Associations between atypical intracortical myelin content and neuropsychological functions in middle to older aged adults with ASD.

INTRODUCTION: In vivo myeloarchitectonic mapping based on Magnetic Resonance Imaging (MRI) provides a unique view of gray matter myelin content and offers information complementary to other morphological indices commonly employed in studies of autism spectrum disorder (ASD). The current study sought to determine if intracortical myelin content (MC) and its age-related trajectories differ between middle aged to older adults with ASD and age-matched typical comparison participants. METHODS: Data from 30 individuals with ASD and 36 age-matched typical comparison participants aged 40-70 years were analyzed. Given substantial heterogeneity in both etiology and outcomes in ASD, we utilized both group-level and subject-level analysis approaches to test for signs of atypical intracortical MC as estimated by T1w/T2w ratio. RESULTS: Group-level analyses showed no significant differences in average T1w/T2w ratio or its associations with age between groups, but revealed significant positive main effects of age bilaterally, with T1w/T2w ratio increasing with age across much of the cortex. In subject-level analyses, participants were classified into subgroups based on presence or absence of clusters of aberrant T1w/T2w ratio, and lower neuropsychological function was observed in the ASD subgroup with atypically high T1w/T2w ratio in spatially heterogeneous cortical regions. These differences were observed across several neuropsychological domains, including overall intellectual functioning, processing speed, and aspects of executive function. CONCLUSIONS: The group-level and subject-level approaches employed here demonstrate the value of examining inter-individual variability and provide important preliminary insights into relationships between brain structure and cognition in the second half of the lifespan in ASD, suggesting shared factors contributing to atypical intracortical myelin content and poorer cognitive outcomes for a subset of middle aged to older autistic adults. These atypicalities likely reflect diverse histories of neurodevelopmental deficits, and possible compensatory changes, compounded by processes of aging, and may serve as useful markers of vulnerability to further cognitive decline in older adults with ASD.

Reduced covariation between brain morphometry and local spontaneous activity in young children with ASD.

While disruptions in brain maturation in the first years of life in ASD are well documented, little is known about how the brain structure and function are related in young children with ASD compared to typically developing peers. We applied a multivariate pattern analysis to examine the covariation patterns between brain morphometry and local brain spontaneous activity in 38 toddlers and preschoolers with ASD and 31 typically developing children using T1-weighted structural MRI and resting-state fMRI data acquired during natural sleep. The results revealed significantly reduced brain structure-function correlations in ASD. The resultant brain structure and function composite indices were associated with age among typically developing children, but not among those with ASD, suggesting mistiming of typical brain maturational trajectories early in life in autism. Additionally, the brain function composite indices were associated with the overall developmental and adaptive behavior skills in the ASD group, highlighting the neurodevelopmental significance of early local brain activity in autism.

Sleep Problems in Preschoolers With Autism Spectrum Disorder Are Associated With Sensory Sensitivities and Thalamocortical Overconnectivity.

BACKGROUND: Projections between the thalamus and sensory cortices are established early in development and play an important role in regulating sleep as well as in relaying sensory information to the cortex. Atypical thalamocortical functional connectivity frequently observed in children with autism spectrum disorder (ASD) might therefore be linked to sensory and sleep problems common in ASD. METHODS: Here, we investigated the relationship between auditory-thalamic functional connectivity measured during natural sleep functional magnetic resonance imaging, sleep problems, and sound sensitivities in 70 toddlers and preschoolers (1.5-5 years old) with ASD compared with a matched group of 46 typically developing children. RESULTS: In children with ASD, sleep problems and sensory sensitivities were positively correlated, and increased sleep latency was associated with overconnectivity between the thalamus and auditory cortex in a subsample with high-quality magnetic resonance imaging data (n = 29). In addition, auditory cortex blood oxygen level-dependent signal amplitude was elevated in children with ASD, potentially reflecting reduced sensory gating or a lack of auditory habituation during natural sleep. CONCLUSIONS: These findings indicate that atypical thalamocortical functional connectivity can be detected early in development and may play a crucial role in sleep problems and sensory sensitivities in ASD.

Cortical myelination in toddlers and preschoolers with autism spectrum disorder.

Intracortical myelin is thought to play a significant role in the development of neural circuits and functional networks, with consistent evidence of atypical network connectivity in children with autism spectrum disorder (ASD). However, little is known about the development of intracortical myelin in the first years of life in ASD, during the critical neurodevelopmental period when autism symptoms first emerge. Using T1-weighted (T1w) and T2w structural magnetic resonance imaging (MRI) in 21 young children with ASD and 16 typically developing (TD) children, ages 1.5-5.5 years, we demonstrate the feasibility of estimating intracortical myelin in vivo using the T1w/T2w ratio as a proxy. The resultant T1w/T2w maps were largely comparable with those reported in prior T1w/T2w studies in TD children and adults, and revealed no group differences between TD children and those with ASD. However, differential associations between T1w/T2w and age were identified in several early myelinated regions (e.g., visual, posterior cingulate, precuneus cortices) in the ASD and TD groups, with age-related increase in estimated myelin content across the toddler and preschool years detected in TD children, but not in children with ASD. The atypical age-related effects in intracortical myelin, suggesting a disrupted myelination in the first years of life in ASD, may be related to the aberrant brain network connectivity reported in young children with ASD in some of the same cortical regions and circuits.

Externalizing Behaviors are Associated with Increased Parenting Stress in Caregivers of Young Children with Autism.

Parents of children diagnosed with autism spectrum disorder (ASD) report higher levels of stress than parents of typically developing children. Few studies have examined factors associated with parental stress in early childhood. Even fewer have investigated the simultaneous influence of sociodemographic, clinical, and developmental variables on parental stress. We examined factors associated with stress in parents of young children with ASD. Multiple regression models were used to test for associations between socioeconomic indices, developmental measures, and parental stress. Externalizing behaviors, communication, and socialization skills accounted for variance in parental stress, controlling for ASD diagnosis. Results highlight the importance of interventions aimed at reducing externalizing behaviors in young children as well as addressing stress in caregivers of children with ASD.

Resting state functional networks in 1-to-3-year-old typically developing children.

Brain functional networks undergo substantial development and refinement during the first years of life. Yet, the maturational pathways of functional network development remain poorly understood. Using resting-state fMRI data acquired during natural sleep from 24 typically developing toddlers, ages 1.5-3.5 years, we aimed to examine the large-scale resting-state functional networks and their relationship with age and developmental skills. Specifically, two network organization indices reflecting network connectivity and spatial variability were derived. Our results revealed that reduced spatial variability or increased network homogeneity in one of the default mode network components was associated with age, with older children displaying less spatially variable posterior DMN subcomponent, consistent with the notion of increased spatial and functional specialization. Further, greater network homogeneity in higher-order functional networks, including the posterior default mode, salience, and language networks, was associated with more advanced developmental skills measured with a standardized assessment of early learning, regardless of age. These results not only improve our understanding of brain functional network development during toddler years, but also inform the relationship between brain network organization and emerging cognitive and behavioral skills.

Performance of machine learning classification models of autism using resting-state fMRI is contingent on sample heterogeneity.

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental conditions. In fMRI studies, including most machine learning studies seeking to distinguish ASD from typical developing (TD) samples, cohorts differing in gender and symptom severity composition are often treated statistically as one "ASD group". Using resting-state functional connectivity (FC) data, we implemented random forest to build diagnostic classifiers in 4 ASD samples including a total of 656 participants (NASD = 306, NTD = 350, ages 6-18). Groups were manipulated to titrate heterogeneity of gender and symptom severity and partially overlapped. Each sample differed on inclusionary criteria: (1) all genders, unrestricted severity range; (2) only male participants, unrestricted severity; (3) all genders, higher severity only; (4) only male participants, higher severity. Each set consisted of 200 participants per group (ASD, TD; matched on age and head motion), 160 for training and 40 for validation. FMRI time series from 237 regions of interest (ROIs) were Pearson correlated in a 237×237 FC matrix and classifiers were built using random forest in training samples. Classification accuracies in validation samples were 62.5%, 65%, 70% and 73.75%, respectively for samples 1-4. Connectivity within cingulo-opercular task control (COTC) network, and between COTC ROIs and default mode and dorsal attention network contributed overall most informative features, but features differed across sets. Findings suggest that diagnostic classifiers vary depending on ASD sample composition. Specifically, greater homogeneity of samples regarding gender and symptom severity enhances classifier performance. However, given the true heterogeneity of ASDs, performance metrics alone may not adequately reflect classifier utility.

[Formula: see text] Neural correlates of socioeconomic status in early childhood: a systematic review of the literature.

It is now established that socioeconomic variables are associated with cognitive, academic achievement, and psychiatric outcomes. Recent years have shown the advance in our understanding of how socioeconomic status (SES) relates to brain development in the first years of life (ages 0-5 years). However, it remains unknown which neural structures and functions are most sensitive to the environmental experiences associated with SES. Pubmed, PsycInfo, and Google Scholar databases from January 1, 2000, to December 31, 2019, were systematically searched using terms "Neural" OR "Neuroimaging" OR "Brain" OR "Brain development," AND "Socioeconomic" OR "SES" OR "Income" OR "Disadvantage" OR "Education," AND "Early childhood" OR "Early development". Nineteen studies were included in the full review after applying all exclusion criteria. Studies revealed associations between socioeconomic and neural measures and indicated that, in the first years of life, certain neural functions and structures (e.g., those implicated in language and executive function) may be more sensitive to socioeconomic context than others. Findings broadly support the hypothesis that SES associations with neural structure and function operate on a gradient. Socioeconomic status is reflected in neural architecture and function of very young children, as early as shortly after birth, with its effects possibly growing throughout early childhood as a result of postnatal experiences. Although socioeconomic associations with neural measures were relatively consistent across studies, results from this review are not conclusive enough to supply a neural phenotype of low SES. Further work is necessary to understand causal mechanisms underlying SES-brain associations.

Greater functional connectivity between sensory networks is related to symptom severity in toddlers with autism spectrum disorder.

BACKGROUND: Symptoms of autism spectrum disorder (ASD) emerge in the first years of life. Yet, little is known about the organization and development of functional brain networks in ASD proximally to the symptom onset. Further, the relationship between brain network connectivity and emerging ASD symptoms and overall functioning in early childhood is not well understood. METHODS: Resting-state fMRI data were acquired during natural sleep from 24 young children with ASD and 23 typically developing (TD) children, aged 17-45 months. Intrinsic functional connectivity (iFC) within and between resting-state functional networks was derived with independent component analysis (ICA). RESULTS: Increased iFC between visual and sensorimotor networks was found in young children with ASD compared to TD participants. Within the ASD group, the degree of overconnectivity between visual and sensorimotor networks was associated with greater autism symptoms. Age-related weakening of the visual-auditory between-network connectivity was observed in the ASD but not the TD group. CONCLUSIONS: Taken together, these results provide evidence for disrupted functional network maturation and differentiation, particularly involving visual and sensorimotor networks, during the first years of life in ASD. The observed pattern of greater visual-sensorimotor between-network connectivity associated with poorer clinical outcomes suggests that disruptions in multisensory brain circuitry may play a critical role for early development of behavioral skills and autism symptomatology in young children with ASD.

MEG Theta during Lexico-Semantic and Executive Processing Is Altered in High-Functioning Adolescents with Autism.

Neuroimaging studies have revealed atypical activation during language and executive tasks in individuals with autism spectrum disorders (ASD). However, the spatiotemporal stages of processing associated with these dysfunctions remain poorly understood. Using an anatomically constrained magnetoencephalography approach, we examined event-related theta oscillations during a double-duty lexical decision task that combined demands on lexico-semantic processing and executive functions. Relative to typically developing peers, high-functioning adolescents with ASD had lower performance accuracy on trials engaging selective semantic retrieval and cognitive control. They showed an early overall theta increase in the left fusiform cortex followed by greater activity in the left-lateralized temporal (starting at ~250 ms) and frontal cortical areas (after ~450 ms) known to contribute to language processing. During response preparation and execution, the ASD group exhibited elevated theta in the anterior cingulate cortex, indicative of greater engagement of cognitive control. Simultaneously increased activity in the ipsilateral motor cortex may reflect a less lateralized and suboptimally organized motor circuitry. Spanning early sensory-specific and late response selection stages, the higher event-related theta responsivity in ASD may indicate compensatory recruitment to offset inefficient lexico-semantic retrieval under cognitively demanding conditions. Together, these findings provide further support for atypical language and executive functions in high-functioning ASD.

Underconnectivity Between Visual and Salience Networks and Links With Sensory Abnormalities in Autism Spectrum Disorders.

OBJECTIVE: The anterior insular cortex (AI), which is a part of the salience network, is critically involved in visual awareness, multisensory perception, and social and emotional processing, among other functions. In children and adolescents with autism spectrum disorders (ASDs), evidence has suggested aberrant functional connectivity (FC) of AI compared with typically developing peers. While recent studies have primarily focused on the functional connections between salience and social networks, much less is known about connectivity between AI and primary sensory regions, including visual areas, and how these patterns may be linked to autism symptomatology. METHOD: The current investigation implemented functional magnetic resonance imaging to examine resting-state FC patterns of salience and visual networks in children and adolescents with ASDs compared with typically developing controls, and to relate them to behavioral measures. RESULTS: Functional underconnectivity was found in the ASD group between left AI and bilateral visual cortices. Moreover, in an ASD subgroup with more atypical visual sensory profiles, FC was positively correlated with abnormal social motivational responsivity. CONCLUSION: Findings of reduced FC between salience and visual networks in ASDs potentially indicate deficient selection of salient information. Moreover, in children and adolescents with ASDs who show strongly atypical visual sensory profiles, connectivity at seemingly more neurotypical levels may be paradoxically associated with greater impairment of social motivation.

Socioeconomic Factors Account for Variability in Language Skills in Preschoolers with Autism Spectrum Disorders.

OBJECTIVE: Although no longer required for a diagnosis, language delays are extremely common in children diagnosed with autism spectrum disorders (ASD). Factors associated with socioeconomic status (SES) have broad-reaching impact on language development in early childhood. Despite recent advances in characterizing autism in early childhood, the relationship between SES and language development in ASD has not received much attention. THE OBJECTIVE OF THIS STUDY WAS: to examine whether toddlers and preschoolers with ASD from low-resource families are more likely to experience language delays above and beyond those associated with autism itself. METHODS: Developmental and diagnostic assessments including the Mullen Scales of Early Learning, the Autism Diagnostic Observation Schedule, Second Edition, and the Vineland Adaptive Behavior Scales were obtained from 62 young children with ASD and 45 typically developing children aged 15 to 64 months. Sociodemographic information including household income, maternal education, and racial/ethnic identity was obtained from caregivers. Multiple regression models were used to test for associations between socioeconomic indices and language scores. RESULTS: Maternal education accounted for variability in expressive language (EL) and receptive language (RL), with lower SES indices associated with lower language skills, and more so in children with ASD. CONCLUSION: These results demonstrate that variability in EL and RL skills in young children with autism can be accounted for by socioeconomic variables. These findings highlight the necessity for targeted intervention and effective implementation strategies for children with ASD from low-resource households and communities and for policies designed to improve learning opportunities and access to services for these young children and their families.

Sex-related patterns of intrinsic functional connectivity in children and adolescents with autism spectrum disorders.

LAY SUMMARY: We investigated whether children and adolescents with autism spectrum disorders show sex-specific patterns of brain function (using functional magnetic resonance imaging) that are well documented in typically developing males and females. We found, unexpectedly, that boys and girls with autism do not differ in their brain functional connectivity, whereas typically developing boys and girls showed differences in a brain network involved in thinking about self and others (the default mode network). Results suggest that autism may be characterized by a lack of brain sex differentiation.

The language network in autism: Atypical functional connectivity with default mode and visual regions.

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.

The cingulum and cingulate U-fibers in children and adolescents with autism spectrum disorders.

The cingulum is the major fiber system connecting the cingulate and surrounding medial cortex and medial temporal lobe internally and with other brain areas. It is important for social and emotional functions related to core symptomatology in autism spectrum disorders (ASDs). While the cingulum has been examined in autism, the extensive system of cingulate U-fibers has not been studied. Using probabilistic tractography, we investigated white matter fibers of the cingulate cortex by distinguishing its deep intra-cingulate bundle (cingulum proper) and short rostral anterior, caudal anterior, posterior, and isthmus cingulate U-fibers in 61 ASD and 54 typically developing children and adolescents. Increased mean and radial diffusivity of the left cingulum proper was observed in the ASD group, replicating previous findings on the cingulum. For cingulate U-fibers, an atypical age-related decline in right posterior cingulate U-fiber volume was found in the ASD group, which appeared to be driven by an abnormally large volume in younger children. History of repetitive and restrictive behavior was negatively associated with right caudal anterior cingulate U-fiber volume, linking cingulate motor areas with neighboring gyri. Aberrant development in U-fiber volume of the right posterior cingulate gyrus may underlie functional abnormalities found in this region, such as in the default mode network.

Transient states of network connectivity are atypical in autism: A dynamic functional connectivity study.

There is ample evidence of atypical functional connectivity (FC) in autism spectrum disorders (ASDs). However, transient relationships between neural networks cannot be captured by conventional static FC analyses. Dynamic FC (dFC) approaches have been used to identify repeating, transient connectivity patterns ("states"), revealing spatiotemporal network properties not observable in static FC. Recent studies have found atypical dFC in ASDs, but questions remain about the nature of group differences in transient connectivity, and the degree to which states persist or change over time. This study aimed to: (a) describe and relate static and dynamic FC in typical development and ASDs, (b) describe group differences in transient states and compare them with static FC patterns, and (c) examine temporal stability and flexibility between identified states. Resting-state functional magnetic resonance imaging (fMRI) data were collected from 62 ASD and 57 typically developing (TD) children and adolescents. Whole-brain, data-driven regions of interest were derived from group independent component analysis. Sliding window analysis and k-means clustering were used to explore dFC and identify transient states. Across all regions, static overconnnectivity and increased variability over time in ASDs predominated. Furthermore, significant patterns of group differences emerged in two transient states that were not observed in the static FC matrix, with group differences in one state primarily involving sensory and motor networks, and in the other involving higher-order cognition networks. Default mode network segregation was significantly reduced in ASDs in both states. Results highlight that dynamic approaches may reveal more nuanced transient patterns of atypical FC in ASDs.

Local Cortical Gyrification is Increased in Children With Autism Spectrum Disorders, but Decreases Rapidly in Adolescents.

Extensive MRI evidence indicates early brain overgrowth in autism spectrum disorders (ASDs). Local gyrification may reflect the distribution and timing of aberrant cortical expansion in ASDs. We examined MRI data from (Study 1) 64 individuals with ASD and 64 typically developing (TD) controls (7-19 years), and from (Study 2) an independent sample from the Autism Brain Imaging Data Exchange (n = 31/group). Local Gyrification Index (lGI), cortical thickness (CT), and surface area (SA) were measured. In Study 1, differences in lGI (ASD > TD) were found in left parietal and temporal and right frontal and temporal regions. lGI decreased bilaterally with age, but more steeply in ASD in left precentral, right lateral occipital, and middle frontal clusters. CT differed between groups in right perisylvian cortex (TD > ASD), but no differences were found for SA. Partial correlations between lGI and CT were generally negative, but associations were weaker in ASD in several clusters. Study 2 results were consistent, though less extensive. Altered gyrification may reflect unique information about the trajectory of cortical development in ASDs. While early overgrowth tends to be undetectable in later childhood in ASDs, findings may indicate that a trace of this developmental abnormality could remain in a disorder-specific pattern of gyrification.

Atypical Local and Distal Patterns of Occipito-frontal Functional Connectivity are Related to Symptom Severity in Autism.

Autism spectrum disorders (ASDs) are increasingly prevalent neurodevelopmental disorders characterized by sociocommunicative impairments. Growing consensus indicates that neurobehavioral abnormalities require explanation in terms of interconnected networks. Despite theoretical speculations about increased local and reduced distal connectivity, links between local and distal functional connectivity have not been systematically investigated in ASDs. Specifically, it remains open whether hypothesized local overconnectivity may reflect isolated versus overly integrative processing. Resting state functional MRI data from 57 children and adolescents with ASDs and 51 typically developing (TD) participants were included. In regional homogeneity (ReHo) analyses, pericalcarine visual cortex was found be locally overconnected (ASD > TD). Using this region as seed in whole-brain analyses, we observed overconnectivity in distal regions, specifically middle frontal gyri, for an ASD subgroup identified through k-means clustering. While in this subgroup local occipital to distal frontal overconnectivity was associated with greater symptom severity, a second subgroup showed the opposite pattern of connectivity and symptom severity correlations. Our findings suggest that increased local connectivity in ASDs is region-specific and may be partially associated with more integrative long-distance connectivity. Results also highlight the need to test for subtypes, as differential patterns of brain-behavior links were observed in two distinct subgroups of our ASD cohort.

Distinct Patterns of Atypical Functional Connectivity in Lower-Functioning Autism.

BACKGROUND: Functional magnetic resonance imaging research on autism spectrum disorders (ASDs) has been largely limited to individuals with near-average intelligence. Although cognitive impairment is common in ASDs, functional network connectivity in this population remains poorly understood. Specifically, it remains unknown whether lower-functioning individuals exhibit exacerbated connectivity abnormalities similar to those previously detected in higher-functioning samples or specific divergent patterns of connectivity. METHODS: Resting-state functional magnetic resonance imaging data from 88 children (44 ASD, 44 typically developing; average age: 11 years) were included. Based on IQ, individuals with ASDs were assigned to either a lower-functioning group (mean IQ = 77 ± 6) or a higher-functioning group (mean IQ = 123 ± 8). Two typically developing comparison groups were matched to these groups on head motion, handedness, and age. Seeds in the medial prefrontal cortex, posterior cingulate cortex, posterior superior temporal sulcus, insula, and amygdala were used to contrast whole-brain functional connectivity across groups. RESULTS: Lower-functioning ASD participants (compared with higher-functioning ASD participants) showed significant underconnectivity within the default mode network and the ventral visual stream. Higher-functioning ASD participants (compared with matched typically developing participants) showed significantly decreased anticorrelations among default mode, salience, and task-positive regions. Effect sizes of detected differences were large (Cohen's d > 1.46). CONCLUSIONS: Lower- and higher-functioning individuals with ASDs demonstrated distinct patterns of atypical connectivity. Findings suggest a gross pattern of predominantly reduced network integration in lower-functioning ASDs (affecting default mode and visual networks) and predominantly reduced network segregation in higher-functioning ASDs. Results indicate the need for stratification by general functional level in studies of functional connectivity in ASDs.

Brain Connectivity and Neuroimaging of Social Networks in Autism.

Impairments in social communication (SC) predominate among the core diagnostic features of autism spectrum disorders (ASDs). Neuroimaging has revealed numerous findings of atypical activity and connectivity of 'social brain' networks, yet no consensus view on crucial developmental causes of SC deficits has emerged. Aside from methodological challenges, the deeper problem concerns the clinical label of ASD. While genetic studies have not comprehensively explained the causes of nonsyndromic ASDs, they highlight that the clinical label encompasses many etiologically different disorders. The question of how potential causes and etiologies converge onto a comparatively narrow set of SC deficits remains. Only neuroimaging designs searching for subtypes within ASD cohorts (rather than conventional group level designs) can provide translationally informative answers.