efficiency for cognitive and social functioning and trigger compensatory responses from supporting glial cells, which subsequently increase rCBF to affected white matter. These findings, if confirmed, suggest cellular and molecular targets for novel therapeutics that address axonal pathology and bolster glial compensatory responses in ASD.


Assuntos
Ácido Aspártico/análogos & derivados , Transtorno do Espectro Autista , Circulação Cerebrovascular/fisiologia , Lobo Frontal , Substância Cinzenta , Substância Branca , Adolescente , Adulto , Ácido Aspártico/metabolismo , Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Criança , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/metabolismo , Lobo Frontal/fisiopatologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Substância Cinzenta/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Neuroimagem , Marcadores de Spin , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/fisiopatologia , Adulto Jovem
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