Neuroadaptive Bayesian optimisation can allow integrative design spaces at the individual level in the social and behavioural sciences and beyond.

Almaatouq et al. propose an integrative experiment design space combined with large samples for scientific advancement. We argue recent innovative designs combining closed-loop experiment designs and Bayesian optimisation allow for integrative experiments at an individual level during a single session, circumventing the necessity for large samples. This method can be applied across disciplines, including developmental and clinical research.

Development of the pupillary light reflex from 9 to 24 months: association with common autism spectrum disorder (ASD) genetic liability and 3-year ASD diagnosis.

BACKGROUND: Although autism spectrum disorder (ASD) is heritable, the mechanisms through which genes contribute to symptom emergence remain unclear. Investigating candidate intermediate phenotypes such as the pupillary light reflex (PLR) prospectively from early in development could bridge genotype and behavioural phenotype. METHODS: Using eye tracking, we longitudinally measured the PLR at 9, 14 and 24 months in a sample of infants (N = 264) enriched for a family history of ASD; 27 infants received an ASD diagnosis at 3 years. We examined the 9- to 24-month developmental trajectories of PLR constriction latency (onset; ms) and amplitude (%) and explored their relation to categorical 3-year ASD outcome, polygenic liability for ASD and dimensional 3-year social affect (SA) and repetitive/restrictive behaviour (RRB) traits. Polygenic scores for ASD (PGSASD ) were calculated for 190 infants. RESULTS: While infants showed a decrease in latency between 9 and 14 months, higher PGSASD was associated with a smaller decrease in latency in the first year (ß = -.16, 95% CI = -0.31, -0.002); infants with later ASD showed a significantly steeper decrease in latency (a putative 'catch-up') between 14 and 24 months relative to those with other outcomes (typical: ß = .54, 95% CI = 0.08, 0.99; other: ß = .53, 95% CI = 0.02, 1.04). Latency development did not associate with later dimensional variation in ASD-related traits. In contrast, change in amplitude was not related to categorical ASD or genetics, but decreasing 9- to 14-month amplitude was associated with higher SA (ß = .08, 95% CI = 0.01, 0.14) and RRB (ß = .05, 95% CI = 0.004, 0.11) traits. CONCLUSIONS: These findings corroborate PLR development as possible intermediate phenotypes being linked to both genetic liability and phenotypic outcomes. Future work should incorporate alternative measures (e.g. functionally informed structural and genetic measures) to test whether distinct neural mechanisms underpin PLR alterations.

Look duration at the face as a developmental endophenotype: elucidating pathways to autism and ADHD.

Identifying developmental endophenotypes on the pathway between genetics and behavior is critical to uncovering the mechanisms underlying neurodevelopmental conditions. In this proof-of-principle study, we explored whether early disruptions in visual attention are a unique or shared candidate endophenotype of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We calculated the duration of the longest look (i.e., peak look) to faces in an array-based eye-tracking task for 335 14-month-old infants with and without first-degree relatives with ASD and/or ADHD. We leveraged parent-report and genotype data available for a proportion of these infants to evaluate the relation of looking behavior to familial (n = 285) and genetic liability (using polygenic scores, n = 185) as well as ASD and ADHD-relevant temperament traits at 2 years of age (shyness and inhibitory control, respectively, n = 272) and ASD and ADHD clinical traits at 6 years of age (n = 94).Results showed that longer peak looks at the face were associated with elevated polygenic scores for ADHD (ß = 0.078, p = .023), but not ASD (ß = 0.002, p = .944), and with elevated ADHD traits in mid-childhood (F(1,88) = 6.401, p = .013, $\eta _p^2$=0.068; ASD: F (1,88) = 3.218, p = .076), but not in toddlerhood (ps > 0.2). This pattern of results did not emerge when considering mean peak look duration across face and nonface stimuli. Thus, alterations in attention to faces during spontaneous visual exploration may be more consistent with a developmental endophenotype of ADHD than ASD. Our work shows that dissecting paths to neurodevelopmental conditions requires longitudinal data incorporating polygenic contribution, early neurocognitive function, and clinical phenotypic variation.

The potential and translational application of infant genetic research.

In the current genomic revolution, the infancy life stage is the most neglected. Although clinical genetics recognizes the value of early identification in infancy of rare genetic causes of disorders and delay, common genetic variation is almost completely ignored in research on infant behavioral and neurodevelopmental traits. In this Perspective, we argue for a much-needed surge in research on common genetic variation influencing infant neurodevelopment and behavior, findings that would be relevant for all children. We now see convincing evidence from different research designs to suggest that developmental milestones, skills and behaviors of infants are heritable and thus are suitable candidates for gene-discovery research. We highlight the resources available to the field, including genotyped infant cohorts, and we outline, with recommendations, special considerations needed for infant data. Therefore, infant genetic research has the potential to impact basic science and to affect educational policy, public health and clinical practice.

An axis of genetic heterogeneity in autism is indexed by age at diagnosis and is associated with varying developmental and mental health profiles.

There is growing recognition that earliest signs of autism need not clearly manifest in the first three years of life. To what extent is this variation in developmental trajectories associated with age at autism diagnosis? Does the genetic profile of autism vary with age at autism diagnosis? Using longitudinal data from four birth cohorts, we demonstrate that two different trajectories of socio-emotional behaviours are associated with age at diagnosis. We further demonstrate that the age at autism diagnosis is partly heritable (h2 SNP = 0.12, s.e.m = 0.01), and is associated with two moderately correlated (rg = 0.38, s.e.m = 0.07) autism polygenic factors. One of these factors is associated with earlier diagnosis of autism, lower social and communication abilities in early childhood. The second factor is associated with later autism diagnosis, increased socio-emotional difficulties in adolescence, and has moderate to high positive genetic correlations with Attention-Deficit/Hyperactivity Disorder, mental health conditions, and trauma. Overall, our research identifies an axis of heterogeneity in autism, indexed by age at diagnosis, which partly explains heterogeneity in autism and the profiles of co-occurring neurodevelopmental and mental health profiles. Our findings have important implications for how we conceptualise autism and provide one model to explain some of the diversity within autism.

Children's total blindness as a risk factor for early parent-child relationships: preliminary findings from an Italian sample.

Background: Vision provides crucial information for parent-child attunement that scaffolds social development from the first months of life. Congenital blindness might affect both parental wellbeing and children's behavior during parent-child interaction. In this study, we compared families of young children with total versus partial blindness to understand the link between residual vision, parenting stress and perceived social support, and children's behavior during parent-child interaction. Methods: Participants were 42 white parents (21 fathers and 21 mothers) and their congenitally blind children (14 females, mean age = 14.81 months, SD = 10.46) with no co-occurring disability, recruited at the Robert Hollman Foundation rehabilitation centers in Italy. Parents' scores on the Parenting Stress Index and Multidimensional Scale of Perceived Social Support questionnaires, as well as children's behaviors signaling joint engagement during video-recorded episodes of parent-child interaction, were compared between the Total Blindness (TB, n = 12 children with no light perception or light perception in the dark but no quantifiable visual acuity) and Partial Blindness (PB, n = 9 children with a residual visual acuity below 3/60) groups. Results: We found that parents of TB children had higher parenting stress and lower perceived social support scores than parents of PB children. In fathers, total stress and stress linked to perceiving the child as difficult negatively correlated with perceived support from friends. There was no difference in the time TB and PB children spent displaying joint engagement behaviors during parent-child interaction. However, TB children directed their gaze and face less often toward their parents than PB children. We observed a trend of association between this behavior and maternal stress. Conclusion: These preliminary results suggest that the complete absence of vision from birth has adverse effects on stress linked to parenting and parental perceived social support. These findings support the importance of early family-centered interventions that extend to the parents' communities and facilitate the parent-child dyad's communication through non-visual behaviors. Replication is warranted in larger and more diverse samples.

Real-time monitoring of infant theta power during naturalistic social experiences.

Infant-directed speech and direct gaze are important social cues that shape infant's attention to their parents. Traditional methods for probing their effect on infant attention involve a small number of pre-selected screen-based stimuli, which do not capture the complexity of real-world interactions. Here, we used neuroadaptive Bayesian Optimization (NBO) to search a large 'space' of different naturalistic social experiences that systematically varied in their visual (gaze direct to averted) and auditory properties (infant directed speech to nonvocal sounds). We measured oscillatory brain responses (relative theta power) during episodes of naturalistic social experiences in 57 typically developing 6- to 12-month-old infants. Relative theta power was used as input to the NBO algorithm to identify the naturalistic social context that maximally elicited attention in each individual infant. Results showed that individual infants were heterogeneous in the stimulus that elicited maximal theta with no overall stronger attention for direct gaze or infant-directed speech; however, individual differences in attention towards averted gaze were related to interpersonal skills and greater likelihood of preferring speech and direct gaze was observed in infants whose parents showed more positive affect. Our work indicates NBO may be a fruitful method for probing the role of distinct social cues in eliciting attention in naturalistic social contexts at the individual level.

Face Processing in Early Development: A Systematic Review of Behavioral Studies and Considerations in Times of COVID-19 Pandemic.

Human faces are one of the most prominent stimuli in the visual environment of young infants and convey critical information for the development of social cognition. During the COVID-19 pandemic, mask wearing has become a common practice outside the home environment. With masks covering nose and mouth regions, the facial cues available to the infant are impoverished. The impact of these changes on development is unknown but is critical to debates around mask mandates in early childhood settings. As infants grow, they increasingly interact with a broader range of familiar and unfamiliar people outside the home; in these settings, mask wearing could possibly influence social development. In order to generate hypotheses about the effects of mask wearing on infant social development, in the present work, we systematically review N = 129 studies selected based on the most recent PRISMA guidelines providing a state-of-the-art framework of behavioral studies investigating face processing in early infancy. We focused on identifying sensitive periods during which being exposed to specific facial features or to the entire face configuration has been found to be important for the development of perceptive and socio-communicative skills. For perceptive skills, infants gradually learn to analyze the eyes or the gaze direction within the context of the entire face configuration. This contributes to identity recognition as well as emotional expression discrimination. For socio-communicative skills, direct gaze and emotional facial expressions are crucial for attention engagement while eye-gaze cuing is important for joint attention. Moreover, attention to the mouth is particularly relevant for speech learning. We discuss possible implications of the exposure to masked faces for developmental needs and functions. Providing groundwork for further research, we encourage the investigation of the consequences of mask wearing for infants' perceptive and socio-communicative development, suggesting new directions within the research field.

Qualitative differences in the spatiotemporal brain states supporting configural face processing emerge in adolescence in autism.

BACKGROUND: Studying the neural processing of faces can illuminate the mechanisms of compromised social expertise in autism. To resolve a longstanding debate, we examined whether differences in configural face processing in autism are underpinned by quantitative differences in the activation of typical face processing pathways, or the recruitment of non-typical neural systems. METHODS: We investigated spatial and temporal characteristics of event-related EEG responses to upright and inverted faces in a large sample of children, adolescents, and adults with and without autism. We examined topographic analyses of variance and global field power to identify group differences in the spatial and temporal response to face inversion. We then examined how quasi-stable spatiotemporal profiles - microstates - are modulated by face orientation and diagnostic group. RESULTS: Upright and inverted faces produced distinct profiles of topography and strength in the topographical analyses. These topographical profiles differed between diagnostic groups in adolescents, but not in children or adults. In the microstate analysis, the autistic group showed differences in the activation strength of normative microstates during early-stage processing at all ages, suggesting consistent quantitative differences in the operation of typical processing pathways; qualitative differences in microstate topographies during late-stage processing became prominent in adults, suggesting the increasing involvement of non-typical neural systems with processing time and over development. CONCLUSIONS: These findings suggest that early difficulties with configural face processing may trigger later compensatory processes in autism that emerge in later development.

Attentive brain states in infants with and without later autism.

Early difficulties in engaging attentive brain states in social settings could affect learning and have cascading effects on social development. We investigated this possibility using multichannel electroencephalography during a face/non-face paradigm in 8-month-old infants with (FH, n = 91) and without (noFH, n = 40) a family history of autism spectrum disorder (ASD). An event-related potential component reflecting attention engagement, the Nc, was compared between FH infants who received a diagnosis of ASD at 3 years of age (FH-ASD; n = 19), FH infants who did not (FH-noASD; n = 72) and noFH infants (who also did not, hereafter noFH-noASD; n = 40). 'Prototypical' microstates during social attention were extracted from the noFH-noASD group and examined in relation to later categorical and dimensional outcome. Machine-learning was used to identify the microstate features that best predicted ASD and social adaptive skills at three years. Results suggested that whilst measures of brain state timing were related to categorical ASD outcome, brain state strength was related to dimensional measures of social functioning. Specifically, the FH-ASD group showed shorter Nc latency relative to other groups, and duration of the attentive microstate responses to faces was informative for categorical outcome prediction. Reduced Nc amplitude difference between faces with direct gaze and a non-social control stimulus and strength of the attentive microstate to faces contributed to the prediction of dimensional variation in social skills. Taken together, this provides consistent evidence that atypical attention engagement precedes the emergence of difficulties in socialization and indicates that using the spatio-temporal characteristics of whole-brain activation to define brain states in infancy provides an important new approach to understanding of the neurodevelopmental mechanisms that lead to ASD.

Social attention: What is it, how can we measure it, and what can it tell us about autism and ADHD?

Neurodevelopmental disorders like autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) affect 2-10% of children worldwide but are still poorly understood. Prospective studies of infants with an elevated familial likelihood of ASD or ADHD can provide insight into early mechanisms that canalize development down a typical or atypical course. Such work holds potential for earlier identification and intervention to support optimal outcomes in individuals with neurodevelopmental disorders. Disrupted attention may be involved in developmental trajectories to ASD and ADHD. Specifically, altered attention to social stimuli has been suggested as a possible endophenotype of ASD, lying between genetic factors impacting brain development and later symptoms. Similarly, changes in domain-general aspects of attention are commonly seen in ADHD and emerging evidence suggests these may begin in infancy. Could these patterns point to a common risk factor for both disorders? Or does social attention reflect the activity of a particular network of brain systems that is distinct to those underpinning general attention skills? One challenge to addressing such questions is our lack of understanding of the relation between social and general attention. In this chapter we review evidence from infants with later ASD and ADHD that illuminates this question.

Leveraging epigenetics to examine differences in developmental trajectories of social attention: A proof-of-principle study of DNA methylation in infants with older siblings with autism.

Preliminary evidence suggests that changes in DNA methylation, a widely studied epigenetic mechanism, contribute to the etiology of Autism Spectrum Disorder (ASD). However, data is primarily derived from post-mortem brain samples or peripheral tissue from adults. Deep-phenotyped longitudinal infant cohorts are essential to understand how epigenetic modifications relate to early developmental trajectories and emergence of ASD symptoms. We present a proof-of-principle study designed to evaluate the potential of prospective epigenetic studies of infant siblings of children with ASD. Illumina genome-wide 450 K DNA methylation data from buccal swabs was generated for 63 male infants at multiple time-points from 8 months to 2 years of age (total N = 107 samples). 11 of those infants received a diagnosis of ASD at 3 years. We conducted a series of analyses to characterize DNA methylation signatures associated with categorical outcome and neurocognitive measures from parent-report questionnaire, eye-tracking and electro-encephalography. Effects observed across the entire genome (epigenome-wide association analyses) suggest that collecting DNA methylation samples within infant-sibling designs allows for the detection of meaningful signals with smaller sample sizes than previously estimated. Mapping networks of co-methylated probes associated with neural correlates of social attention implicated enrichment of pathways involved in brain development. Longitudinal modelling found covariation between phenotypic traits and DNA methylation levels in the proximity of genes previously associated with cognitive development, although larger samples and more complete datasets are needed to obtain generalizable results. In conclusion, assessment of DNA methylation profiles at multiple time-points in infant-sibling designs is a promising avenue to comprehend developmental origins and mechanisms of ASD.