Atypical genomic cortical patterning in autism with poor early language outcome.
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ABSTRACT:
SUBMITTER: Lombardo MV
PROVIDER: S-EPMC8442861 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Autism (ASD) is vastly heterogeneous, particularly in early language development. While ASD language trajectories in the first years of life are highly unstable, by early childhood these trajectories stabilize and are predictive of longer-term outcome. Early neural substrates that predict/precede such outcomes are largely unknown, but could have considerable translational and clinical impact. Pre-diagnosis fMRI response to speech in ASD toddlers with relatively good language outcome was highly similar to non-ASD comparison groups and robustly recruited language-sensitive superior temporal cortices. In contrast, language-sensitive superior temporal cortices were hypoactive in ASD toddlers with poor language outcome. Brain-behavioral relationships were atypically reversed in ASD, and a multimodal combination of pre-diagnostic clinical behavioral measures and speech-related fMRI response showed the most promise as an ASD prognosis classifier. Thus, before ASD diagnoses and outcome become clinically clear, distinct functional neuroimaging phenotypes are already present that can shed insight on an ASD toddler's later outcome. VIDEO ABSTRACT.
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Project description:Measurement of language atypicalities in Autism Spectrum Disorder (ASD) is cumbersome and costly. Better language outcome measures are needed. Using language transcripts, we generated Automated Language Measures (ALMs) and tested their validity. 169 participants (96 ASD, 28 TD, 45 ADHD) ages 7 to 17 were evaluated with the Autism Diagnostic Observation Schedule. Transcripts of one task were analyzed to generate seven ALMs: mean length of utterance in morphemes, number of different word roots (NDWR), um proportion, content maze proportion, unintelligible proportion, c-units per minute, and repetition proportion. With the exception of repetition proportion (p [Formula: see text]), nonparametric ANOVAs showed significant group differences (p[Formula: see text]). The TD and ADHD groups did not differ from each other in post-hoc analyses. With the exception of NDWR, the ASD group showed significantly (p[Formula: see text]) lower scores than both comparison groups. The ALMs were correlated with standardized clinical and language evaluations of ASD. In age- and IQ-adjusted logistic regression analyses, four ALMs significantly predicted ASD status with satisfactory accuracy (67.9-75.5%). When ALMs were combined together, accuracy improved to 82.4%. These ALMs offer a promising approach for generating novel outcome measures.
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Project description:Recent longitudinal neuroimaging and neurophysiological studies have shown that tracking relative age-related changes in neural signals, rather than a static snapshot of a neural measure, could offer higher sensitivity for discriminating typically developing (TD) individuals from those with autism spectrum disorder (ASD). It is not clear, however, which aspects of age-related changes (trajectories) would be optimal for identifying atypical brain development in ASD. Using a large cross-sectional data set (Autism Brain Imaging Data Exchange [ABIDE] repository; releases I and II), we aimed to explore age-related changes in cortical thickness (CT) in TD and ASD populations (age range 6-30 years old). Cortical thickness was estimated from T1-weighted MRI images at three scales of spatial coarseness (three parcellations with different numbers of regions of interest). For each parcellation, three polynomial models of age-related changes in CT were tested. Specifically, to characterize alterations in CT trajectories, we compared the linear slope, curvature, and aberrancy of CT trajectories across experimental groups, which was estimated using linear, quadratic, and cubic polynomial models, respectively. Also, we explored associations between age-related changes with ASD symptomatology quantified as the Autism Diagnostic Observation Schedule (ADOS) scores. While no overall group differences in cortical thickness were observed across the entire age range, ASD and TD populations were different in terms of age-related changes, which were located primarily in frontal and tempo-parietal areas. These atypical age-related changes were also associated with ADOS scores in the ASD group and used to predict ASD from TD development. These results indicate that the curvature is the most reliable feature for localizing brain areas developmentally atypical in ASD with a more pronounced effect with symptomatology and is the most sensitive in predicting ASD development.
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Project description:Subjects with autism often show language difficulties, but it is unclear how they relate to neurophysiological anomalies of cortical speech processing. We used combined EEG and fMRI in 13 subjects with autism and 13 control participants and show that in autism, gamma and theta cortical activity do not engage synergistically in response to speech. Theta activity in left auditory cortex fails to track speech modulations, and to down-regulate gamma oscillations in the group with autism. This deficit predicts the severity of both verbal impairment and autism symptoms in the affected sample. Finally, we found that oscillation-based connectivity between auditory and other language cortices is altered in autism. These results suggest that the verbal disorder in autism could be associated with an altered balance of slow and fast auditory oscillations, and that this anomaly could compromise the mapping between sensory input and higher-level cognitive representations.
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Project description:Pitch processing at cortical and subcortical stages of processing is shaped by language experience. We recently demonstrated that specific components of the cortical pitch response (CPR) index the more rapidly-changing portions of the high rising Tone 2 of Mandarin Chinese, in addition to marking pitch onset and sound offset. In this study, we examine how language experience (Mandarin vs. English) shapes the processing of different temporal attributes of pitch reflected in the CPR components using stimuli representative of within-category variants of Tone 2. Results showed that the magnitude of CPR components (Na-Pb and Pb-Nb) and the correlation between these two components and pitch acceleration were stronger for the Chinese listeners compared to English listeners for stimuli that fell within the range of Tone 2 citation forms. Discriminant function analysis revealed that the Na-Pb component was more than twice as important as Pb-Nb in grouping listeners by language affiliation. In addition, a stronger stimulus-dependent, rightward asymmetry was observed for the Chinese group at the temporal, but not frontal, electrode sites. This finding may reflect selective recruitment of experience-dependent, pitch-specific mechanisms in right auditory cortex to extract more complex, time-varying pitch patterns. Taken together, these findings suggest that long-term language experience shapes early sensory level processing of pitch in the auditory cortex, and that the sensitivity of the CPR may vary depending on the relative linguistic importance of specific temporal attributes of dynamic pitch.
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Project description:The way that parents communicate with their typically developing infants is associated with later infant language development. Here we aim to show that these associations are observed in infants subsequently diagnosed with autism spectrum disorder (ASD). This study had three groups: high-familial-risk infants who did not have ASD (n = 46); high-familial-risk infants who had ASD (n = 14); and low-familial-risk infants who exhibited typical development (n = 36). All-day home language recordings were collected at 9 and 15?months, and language skills were assessed at 24?months. Across all infants in the study, including those with ASD, a richer home language environment (e.g., hearing more adult words and experiencing more conversational turns) at 9 and 15?months was associated with better language skills. Higher parental educational attainment was associated with a richer home language environment. Mediation analyses showed that the effect of education on child language skills was explained by the richness of the home language environment. Exploratory analyses revealed that typically developing infants experience an increase in caregiver-child conversational turns across 9-15?months, a pattern not seen in children with ASD. The current study shows that parent behavior during the earliest stages of life can have a significant impact on later development, highlighting the home language environment as means to support development in infants with ASD. Autism Res 2019, 12: 1784-1795. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It has long been understood that caregiver speech supports language skills in typically developing infants. In this study, parents of infants who were later diagnosed with ASD and parents of infants in the control groups completed all-day home language recordings. We found that for all infants in our study, those who heard more caregiver speech had better language skills later in life. Parental education level was also related to how much caregiver speech an infant experienced.
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Project description:Analysis of genetic alterations within pulmonary carcinoids by array comparative genomic hybridization
2011-06-01 | E-MEXP-3145 | biostudies-arrayexpress
Project description:Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD.
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Project description:Autism spectrum disorders (ASDs) are neurodevelopmental disorders associated with atypical brain connectivity. Although language abilities vary widely, they are impaired or atypical in most children with ASDs. Underlying brain mechanisms, however, are not fully understood. The present study examined intrinsic functional connectivity (iFC) of the extended language network in a cohort of 52 children and adolescents with ASDs (ages 8-18?years), using resting-state functional magnetic resonance imaging. We found that, in comparison to typically developing peers (n = 50), children with ASDs showed increased connectivity between some language regions. In addition, seed-to-whole brain analyses revealed increased connectivity of language regions with posterior cingulate cortex (PCC) and visual regions in the ASD group. Post hoc effective connectivity analyses revealed a mediation effect of PCC on the iFC between bilateral inferior frontal and visual regions in an ASD subgroup. This finding qualifies and expands on previous reports of recruitment of visual areas in language processing in ASDs. In addition, increased iFC between PCC and visual regions was linked to lower language scores in this ASD subgroup, suggesting that increased connectivity with visual cortices, mediated by default mode regions, may be detrimental to language abilities. Autism Res 2019, 12: 1344-1355. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined the functional connectivity between regions of the language network in children with autism spectrum disorders (ASDs) compared to typically developing peers. We found connectivity to be intact between core language in the ASD group, but also showed abnormally increased connectivity between regions of an extended language network. Additionally, connectivity was increased with regions associated with brain networks responsible for self-reflection and visual processing.
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Project description:We present two experiments examining the universality and uniqueness of reduced context sensitivity in language processing in Autism Spectrum Disorders (ASD), as proposed by the Weak Central Coherence account (Happé & Frith, 2006, Journal of Autism and Developmental Disorders, 36(1), 25). That is, do all children with ASD exhibit decreased context sensitivity, and is this characteristic specific to ASD versus other neurodevelopmental conditions? Experiment 1, conducted in English, was a comparison of children with ASD with normal language and their typically-developing peers on a picture selection task where interpretation of sentential context was required to identify homonyms. Contrary to the predictions of Weak Central Coherence, the ASD-normal language group exhibited no difficulty on this task. Experiment 2, conducted in German, compared children with ASD with variable language abilities, typically-developing children, and a second control group of children with Language Impairment (LI) on a sentence completion task where a context sentence had to be considered to produce the continuation of an ambiguous sentence fragment. Both ASD-variable language and LI groups exhibited reduced context sensitivity and did not differ from each other. Finally, to directly test which factors contribute to reduced context sensitivity, we conducted a regression analysis for each experiment, entering nonverbal IQ, structural language ability, and autism diagnosis as predictors. For both experiments structural language ability emerged as the only significant predictor. These convergent findings demonstrate that reduced sensitivity to context in language processing is linked to low structural language rather than ASD diagnosis.
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