White matter development and language abilities during infancy in autism spectrum disorder.

White matter (WM) fiber tract differences are present in autism spectrum disorder (ASD) and could be important markers of behavior. One of the earliest phenotypic differences in ASD are language atypicalities. Although language has been linked to WM in typical development, no work has evaluated this association in early ASD. Participants came from the Infant Brain Imaging Study and included 321 infant siblings of children with ASD at high likelihood (HL) for developing ASD; 70 HL infants were later diagnosed with ASD (HL-ASD), and 251 HL infants were not diagnosed with ASD (HL-Neg). A control sample of 140 low likelihood infants not diagnosed with ASD (LL-Neg) were also included. Infants contributed expressive language, receptive language, and diffusion tensor imaging data at 6-, 12-, and 24 months. Mixed effects regression models were conducted to evaluate associations between WM and language trajectories. Trajectories of microstructural changes in the right arcuate fasciculus were associated with expressive language development. HL-ASD infants demonstrated a different developmental pattern compared to the HL-Neg and LL-Neg groups, wherein the HL-ASD group exhibited a positive association between WM fractional anisotropy and language whereas HL-Neg and LL-Neg groups showed weak or no association. No other fiber tracts demonstrated significant associations with language. In conclusion, results indicated arcuate fasciculus WM is linked to language in early toddlerhood for autistic toddlers, with the strongest associations emerging around 24 months. To our knowledge, this is the first study to evaluate associations between language and WM development during the pre-symptomatic period in ASD.

Atypical functional connectivity between the amygdala and visual, salience regions in infants with genetic liability for autism.

The amygdala undergoes a period of overgrowth in the first year of life, resulting in enlarged volume by 12 months in infants later diagnosed with ASD. The overgrowth of the amygdala may have functional consequences during infancy. We investigated whether amygdala connectivity differs in 12-month-olds at high likelihood (HL) for ASD (defined by having an older sibling with autism), compared to those at low likelihood (LL). We examined seed-based connectivity of left and right amygdalae, hypothesizing that the HL and LL groups would differ in amygdala connectivity, especially with the visual cortex, based on our prior reports demonstrating that components of visual circuitry develop atypically and are linked to genetic liability for autism. We found that HL infants exhibited weaker connectivity between the right amygdala and the left visual cortex, as well as between the left amygdala and the right anterior cingulate, with evidence that these patterns occur in distinct subgroups of the HL sample. Amygdala connectivity strength with the visual cortex was related to motor and communication abilities among HL infants. Findings indicate that aberrant functional connectivity between the amygdala and visual regions is apparent in infants with genetic liability for ASD and may have implications for early differences in adaptive behaviors.

White matter connectivity and social functioning in survivors of pediatric brain tumor.

OBJECTIVE: Survivors of pediatric brain tumors (SPBT) are at risk for social deficits, fewer friendships, and poor peer relations. SPBT also experience reduced brain connectivity via microstructural disruptions to white matter from neurological insults. Research with other populations implicates white matter connectivity as a key contributor to poor social functioning. This case-controlled diffusion-weighted imaging study evaluated structural connectivity in SPBT and typically developing controls (TDC) and associations between metrics of connectivity and social functioning. METHODS: Diffusion weighted-imaging results from 19 SPBT and 19 TDC were analyzed using probabilistic white matter tractography. Survivors were at least 5 years post-diagnosis and 2 years off treatment. Graph theory statistics measured group differences across several connectivity metrics, including average strength, global efficiency, assortativity, clustering coefficient, modularity, and betweenness centrality. Analyses also evaluated the effects of neurological risk on connectivity among SPBT. Correlational analyses evaluated associations between connectivity and indices of social behavior. RESULTS: SPBT demonstrated reduced global connectivity compared to TDC. Several medical factors (e.g., chemotherapy, recurrence, multimodal therapy) were related to decreased connectivity across metrics of integration (e.g., average strength, global efficiency) in SPBT. Connectivity metrics were related to peer relationship quality and social challenges in the SPBT group and to social challenges in the total sample. CONCLUSIONS: Microstructural white matter connectivity is diminished in SPBT and related to neurological risk and peer relationship quality. Additional neuroimaging research is needed to evaluate associations between brain connectivity metrics and social functioning in SPBT.

Social impairment in survivors of pediatric brain tumors via reduced social attention and emotion-specific facial expression recognition.

BACKGROUND/OBJECTIVES: Survivors of pediatric brain tumors (SPBT) experience significant social challenges, including fewer friends and greater isolation than peers. Difficulties in face processing and visual social attention have been implicated in these outcomes. This study evaluated facial expression recognition (FER), social attention, and their associations with social impairments in SPBT. METHODS: SPBT (N = 54; ages 7-16) at least 2 years post treatment completed a measure of FER, while parents completed measures of social impairment. A subset (N = 30) completed a social attention assessment that recorded eye gaze patterns while watching videos depicting pairs of children engaged in joint play. Social Prioritization scores were calculated, with higher scores indicating more face looking. Correlations and regression analyses evaluated associations between variables, while a path analysis modeling tool (PROCESS) evaluated the indirect effects of Social Prioritization on social impairments through emotion-specific FER. RESULTS: Poorer recognition of angry and sad facial expressions was significantly correlated with greater social impairment. Social Prioritization was positively correlated with angry FER but no other emotions. Social Prioritization had significant indirect effects on social impairments through angry FER. CONCLUSION: Findings suggest interventions aimed at improving recognition of specific emotions may mitigate social impairments in SPBT. Further, reduced social attention (i.e., diminished face looking) could be a factor in reduced face processing ability, which may result in social impairments. Longitudinal research is needed to elucidate temporal associations between social attention, face processing, and social impairments.

Quantifying latent social motivation and its associations with joint attention and language in infants at high and low likelihood for autism spectrum disorder.

Social motivation-the psychobiological predisposition for social orienting, seeking social contact, and maintaining social interaction-manifests in early infancy and is hypothesized to be foundational for social communication development in typical and atypical populations. However, the lack of infant social-motivation measures has hindered delineation of associations between infant social motivation, other early-arising social abilities such as joint attention, and language outcomes. To investigate how infant social motivation contributes to joint attention and language, this study utilizes a mixed longitudinal sample of 741 infants at high (HL = 515) and low (LL = 226) likelihood for ASD. Using moderated nonlinear factor analysis (MNLFA), we incorporated items from parent-report measures to establish a novel latent factor model of infant social motivation that exhibits measurement invariance by age, sex, and familial ASD likelihood. We then examined developmental associations between 6- and 12-month social motivation, joint attention at 12-15 months, and language at 24 months of age. On average, greater social-motivation growth from 6-12 months was associated with greater initiating joint attention (IJA) and trend-level increases in sophistication of responding to joint attention (RJA). IJA and RJA were both positively associated with 24-month language abilities. There were no additional associations between social motivation and future language in our path model. These findings substantiate a novel, theoretically driven approach to modeling social motivation and suggest a developmental cascade through which social motivation impacts other foundational skills. These findings have implications for the timing and nature of intervention targets to support social communication development in infancy. HIGHLIGHTS: We describe a novel, theoretically based model of infant social motivation wherein multiple parent-reported indicators contribute to a unitary latent social-motivation factor. Analyses revealed social-motivation factor scores exhibited measurement invariance for a longitudinal sample of infants at high and low familial ASD likelihood. Social-motivation growth from ages 6-12 months is associated with better 12-15-month joint attention abilities, which in turn are associated with greater 24-month language skills. Findings inform timing and targets of potential interventions to support healthy social communication in the first year of life.

Early brain development in infants at high risk for autism spectrum disorder.

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6-12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

Reduced Fusiform Gyrus Activation During Face Processing in Pediatric Brain Tumor Survivors.

OBJECTIVE: The neural mechanisms contributing to the social problems of pediatric brain tumor survivors (PBTS) are unknown. Face processing is important to social communication, social behavior, and peer acceptance. Research with other populations with social difficulties, namely autism spectrum disorder, suggests atypical brain activation in areas important for face processing. This case-controlled functional magnetic resonance imaging (fMRI) study compared brain activation during face processing in PBTS and typically developing (TD) youth. METHODS: Participants included 36 age-, gender-, and IQ-matched youth (N = 18 per group). PBTS were at least 5 years from diagnosis and 2 years from the completion of tumor therapy. fMRI data were acquired during a face identity task and a control condition. Groups were compared on activation magnitude within the fusiform gyrus for the faces condition compared to the control condition. Correlational analyses evaluated associations between neuroimaging metrics and indices of social behavior for PBTS participants. RESULTS: Both groups demonstrated face-specific activation within the social brain for the faces condition compared to the control condition. PBTS showed significantly decreased activation for faces in the medial portions of the fusiform gyrus bilaterally compared to TD youth, ps ≤ .004. Higher peak activity in the left fusiform gyrus was associated with better socialization (r = .53, p < .05). CONCLUSIONS: This study offers initial evidence of atypical activation in a key face processing area in PBTS. Such atypical activation may underlie some of the social difficulties of PBTS. Social cognitive neuroscience methodologies may elucidate the neurobiological bases for PBTS social behavior.

Examining the factor structure and discriminative utility of the Infant Behavior Questionnaire-Revised in infant siblings of autistic children.

Using the Infant Behavior Questionnaire-Revised in a longitudinal sample of infant siblings of autistic children (HR; n = 427, 171 female, 83.4% White) and a comparison group of low-risk controls (LR, n = 200, 86 female, 81.5% White), collected between 2007 and 2017, this study identified an invariant factor structure of temperament traits across groups at 6 and 12 months. Second, after partitioning the groups by familial risk and diagnostic outcome at 24 months, results reveal an endophenotypic pattern of Positive Emotionality at both 6 and 12 months, (HR-autism spectrum disorder [ASD] < HR-no-ASD < LR). Third, increased 'Duration of Orienting' at 12 months was associated with lower scores on the 24-month developmental outcomes in HR infants. These findings may augment efforts for early identification of ASD.

Infant vocalizing and phenotypic outcomes in autism: Evidence from the first 2 years.

Infant vocalizations are early-emerging communicative markers shown to be atypical in autism spectrum disorder (ASD), but few longitudinal, prospective studies exist. In this study, 23,850 infant vocalizations from infants at low (LR)- and high (HR)-risk for ASD (HR-ASD = 23, female = 3; HR-Neg = 35, female = 13; LR = 32, female = 10; 80% White; collected from 2007 to 2017 near Philadelphia) were analyzed at 6, 12, and 24 months. At 12 months, HR-ASD infants produced fewer vocalizations than HR-Neg infants. From 6 to 24 months, HR-Neg infants demonstrated steeper vocalization growth compared to HR-ASD and LR infants. Finally, among HR infants, vocalizing at 12 months was associated with language, social phenotype, and diagnosis at age 2. Infant vocalizing is an objective behavioral marker that could facilitate earlier detection of ASD.

Social motivation in infancy is associated with familial recurrence of ASD.

Pre-diagnostic deficits in social motivation are hypothesized to contribute to autism spectrum disorder (ASD), a heritable neurodevelopmental condition. We evaluated psychometric properties of a social motivation index (SMI) using parent-report item-level data from 597 participants in a prospective cohort of infant siblings at high and low familial risk for ASD. We tested whether lower SMI scores at 6, 12, and 24 months were associated with a 24-month ASD diagnosis and whether social motivation's course differed relative to familial ASD liability. The SMI displayed good internal consistency and temporal stability. Children diagnosed with ASD displayed lower mean SMI T-scores at all ages and a decrease in mean T-scores across age. Lower group-level 6-month scores corresponded with higher familial ASD liability. Among high-risk infants, strong decline in SMI T-scores was associated with 10-fold odds of diagnosis. Infant social motivation is quantifiable by parental report, differentiates children with versus without later ASD by age 6 months, and tracks with familial ASD liability, consistent with a diagnostic and susceptibility marker of ASD. Early decrements and decline in social motivation indicate increased likelihood of ASD, highlighting social motivation's importance to risk assessment and clarification of the ontogeny of ASD.