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.

Differential cognitive and behavioral development from 6 to 24 months in autism and fragile X syndrome.

BACKGROUND: Specifying early developmental differences among neurodevelopmental disorders with distinct etiologies is critical to improving early identification and tailored intervention during the first years of life. Recent studies have uncovered important differences between infants with fragile X syndrome (FXS) and infants with familial history of autism spectrum disorder who go on to develop autism themselves (FH-ASD), including differences in brain development and behavior. Thus far, there have been no studies longitudinally investigating differential developmental skill profiles in FXS and FH-ASD infants. METHODS: The current study contrasted longitudinal trajectories of verbal (expressive and receptive language) and nonverbal (gross and fine motor, visual reception) skills in FXS and FH-ASD infants, compared to FH infants who did not develop ASD (FH-nonASD) and typically developing controls. RESULTS: Infants with FXS showed delays on a nonverbal composite compared to FH-ASD (as well as FH-nonASD and control) infants as early as 6 months of age. By 12 months an ordinal pattern of scores was established between groups on all domains tested, such that controls > FH-nonASD > FH-ASD > FXS. This pattern persisted through 24 months. Cognitive level differentially influenced developmental trajectories for FXS and FH-ASD. CONCLUSIONS: Our results demonstrate detectable group differences by 6 months between FXS and FH-ASD as well as differential trajectories on each domain throughout infancy. This work further highlights an earlier onset of global cognitive delays in FXS and, conversely, a protracted period of more slowly emerging delays in FH-ASD. Divergent neural and cognitive development in infancy between FXS and FH-ASD contributes to our understanding of important distinctions in the development and behavioral phenotype of these two groups.

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.

Enlarged Perivascular Spaces in Infancy and Autism Diagnosis, Cerebrospinal Fluid Volume, and Later Sleep Problems.

Importance: Perivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume. Objective: To examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood. Design, Setting, and Participants: This prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022. Exposure: PVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging). Main Outcomes and Measures: Outcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years. Results: A total of 311 infants (197 [63.3%] male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group (P = .02) and 22 infants in the control group (26.2%) (P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (ß = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age (F = 7.76; η2 = 0.08; P = .006). Conclusions and Relevance: These findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.

Donor perspectives on informed consent and use of biospecimens for brain organoid research.

Debates about the ethics of human brain organoids have proceeded without the input of individuals whose brains are being modeled. Interviews with donors of biospecimens for brain organoid research revealed overall enthusiasm for brain organoids as a tool for biomedical discovery, alongside a desire for ongoing engagement with research teams to learn the results of the research, to allow transfer of decision-making authority over time, and to ensure ethical boundaries are not crossed. Future work is needed to determine the most feasible and resource-efficient way to longitudinally engage donors participating in brain organoid research.

Association of Sex With Neurobehavioral Markers of Executive Function in 2-Year-Olds at High and Low Likelihood of Autism.

Importance: Children with autism and their siblings exhibit executive function (EF) deficits early in development, but associations between EF and biological sex or early brain alterations in this population are largely unexplored. Objective: To investigate the interaction of sex, autism likelihood group, and structural magnetic resonance imaging alterations on EF in 2-year-old children at high familial likelihood (HL) and low familial likelihood (LL) of autism, based on having an older sibling with autism or no family history of autism in first-degree relatives. Design, Setting, and Participants: This prospective cohort study assessed 165 toddlers at HL (n = 110) and LL (n = 55) of autism at 4 university-based research centers. Data were collected from January 1, 2007, to December 31, 2013, and analyzed between August 2021 and June 2022 as part of the Infant Brain Imaging Study. Main Outcomes and Measures: Direct assessments of EF and acquired structural magnetic resonance imaging were performed to determine frontal lobe, parietal lobe, and total cerebral brain volume. Results: A total of 165 toddlers (mean [SD] age, 24.61 [0.95] months; 90 [54%] male, 137 [83%] White) at HL for autism (n = 110; 17 diagnosed with ASD) and LL for autism (n = 55) were studied. The toddlers at HL for autism scored lower than the toddlers at LL for autism on EF tests regardless of sex (mean [SE] B = -8.77 [4.21]; 95% CI, -17.09 to -0.45; η2p = 0.03). With the exclusion of toddlers with autism, no group (HL vs LL) difference in EF was found in boys (mean [SE] difference, -7.18 [4.26]; 95% CI, 1.24-15.59), but EF was lower in HL girls than LL girls (mean [SE] difference, -9.75 [4.34]; 95% CI, -18.32 to -1.18). Brain-behavior associations were examined, controlling for overall cerebral volume and developmental level. Sex differences in EF-frontal (B [SE] = 16.51 [7.43]; 95% CI, 1.36-31.67; η2p = 0.14) and EF-parietal (B [SE] = 17.68 [6.99]; 95% CI, 3.43-31.94; η2p = 0.17) associations were found in the LL group but not the HL group (EF-frontal: B [SE] = -1.36 [3.87]; 95% CI, -9.07 to 6.35; η2p = 0.00; EF-parietal: B [SE] = -2.81 [4.09]; 95% CI, -10.96 to 5.34; η2p = 0.01). Autism likelihood group differences in EF-frontal (B [SE] = -9.93 [4.88]; 95% CI, -19.73 to -0.12; η2p = 0.08) and EF-parietal (B [SE] = -15.44 [5.18]; 95% CI, -25.86 to -5.02; η2p = 0.16) associations were found in girls not boys (EF-frontal: B [SE] = 6.51 [5.88]; 95% CI, -5.26 to 18.27; η2p = 0.02; EF-parietal: B [SE] = 4.18 [5.48]; 95% CI, -6.78 to 15.15; η2p = 0.01). Conclusions and Relevance: This cohort study of toddlers at HL and LL of autism suggests that there is an association between sex and EF and that brain-behavior associations in EF may be altered in children at HL of autism. Furthermore, EF deficits may aggregate in families, particularly in girls.

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.

IcoConv : Explainable brain cortical surface analysis for ASD classification.

In this study, we introduce a novel approach for the analysis and interpretation of 3D shapes, particularly applied in the context of neuroscientific research. Our method captures 2D perspectives from various vantage points of a 3D object. These perspectives are subsequently analyzed using 2D Convolutional Neural Networks (CNNs), uniquely modified with custom pooling mechanisms. We sought to assess the efficacy of our approach through a binary classification task involving subjects at high risk for Autism Spectrum Disorder (ASD). The task entailed differentiating between high-risk positive and high-risk negative ASD cases. To do this, we employed brain attributes like cortical thickness, surface area, and extra-axial cerebral spinal measurements. We then mapped these measurements onto the surface of a sphere and subsequently analyzed them via our bespoke method. One distinguishing feature of our method is the pooling of data from diverse views using our icosahedron convolution operator. This operator facilitates the efficient sharing of information between neighboring views. A significant contribution of our method is the generation of gradient-based explainability maps, which can be visualized on the brain surface. The insights derived from these explainability images align with prior research findings, particularly those detailing the brain regions typically impacted by ASD. Our innovative approach thereby substantiates the known understanding of this disorder while potentially unveiling novel areas of study.

Social attention during object engagement: toward a cross-species measure of preferential social orienting.

BACKGROUND: A central challenge in preclinical research investigating the biology of autism spectrum disorder (ASD) is the translation of ASD-related social phenotypes across humans and animal models. Social orienting, an observable, evolutionarily conserved behavior, represents a promising cross-species ASD phenotype given that disrupted social orienting is an early-emerging ASD feature with evidence for predicting familial recurrence. Here, we adapt a competing-stimulus social orienting task from domesticated dogs to naturalistic play behavior in human toddlers and test whether this approach indexes decreased social orienting in ASD. METHODS: Play behavior was coded from the Autism Diagnostic Observation Schedule (ADOS) in two samples of toddlers, each with and without ASD. Sample 1 (n = 16) consisted of community-ascertained research participants, while Sample 2 involved a prospective study of infants at a high or low familial liability for ASD (n = 67). Coding quantified the child's looks towards the experimenter and caregiver, a social stimulus, while playing with high-interest toys, a non-social stimulus. A competing-stimulus measure of "Social Attention During Object Engagement" (SADOE) was calculated by dividing the number of social looks by total time spent playing with toys. SADOE was compared based on ASD diagnosis and differing familial liability for ASD. RESULTS: In both samples, toddlers with ASD exhibited significantly lower SADOE compared to toddlers without ASD, with large effect sizes (Hedges' g ≥ 0.92) driven by a lower frequency of child-initiated spontaneous looks. Among toddlers at high familial likelihood of ASD, toddlers with ASD showed lower SADOE than toddlers without ASD, while SADOE did not differ based on presence or absence of familial ASD risk alone. SADOE correlated negatively with ADOS social affect calibrated severity scores and positively with the Communication and Symbolic Behavior Scales social subscale. In a binary logistic regression model, SADOE alone correctly classified 74.1% of cases, which rose to 85.2% when combined with cognitive development. CONCLUSIONS: This work suggests that a brief behavioral measure pitting a high-interest nonsocial stimulus against the innate draw of social partners can serve as a feasible cross-species measure of social orienting, with implications for genetically informative behavioral phenotyping of social deficits in ASD and other neurodevelopmental disorders.

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.