Salience network connectivity is altered in 6-week-old infants at heightened likelihood for developing autism.

Converging evidence implicates disrupted brain connectivity in autism spectrum disorder (ASD); however, the mechanisms linking altered connectivity early in development to the emergence of ASD symptomatology remain poorly understood. Here we examined whether atypicalities in the Salience Network - an early-emerging neural network involved in orienting attention to the most salient aspects of one's internal and external environment - may predict the development of ASD symptoms such as reduced social attention and atypical sensory processing. Six-week-old infants at high likelihood of developing ASD based on family history exhibited stronger Salience Network connectivity with sensorimotor regions; infants at typical likelihood of developing ASD demonstrated stronger Salience Network connectivity with prefrontal regions involved in social attention. Infants with higher connectivity with sensorimotor regions had lower connectivity with prefrontal regions, suggesting a direct tradeoff between attention to basic sensory versus socially-relevant information. Early alterations in Salience Network connectivity predicted subsequent ASD symptomatology, providing a plausible mechanistic account for the unfolding of atypical developmental trajectories associated with vulnerability to ASD.

Attention Allocation During Exploration of Visual Arrays in ASD: Results from the ABC-CT Feasibility Study.

Visual exploration paradigms involving object arrays have been used to examine salience of social stimuli such as faces in ASD. Recent work suggests performance on these paradigms may associate with clinical features of ASD. We evaluate metrics from a visual exploration paradigm in 4-to-11-year-old children with ASD (n = 23; 18 males) and typical development (TD; n = 23; 13 males). Presented with arrays containing faces and nonsocial stimuli, children with ASD looked less at (p = 0.002) and showed fewer fixations to (p = 0.022) faces than TD children, and spent less time looking at each object on average (p = 0.004). Attention to the screen and faces correlated positively with social and cognitive skills in the ASD group (ps < .05). This work furthers our understanding of objective measures of visual exploration in ASD and its potential for quantifying features of ASD.

Atypical cerebellar functional connectivity at 9 months of age predicts delayed socio-communicative profiles in infants at high and low risk for autism.

BACKGROUND: While the cerebellum is traditionally known for its role in sensorimotor control, emerging research shows that particular subregions, such as right Crus I (RCrusI), support language and social processing. Indeed, cerebellar atypicalities are commonly reported in autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by socio-communicative impairments. However, the cerebellum's contribution to early socio-communicative development remains virtually unknown. METHODS: Here, we characterized functional connectivity within cerebro-cerebellar networks implicated in language/social functions in 9-month-old infants who exhibit distinct 3-year socio-communicative developmental profiles. We employed a data-driven clustering approach to stratify our sample of infants at high (n = 82) and low (n = 37) familial risk for ASD into three cohorts-Delayed, Late-Blooming, and Typical-who showed unique socio-communicative trajectories. We then compared the cohorts on indices of language and social development. Seed-based functional connectivity analyses with RCrusI were conducted on infants with fMRI data (n = 66). Cohorts were compared on connectivity estimates from a-priori regions, selected on the basis of reported coactivation with RCrusI during language/social tasks. RESULTS: The three trajectory-based cohorts broadly differed in social communication development, as evidenced by robust differences on numerous indices of language and social skills. Importantly, at 9 months, the cohorts showed striking differences in cerebro-cerebellar circuits implicated in language/social functions. For all regions examined, the Delayed cohort exhibited significantly weaker RCrusI connectivity compared to both the Late-Blooming and Typical cohorts, with no significant differences between the latter cohorts. CONCLUSIONS: We show that hypoconnectivity within distinct cerebro-cerebellar networks in infancy predicts altered socio-communicative development before delays overtly manifest, which may be relevant for early detection and intervention. As the cerebellum is implicated in prediction, our findings point to probabilistic learning as a potential intermediary mechanism that may be disrupted in infancy, cascading into alterations in social communication.

Altered Thalamocortical Connectivity in 6-Week-Old Infants at High Familial Risk for Autism Spectrum Disorder.

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here, we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and low-risk controls (LR). Resting-state functional connectivity and diffusion tensor imaging data were acquired in 52 6-week-old infants. Functional connectivity was examined between 6 cortical seeds-prefrontal, motor, somatosensory, temporal, parietal, and occipital regions-and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared with LR infants. Notably, aberrant connectivity indices at 6 weeks predicted atypical social development between 9 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as 6 weeks of age, providing a possible early marker of risk for ASD.

Visual Traces of Language Acquisition in Toddlers with Autism Spectrum Disorder During the Second Year of Life.

Infants show shifting patterns of visual engagement to faces over the first years of life. To explore the adaptive implications of this engagement, we collected eye-tracking measures on cross-sectional samples of 10-25-month-old typically developing toddlers (TD;N = 28) and those with autism spectrum disorder (ASD;N = 54). Concurrent language assessments were conducted and relationships between visual engagement and expressive and receptive language were analyzed between groups, and within ASD subgroups. TD and ASD toddlers exhibited greater mouth- than eye-looking, with TD exhibiting higher levels of mouth-looking than ASD. Mouth-looking was positively associated with expressive language in TD toddlers, and in ASD toddlers who had acquired first words. Mouth-looking was unrelated to expressive language in ASD toddlers who had not yet acquired first words.

Lack of neural evidence for implicit language learning in 9-month-old infants at high risk for autism.

Word segmentation is a fundamental aspect of language learning, since identification of word boundaries in continuous speech must occur before the acquisition of word meanings can take place. We previously used functional magnetic resonance imaging (fMRI) to show that youth with autism spectrum disorder (ASD) are less sensitive to statistical and speech cues that guide implicit word segmentation. However, little is known about the neural mechanisms underlying this process during infancy and how this may be associated with ASD risk. Here, we examined early neural signatures of language-related learning in 9-month-old infants at high (HR) and low familial risk (LR) for ASD. During natural sleep, infants underwent fMRI while passively listening to three speech streams containing strong statistical and prosodic cues, strong statistical cues only, or minimal statistical cues to word boundaries. Compared to HR infants, LR infants showed greater activity in the left amygdala for the speech stream containing statistical and prosodic cues. While listening to this same speech stream, LR infants also showed more learning-related signal increases in left temporal regions as well as increasing functional connectivity between bilateral primary auditory cortex and right anterior insula. Importantly, learning-related signal increases at 9 months positively correlated with expressive language outcome at 36 months in both groups. In the HR group, greater signal increases were additionally associated with less severe ASD symptomatology at 36 months. These findings suggest that early differences in the neural networks underlying language learning may predict subsequent language development and altered trajectories associated with ASD risk.

Distinct Patterns of Neural Habituation and Generalization in Children and Adolescents With Autism With Low and High Sensory Overresponsivity.

OBJECTIVE: Sensory overresponsivity (SOR), an atypical negative reaction to sensory stimuli, is highly prevalent in autism spectrum disorder (ASD). Previous work has related SOR to increased brain response in sensory-limbic regions. This study investigated where these atypical responses fall in three fundamental stages of sensory processing: arousal (i.e., initial response), habituation (i.e., change in response over time), and generalization of response to novel stimuli. Different areas of atypical response would require distinct intervention approaches. METHODS: Functional MRI was used to examine these patterns of neural habituation to two sets of similar mildly aversive auditory and tactile stimuli in 42 high-functioning children and adolescents with ASD (21 with high levels of SOR and 21 with low levels of SOR) and 27 age-matched typically developing youths (ages 8-17). The relationship between SOR and change in amygdala-prefrontal functional connectivity across the sensory stimulation was also examined. RESULTS: Across repeated sensory stimulation, high-SOR participants with ASD showed reduced ability to maintain habituation in the amygdala and relevant sensory cortices and to maintain inhibition of irrelevant sensory cortices. These results indicate that sensory habituation is a dynamic, time-varying process dependent on sustained regulation across time, which is a particular deficit in high-SOR participants with ASD. However, low-SOR participants with ASD also showed distinct, nontypical neural response patterns, including reduced responsiveness to novel but similar stimuli and increases in prefrontal-amygdala regulation across the sensory exposure. CONCLUSIONS: The results suggest that all children with autism have atypical brain responses to sensory stimuli, but whether they express atypical behavioral responses depends on top-down regulatory mechanisms. Results are discussed in terms of targeted intervention approaches.

Social complexity and the early social environment affect visual social attention to faces.

Diminished attention to socially relevant information appears to be an early emerging risk factor associated with autism spectrum disorders (ASD). However, inconsistencies across studies suggest that atypicalities in visual social attention in infants at high-risk for ASD during the first postnatal year may be subtle and more apparent under certain contexts. Here we explore factors that may moderate developmental trajectories in attention to faces, including the social complexity of the dynamic visual stimuli used to measure visual social attention and the early social environment of the infant as indexed by parental affectedness of ASD-related traits. Across infants at both high (HR) and low risk for ASD, attention to faces increased during the first postnatal year, with overall greater attention being allocated to schematic faces in the simpler video stimulus. Moreover, greater parental affectedness of ASD-related traits was associated with reduced developmental gains in attention to faces. For HR infants, greater attention to faces was positively associated with social communicative competence, including better joint attention skills and lower social impairments. Altogether, our findings highlight the importance of considering developmental level when selecting stimuli to longitudinally examine visual social attention, and the clinical relevance of including measures of infant's social environment in understanding early markers of ASD risk. Autism Res 2019, 12: 445-457 © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Attention to faces is an important means for infants to learn about the social world. The complexity of the social scene and an infant's early social environment both affect the amount of time infants at high- and low-risk for ASD look at faces during the first postnatal year. For infants at high-risk for ASD, greater attention to faces was associated with better social skills. Understanding an infant's social environment may have a positive impact on social communicative development.

Real-world scene perception in infants: What factors guide attention allocation?

The foci of visual attention were modeled as a function of perceptual salience, adult fixation locations, and attentional control mechanisms (measured in separate tasks) in infants (N = 45, 3- to 15-month-olds) as they viewed static real-world scenes. After controlling for the center bias, the results showed that low-level perceptual salience predicts where infants look. In addition, high-level factors also played a role: Infants fixated parts of the scenes frequently fixated by adults and this effect was stronger for older than younger infants. In line with this finding, infant fixation durations were longer on regions more frequently fixated by adults, implying longer time taken to process the available information. Fixation durations decreased with age, and this decline interacted with orienting skills such that fixation durations decreased faster with age for infants with high orienting skills, relative to infants with low orienting skills. There was a further interaction between fixation durations and selective attention abilities: Infants with low selective attention skills showed a decrease in fixation durations with age, whereas infants with higher selective attention skills showed a slight increase in fixation durations with age. These findings imply that infants' visual processing of static real-world stimuli develops in accord with attentional control.

Altered lateralization of dorsal language tracts in 6-week-old infants at risk for autism.

Altered structural connectivity has been identified as a possible biomarker of autism spectrum disorder (ASD) risk in the developing brain. Core features of ASD include impaired social communication and early language delay. Thus, examining white matter tracts associated with language may lend further insight into early signs of ASD risk and the mechanisms that underlie language impairments associated with the disorder. Evidence of altered structural connectivity has previously been detected in 6-month-old infants at high familial risk for developing ASD. However, as language processing begins in utero, differences in structural connectivity between language regions may be present in the early infant brain shortly after birth. Here we investigated key white matter pathways of the dorsal language network in 6-week-old infants at high (HR) and low (LR) risk for ASD to identify atypicalities in structural connectivity that may predict altered developmental trajectories prior to overt language delays and the onset of ASD symptomatology. Compared to HR infants, LR infants showed higher fractional anisotropy (FA) in the left superior longitudinal fasciculus (SLF); in contrast, in the right SLF, HR infants showed higher FA than LR infants. Additionally, HR infants showed more rightward lateralization of the SLF. Across both groups, measures of FA and lateralization of these pathways at 6 weeks of age were related to later language development at 18 months of age as well as ASD symptomatology at 36 months of age. These findings indicate that early differences in the structure of language pathways may provide an early predictor of future language development and ASD risk.

Infant perception of sex differences in biological motion displays.

We examined mechanisms underlying infants' ability to categorize human biological motion stimuli from sex-typed walk motions, focusing on how visual attention to dynamic information in point-light displays (PLDs) contributes to infants' social category formation. We tested for categorization of PLDs produced by women and men by habituating infants to a series of female or male walk motions and then recording posthabituation preferences for new PLDs from the familiar or novel category (Experiment 1). We also tested for intrinsic preferences for female or male walk motions (Experiment 2). We found that infant boys were better able to categorize PLDs than were girls and that male PLDs were preferred overall. Neither of these effects was found to change with development across the observed age range (∼4-18 months). We conclude that infants' categorization of walk motions in PLDs is constrained by intrinsic preferences for higher motion speeds and higher spans of motion and, relatedly, by differences in walk motions produced by men and women.

Selective attention to the mouth is associated with expressive language skills in monolingual and bilingual infants.

Infants increasingly attend to the mouths of others during the latter half of the first postnatal year, and individual differences in selective attention to talking mouths during infancy predict verbal skills during toddlerhood. There is some evidence suggesting that trajectories in mouth-looking vary by early language environment, in particular monolingual or bilingual language exposure, which may have differential consequences in developing sensitivity to the communicative and social affordances of the face. Here, we evaluated whether 6- to 12-month-olds' mouth-looking is related to skills associated with concurrent social communicative development-including early language functioning and emotion discriminability. We found that attention to the mouth of a talking face increased with age but that mouth-looking was more strongly associated with concurrent expressive language skills than chronological age for both monolingual and bilingual infants. Mouth-looking was not related to emotion discrimination. These data suggest that selective attention to a talking mouth may be one important mechanism by which infants learn language regardless of home language environment.

Theory of Mind Indexes the Broader Autism Phenotype in Siblings of Children with Autism at School Age.

Subclinical variants of the social-communicative challenges and rigidity that define autism spectrum disorder (ASD) are known as the broader autism phenotype (BAP). The BAP has been conceptualized categorically (as specific to a subset of relatives of individuals with ASD) and dimensionally (as continuously distributed within the general population). The current study examined the compatibility of these two approaches by assessing associations among autism symptoms and social-communicative skills in young school-age children with ASD, children who have a sibling with ASD, and children without a sibling with ASD. Autism symptoms were associated with reduced Theory of Mind (ToM), adaptive skills, cognitive empathy, and language skills across the full sample. Reduced ToM was a core aspect of the BAP in the current sample regardless of whether the BAP was defined categorically (in terms of siblings of children with ASD who exhibited atypical developmental) or dimensionally (in terms of associations with autism symptoms across the entire sample). Early language skills predicted school-age ToM. Findings support the compatibility of categorical and dimensional approaches to the BAP, highlight reduced ToM as a core aspect of the school-age BAP, and suggest that narrative-based approaches to promoting ToM may be beneficial for siblings of children with ASD.

Does bilingual experience affect early visual perceptual development?

Visual attention and perception develop rapidly during the first few months after birth, and these behaviors are critical components in the development of language and cognitive abilities. Here we ask how early bilingual experiences might lead to differences in visual attention and perception. Experiments 1-3 investigated the looking behavior of monolingual and bilingual infants when presented with social (Experiment 1), mixed (Experiment 2), or non-social (Experiment 3) stimuli. In each of these experiments, infants' dwell times (DT) and number of fixations to areas of interest (AOIs) were analyzed, giving a sense of where the infants looked. To examine how the infants looked at the stimuli in a more global sense, Experiment 4 combined and analyzed the saccade data collected in Experiments 1-3. There were no significant differences between monolingual and bilingual infants' DTs, AOI fixations, or saccade characteristics (specifically, frequency, and amplitude) in any of the experiments. These results suggest that monolingual and bilingual infants process their visual environments similarly, supporting the idea that the substantial cognitive differences between monolinguals and bilinguals in early childhood are more related to active vocabulary production than perception of the environment.