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.

Associations between early trajectories of amygdala development and later school-age anxiety in two longitudinal samples.

Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6-12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In the IBIS sample, children with higher anxiety showed accelerated amygdala growth from 6 to 24 months. ASD diagnosis and ASD familial likelihood were not significant predictors. In the EBDS sample, amygdala growth from birth to 24 months was associated with anxiety. More anxious children had smaller amygdala volume and slower rates of amygdala growth. We explore reasons for the contrasting results between high-familial likelihood for ASD and TD samples, grounding results in the broader literature of variable associations between early amygdala volume and later anxiety. Results have the potential to identify mechanisms linking early amygdala growth to later anxiety in certain groups.

A somato-cognitive action network alternates with effector regions in motor cortex.

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

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.

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.

A Data-Driven Approach in an Unbiased Sample Reveals Equivalent Sex Ratio of Autism Spectrum Disorder-Associated Impairment in Early Childhood.

BACKGROUND: Sex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD. METHODS: We conducted direct assessments of ASD symptoms at 6 to 9, 12 to 15, 24, and 36 to 60 months of age (total nobservations = 1254) with infant siblings of children with ASD (n = 377) and a lower ASD-familial-likelihood comparison group (n = 168; nobservations = 527). We established measurement invariance across age and sex for separate models of SC and RRB. We then conducted latent class growth mixture modeling with the longitudinal data and evaluated for sex differences in trajectory membership. RESULTS: We identified 2 latent classes in the SC and RRB models with equal sex ratios in the high-concern cluster for both SC and RRB. Sex differences were also observed in the SC high-concern cluster, indicating that girls classified as having elevated social concerns demonstrated milder symptoms than boys in this group. CONCLUSIONS: This novel approach for characterizing ASD symptom progression highlights the utility of assessing and adjusting for sex-related measurement bias and identifying sex-specific patterns of symptom emergence.

Infant Visual Brain Development and Inherited Genetic Liability in Autism.

OBJECTIVE: Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings. METHODS: In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months. RESULTS: Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy. CONCLUSIONS: The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.

Variability in Responding to Joint Attention Cues in the First Year is Associated With Autism Outcome.

OBJECTIVE: With development, infants become increasingly responsive to the many attention-sharing cues of adults; however, little work has examined how this ability emerges in typical development or in the context of early autism spectrum disorder (ASD). This study characterized variation in the type of cue needed to elicit a response to joint attention (RJA) using the Dimensional Joint Attention Assessment (DJAA) during naturalistic play. METHOD: We measured the average redundancy of cue type required for infants to follow RJA bids from an experimenter, as well as their response consistency, in 268 infants at high (HR, n = 68) and low (LR, N = 200) familial risk for ASD. Infants were assessed between 8 and 18 months of age and followed up with developmental and clinical assessments at 24 or 36 months. Our sample consisted of LR infants, as well as HR infants who did (HR-ASD) and did not (HR-neg) develop ASD at 24 months. RESULTS: We found that HR and LR infants developed abilities to respond to less redundant (more sophisticated) RJA cues at different rates, and that HR-ASD infants displayed delayed abilities, identifiable as early as 9 months, compared to both HR-neg and LR infants. Interestingly, results suggest that HR-neg infants may exhibit a propensity to respond to less redundant (more sophisticated) RJA cues relative to both HR-ASD and LR infants. CONCLUSION: Using an approach to characterize variable performance of RJA cue-reading abilities, findings from this study enhance our understanding of both typical and ASD-related proficiencies and deficits in RJA development.

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.

Cataloguing and characterizing interests in typically developing toddlers and toddlers who develop ASD.

Intense interests are common in children with and without autism spectrum disorder (ASD), and little research has characterized aspects of interests that are unique to or shared among children with and without ASD. We aimed to characterize interests in a sample of infants at high-familial-risk (HR) and low-familial-risk (LR) for ASD using a novel interview. Participants included HR siblings who were diagnosed with ASD at 24 months (HR-ASD, n = 56), HR siblings who did not receive an ASD diagnosis at 24 months (HR-Neg, n = 187), and a LR comparison group (n = 109). We developed and collected data with the Intense Interests Inventory at 18- and 24-months of age, a semi-structured interview that measures intensity and peculiarity of interests in toddlers and preschool-aged children. Intensity of interests differed by familial risk at 24 months, with HR-ASD and HR-Neg groups demonstrating equivalent intensity of interests that were higher than the LR group. By contrast, peculiarity of interest differed by ASD diagnosis, with the HR-ASD group showing more peculiar interests than the HR-Neg and LR groups at 24 months. At 18 months the HR-ASD group had more peculiar interests than the LR group, though no differences emerged in intensity of interests. This measure may be useful in identifying clinically-relevant features of interests in young children with ASD. We also replicated previous findings of males showing more intense interests at 18 months in our non-ASD sample. These results reveal new information about the nature of interests and preoccupations in the early autism phenotype. LAY SUMMARY: Intense interests are common in young children with autism and their family members. Intense interests are also prevalent among typically-developing children, and especially boys. Here we catalog interests and features of these interests in a large sample of toddlers enriched for autism risk. Children who had family members with autism had more intense interests, and those who developed autism themselves had more unusual interests at 24 months. These results highlight the importance of different aspects of interest in autism.

Presymptomatic Detection and Intervention for Autism Spectrum Disorder.

Universal screening for autism spectrum disorder (ASD) is recommended during pediatric primary care visits in the first 2 years of life. However, many children are missed by initial screening and not diagnosed with ASD until years later. Research efforts are underway to develop and evaluate new objective measures of risk for ASD that can be used in infancy, before symptoms emerge. Initial studies with these tests, particularly MRI-based screening for infants at high familial risk, have shown promise but have not yet been evaluated in clinical trials. We present the study design for a hypothetical clinical trial that would combine presymptomatic detection and intervention for ASD and consider, through commentaries from diverse perspectives, the ethical issues that should be anticipated in advance of beginning such trials. Commentators Drs Pruett and Piven address the social value of the proposed research and importance of researcher-bioethicist collaborations. Drs Estes and Wolff discuss the clinical potential and challenges of developing presymptomatic interventions for infants at risk for ASD. Dr Harrington takes a neurodiversity view of presymptomatic prediction and intervention and their implications for autistic identity and quality of life. Finally, Drs MacDuffie, Peay and Wilfond consider the potential risks and benefits that must be evaluated and weighed in the next phases of research on presymptomatic detection and intervention for ASD.

Diagnostic shifts in autism spectrum disorder can be linked to the fuzzy nature of the diagnostic boundary: a data-driven approach.

BACKGROUND: Diagnostic shifts at early ages may provide invaluable insights into the nature of separation between autism spectrum disorder (ASD) and typical development. Recent conceptualizations of ASD suggest the condition is only fuzzily separated from non-ASD, with intermediate cases between the two. These intermediate cases may shift along a transition region over time, leading to apparent instability of diagnosis. METHODS: We used a cohort of children with high ASD risk, by virtue of having an older sibling with ASD, assessed at 24 months (N = 212) and 36 months (N = 191). We applied machine learning to empirically characterize the classification boundary between ASD and non-ASD, using variables quantifying developmental and adaptive skills. We computed the distance of children to the classification boundary. RESULTS: Children who switched diagnostic labels from 24 to 36 months, in both directions, (dynamic group) had intermediate phenotypic profiles. They were closer to the classification boundary compared to children who had stable diagnoses, both at 24 months (Cohen's d = .52) and at 36 months (d = .75). The magnitude of change in distance between the two time points was similar for the dynamic and stable groups (Cohen's d = .06), and diagnostic shifts were not associated with a large change. At the individual level, a few children in the dynamic group showed substantial change. CONCLUSIONS: Our results suggested that a diagnostic shift was largely due to a slight movement within a transition region between ASD and non-ASD. This fact highlights the need for more vigilant surveillance and intervention strategies. Young children with intermediate phenotypes may have an increased susceptibility to gain or lose their diagnosis at later ages, calling attention to the inherently dynamic nature of early ASD diagnoses.

The Ethics of Predicting Autism Spectrum Disorder in Infancy.

Toward the end of a routine check-in appointment with your young patient-a 3-year-old boy recently diagnosed with autism spectrum disorder (ASD)-his mother shares concerns about his infant sister, currently 6 months old. The mother is aware that her daughter is at increased risk for ASD. She requests a magnetic resonance imaging (MRI) scan of her infant's brain, based on research she has read showing that MRI can be used to predict which infants will go on to develop ASD. The mother communicates that she is eager to know whether her daughter is going to develop autism so that she and her husband can prepare financially, and so she can place her daughter on the long waitlist for autism-specific services in her local community. As this family's psychiatrist, how should you respond to her request?

Brain function distinguishes female carriers and non-carriers of familial risk for autism.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by high population-level heritability and a three-to-one male-to-female ratio that occurs independent of sex linkage. Prior research in a mixed-sex pediatric sample identified neural signatures of familial risk elicited by passive viewing of point light motion displays, suggesting the possibility that both resilience and risk of autism might be associated with brain responses to biological motion. To confirm a relationship between these signatures and inherited risk of autism, we tested them in families enriched for genetic loading through undiagnosed ("carrier") females. METHODS: Using functional magnetic resonance imaging, we examined brain responses to passive viewing of point light displays-depicting biological versus non-biological motion-in a sample of undiagnosed adult females enriched for inherited susceptibility to ASD on the basis of affectation in their respective family pedigrees. Brain responses in carrier females were compared to responses in age-, SRS-, and IQ-matched non-carrier-females-i.e., females unrelated to individuals with ASD. We conducted a hypothesis-driven analysis focused on previously published regions of interest as well as exploratory, brain-wide analyses designed to characterize more fully the rich responses to this paradigm. RESULTS: We observed robust responses to biological motion. Notwithstanding, the 12 regions implicated by prior research did not exhibit the hypothesized interaction between group (carriers vs. controls) and point light displays (biological vs. non-biological motion). Exploratory, brain-wide analyses identified this interaction in three novel regions. Post hoc analyses additionally revealed significant variations in the time course of brain activation in 20 regions spanning occipital and temporal cortex, indicating group differences in response to point light displays (irrespective of the nature of motion) for exploration in future studies. LIMITATIONS: We were unable to successfully eye-track all participants, which prevented us from being able to control for potential differences in eye gaze position. CONCLUSIONS: These methods confirmed pronounced neural signatures that differentiate brain responses to biological and scrambled motion. Our sample of undiagnosed females enriched for family genetic loading enabled discovery of numerous contrasts between carriers and non-carriers of risk of ASD that may index variations in visual attention and motion processing related to genetic susceptibility and inform our understanding of mechanisms incurred by inherited liability for ASD.

Sex differences associated with corpus callosum development in human infants: A longitudinal multimodal imaging study.

The corpus callosum (CC) is the largest connective pathway in the human brain, linking cerebral hemispheres. There is longstanding debate in the scientific literature whether sex differences are evident in this structure, with many studies indicating the structure is larger in females. However, there are few data pertaining to this issue in infancy, during which time the most rapid developmental changes to the CC occur. In this study, we examined longitudinal brain imaging data collected from 104 infants at ages 6, 12, and 24 months. We identified sex differences in brain-size adjusted CC area and thickness characterized by a steeper rate of growth in males versus females from ages 6-24 months. In contrast to studies of older children and adults, CC size was larger for male compared to female infants. Based on diffusion tensor imaging data, we found that CC thickness is significantly associated with underlying microstructural organization. However, we observed no sex differences in the association between microstructure and thickness, suggesting that the role of factors such as axon density and/or myelination in determining CC size is generally equivalent between sexes. Finally, we found that CC length was negatively associated with nonverbal ability among females.

"If He Has it, We Know What to Do": Parent Perspectives on Familial Risk for Autism Spectrum Disorder.

OBJECTIVE: Predictive testing for familial disorders can guide healthcare and reproductive decisions. Familial disorders with onset in childhood (e.g., autism spectrum disorder [ASD]) are promising targets for presymptomatic prediction; however, little is known about parent perceptions of risk to their children in the presymptomatic period. The current study examined risk perceptions in parents of infants at high familial risk for ASD enrolled in a longitudinal study of brain and behavior development. METHODS: Semistructured interviews were conducted with 37 parents of high-risk infants during the presymptomatic window (3-15 months) that precedes an ASD diagnosis. Infants were identified as high familial risk due to having an older sibling with ASD. Parent interview responses were coded and interpreted to distill emerging themes. RESULTS: The majority of parents were aware of the increased risk of ASD for their infants, and risk perceptions were influenced by comparisons to their older child with ASD. Parents reported a variety of negative emotions in response to perceived risk, including worry, fear, and sadness, and described impacts of perceived risk on their behavior: increased vigilance to emerging symptoms, altered reproductive and healthcare decisions, and seeking ongoing assessment through research. CONCLUSIONS: Parents of children at high familial risk for childhood-onset disorders like ASD face a period of challenging uncertainty during early development. In anticipation of a future in which presymptomatic testing for ASD is made available, it is important to understand how parents react to and cope with the elevated-but still highly uncertain-risk conveyed by family history.

Restricted and Repetitive Behavior and Brain Functional Connectivity in Infants at Risk for Developing Autism Spectrum Disorder.

BACKGROUND: Restricted and repetitive behaviors (RRBs), detectable by 12 months in many infants in whom autism spectrum disorder (ASD) is later diagnosed, may represent some of the earliest behavioral markers of ASD. However, brain function underlying the emergence of these key behaviors remains unknown. METHODS: Behavioral and resting-state functional connectivity (fc) magnetic resonance imaging data were collected from 167 children at high and low familial risk for ASD at 12 and 24 months (n = 38 at both time points). Twenty infants met criteria for ASD at 24 months. We divided RRBs into four subcategories (restricted, stereotyped, ritualistic/sameness, self-injurious) and used a data-driven approach to identify functional brain networks associated with the development of each RRB subcategory. RESULTS: Higher scores for ritualistic/sameness behavior were associated with less positive fc between visual and control networks at 12 and 24 months. Ritualistic/sameness and stereotyped behaviors were associated with less positive fc between visual and default mode networks at 12 months. At 24 months, stereotyped and restricted behaviors were associated with more positive fc between default mode and control networks. Additionally, at 24 months, stereotyped behavior was associated with more positive fc between dorsal attention and subcortical networks, whereas restricted behavior was associated with more positive fc between default mode and dorsal attention networks. No significant network-level associations were observed for self-injurious behavior. CONCLUSIONS: These observations mark the earliest known description of functional brain systems underlying RRBs, reinforce the construct validity of RRB subcategories in infants, and implicate specific neural substrates for future interventions targeting RRBs.