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Abstract Face-processing timing differences may underlie visual social attention differences between autistic and non-autistic people, and males and females. This study investigates the timing of the effects of neurotype and sex on face-processing, and their dependence on age. We analysed EEG data during upright and inverted photographs of faces from 492 participants from the Longitudinal European Autism Project (141 neurotypical males, 76 neurotypical females, 202 autistic males, 73 autistic females; age 6–30 years). We detected timings of sex/diagnosis effects on event-related potential amplitudes at the posterior–temporal channel P8 with Bootstrapped Cluster-based Permutation Analysis and conducted Growth Curve Analysis (GCA) to investigate the timecourse and dependence on age of neural signals. The periods of influence of neurotype and sex overlapped but differed in onset (respectively, 260 and 310 ms post-stimulus), with sex effects lasting longer. GCA revealed a smaller and later amplitude peak in autistic female children compared to non-autistic female children; this difference decreased in adolescence and was not significant in adulthood. No age-dependent neurotype difference was significant in males. These findings indicate that sex and neurotype influence longer latency face processing and implicates cognitive rather than perceptual processing. Sex may have more overarching effects than neurotype on configural face processing.

Abstract Background Congenital Heart Disease (CHD) is the most common congenital abnormality. Survival rates are over 90%, however infants with CHD remain at high risk of attention and executive function impairments. These abilities are difficult to assess in toddlers because clinical assessments rely on language abilities which are commonly delayed in CHD. Our aim was to characterise visual attention in toddlers with CHD compared to controls and identify associations with parent‐rated effortful control. Methods Thirty toddlers with CHD (19 male, median (IQR) age at assessment 22.2 (22–23.1) months) and 66 controls from the developing human connectome project (36 male, age at assessment 22 (21.5–23.8) months) using eye‐tracking tasks designed to assess multiple components of visual attention. Analyses of co‐variance and regressions were used to identify differences between groups and relationships between gaze behaviours and parent‐rated effortful control. Results Toddlers with CHD were less accurate when switching behaviours (set‐shifting) [median (IQR) 79%, (28–100)] compared to controls [100% (86–100), pFDR = 0.032], with worse accuracy associated with lower parent‐rated effortful control in CHD but not controls (interaction pFDR = 0.028). Reaction times were slower during selective [CHD 1243 ms (986–1786), controls 1065 ms (0851–1397), pFDR

There is a scarcity of prospective longitudinal research targeted at early postnatal life which maps developmental pathways of early-stage processing and brain specialisation in the context of early adversity. Follow up from infancy into the one-five year age range is key, as it constitutes a critical gap between infant and early childhood studies. Availability of portable neuroimaging (functional near infrared spectroscopy (fNIRS) and electroencephalography (EEG)) has enabled access to rural settings increasing the diversity of our sampling and broadening developmental research to include previously underrepresented ethnic-racial and geographical groups in low- and middle- income countries (LMICs). The primary objective of the Brain Imaging for Global Health (BRIGHT) project was to establish brain function - using longitudinal data from mother - for-age reference curves infant dyads living in the UK and rural Gambia and investigate the association between context-associated moderators and developmental trajectories across the first two years of life in The Gambia. In total, 265 participating families were seen during pregnancy, at 7–14 days, 1-, 5-, 8-, 12-, 18- and 24-months post-partum. An additional visit is now underway at 3–5 years to assess pre-school outcomes. The majority of our Gambian cohort live in poverty, but while resource-poor in many factors they commonly experience a rich and beneficial family and caregiving context with multigenerational care and a close-knit supportive community. Understanding the impact of different factors at play in such an environment (i.e., detrimental undernutrition versus beneficial multigenerational family support) will (i) improve the representativeness of models of general cognitive developmental pathways from birth, (ii) identify causal pathways of altered trajectories associated with early adversity at both individual and group level, and (iii) identify the context-associated moderators (i.e. social context) that protect development despite the presence of poverty-associated challenges. This will in turn contribute to the development of targeted interventions.

Abstract Background Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse. Methods STORY follows 720 young people aged 16–25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings (‘Ōura ring’) unobtrusively measures individuals’ daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months. Discussion By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families.

Introduction Early childhood development forms the foundations for functioning later in life. Thus, accurate monitoring of developmental trajectories is critical. However, such monitoring often relies on time-intensive assessments which necessitate administration by skilled professionals. This difficulty is exacerbated in low-resource settings where such professionals are predominantly concentrated in urban and often private clinics, making them inaccessible to many. This geographic and economic inaccessibility contributes to a significant ‘detection gap’ where many children who might benefit from support remain undetected. The Scalable Transdiagnostic Early Assessment of Mental Health (STREAM) project aims to bridge this gap by developing an open-source, scalable, tablet-based platform administered by non-specialist workers to assess motor, social and cognitive developmental status. The goal is to deploy STREAM through public health initiatives, maximising opportunities for effective early interventions.Methods and analysis The STREAM project will enrol and assess 4000 children aged 0–6 years from Malawi (n=2000) and India (n=2000). It integrates three established developmental assessment tools measuring motor, social and cognitive functioning using gamified tasks, observation checklists, parent-report and audio-video recordings. Domain scores for motor, social and cognitive functioning will be developed and assessed for their validity and reliability. These domain scores will then be used to construct age-adjusted developmental reference curves.Ethics and dissemination Ethical approval has been obtained from local review boards at each site (India: Sangath Institutional Review Board; All India Institute of Medical Science (AIIMS) Ethics Committee; Indian Council of Medical Research—Health Ministry Screening Committee; Malawi: College of Medicine Research and Ethics Committee; Malawi Ministry of Health—Blantyre District Health Office). The study adheres to Good Clinical Practice standards and the ethical guidelines of the 6th (2008) Declaration of Helsinki. Findings from STREAM will be disseminated to participating families, healthcare professionals, policymakers, educators and researchers, at local, national and international levels through meetings, academic journals and conferences.

Background: Measurement of social and cognitive brain development using electroencephalography (EEG) offers the potential for early identification of children with elevated risk of developmental delay. However, there have been no published reports of how acceptable EEG technology is to parents and children within communities, especially in low-resource contexts such as in low and middle income countries (LMICs), which is an important question for the potential scalability of these assessments. We use a mixed-methods approach to examine whether EEG assessments are acceptable to children and their caregivers in a low resource community setting in India. Methods: We assessed the acceptability of neurophysiology research and Braintools (a novel neurodevelopmental assessment toolkit using concurrent EEG and eye-tracking technology) using: 1) a child engagement measure, 2) interviews with caregivers (n=8); 3) survey about caregiver’s experience (n=36). Framework analysis was used to analyse interview data. Results: A high level of child engagement in EEG tasks was demonstrated, with children’s gaze at the screen during the task averaging at 85.4% (±12.06%) of the task time. External distractions and noise during the tasks were measured, but not found to significantly effect child’s attention to the screen during EEG tasks. Key topics were examined using the framework analysis: 1) parental experience of the assessment; and 2) the acceptability of research. From topic 1, four sub-themes were identified: i) caregivers’ experience of the assessment, ii) caregivers’ perception of child's experience of assessment, iii) logistical barriers and facilitators to participation, and iv) recommendations for improvement. Results from interviews and the survey indicated acceptability for gaze-controlled EEG research for parents and children. From topic 2, three themes were identified: i) caregivers' understanding of the research, ii) barriers to participation, and iii) facilitators to participation. Barriers to participation mainly included logistical challenges, such as geographic location and time, whereas involvement of the wider family in decision making was highlighted as an important facilitator to partake in the research. Conclusions: We demonstrate for the first time the acceptability of conducting neurodevelopmental assessments using concurrent EEG and eye-tracking in preschool children in uncontrolled community LMIC settings. This kind of research appears to be acceptable to the community and we identify potential barriers and facilitators of this research, thus allowing for future large scale research projects to be conducted investigating neurodevelopment and risk factors for suboptimal development in LMICs.

Abstract Background Attenuated social attention is a key marker of autism spectrum disorder (ASD). Recent neuroimaging findings also emphasize an altered processing of sensory salience in ASD. The locus coeruleus–norepinephrine system (LC-NE) has been established as a modulator of this sensory salience processing (SSP). We tested the hypothesis that altered LC-NE functioning contributes to different SSP and results in diverging social attention in ASD. Methods We analyzed the baseline eye-tracking data of the EU-AIMS Longitudinal European Autism Project (LEAP) for subgroups of autistic participants (n = 166, age = 6–30 years, IQ = 61–138, gender [female/male] = 41/125) or neurotypical development (TD; n = 166, age = 6–30 years, IQ = 63–138, gender [female/male] = 49/117) that were matched for demographic variables and data quality. Participants watched brief movie scenes (k = 85) depicting humans in social situations (human) or without humans (non-human). SSP was estimated by gazes on physical and motion salience and a corresponding pupillary response that indexes phasic activity of the LC-NE. Social attention is estimated by gazes on faces via manual areas of interest definition. SSP is compared between groups and related to social attention by linear mixed models that consider temporal dynamics within scenes. Models are controlled for comorbid psychopathology, gaze behavior, and luminance. Results We found no group differences in gazes on salience, whereas pupillary responses were associated with altered gazes on physical and motion salience. In ASD compared to TD, we observed pupillary responses that were higher for non-human scenes and lower for human scenes. In ASD, we observed lower gazes on faces across the duration of the scenes. Crucially, this different social attention was influenced by gazes on physical salience and moderated by pupillary responses. Limitations The naturalistic study design precluded experimental manipulations and stimulus control, while effect sizes were small to moderate. Covariate effects of age and IQ indicate that the findings differ between age and developmental subgroups. Conclusions Pupillary responses as a proxy of LC-NE phasic activity during visual attention are suggested to modulate sensory salience processing and contribute to attenuated social attention in ASD.

Abstract The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods—combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6–30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.

Abstract Background Autism is proposed to be characterised by an atypical balance of cortical excitation and inhibition (E/I). However, most studies have examined E/I alterations in older autistic individuals, meaning that findings could in part reflect homeostatic compensation. To assess the directionality of effects, it is necessary to examine alterations in E/I balance early in the lifespan before symptom emergence. Recent explanatory frameworks have argued that it is also necessary to consider how early risk features interact with later developing modifier factors to predict autism outcomes. Method We indexed E/I balance in early infancy by extracting the aperiodic exponent of the slope of the electroencephalogram (EEG) power spectrum (‘1/f’). To validate our index of E/I balance, we tested for differences in the aperiodic exponent in 10-month-old infants with (n = 22) and without (n = 27) neurofibromatosis type 1 (NF1), a condition thought to be characterised by alterations to cortical inhibition. We then tested for E/I alterations in a larger heterogeneous longitudinal cohort of infants with and without a family history of neurodevelopmental conditions (n = 150) who had been followed to early childhood. We tested the relevance of alterations in E/I balance and our proposed modifier, executive attention, by assessing whether associations between 10-month aperiodic slope and 36-month neurodevelopmental traits were moderated by 24-month executive attention. Analyses adjusted for age at EEG assessment, sex and number of EEG trials. Results Infants with NF1 were characterised by a higher aperiodic exponent, indicative of greater inhibition, supporting our infant measure of E/I. Longitudinal analyses showed a significant interaction between aperiodic slope and executive attention, such that higher aperiodic exponents predicted greater autistic traits in childhood, but only in infants who also had weaker executive functioning abilities. Limitations The current study relied on parent report of infant executive functioning-type abilities; future work is required to replicate effects with objective measures of cognition. Conclusions Results suggest alterations in E/I balance are on the developmental pathway to autism outcomes, and that higher executive functioning abilities may buffer the impact of early cortical atypicalities, consistent with proposals that stronger executive functioning abilities may modify the impact of a wide range of risk factors.

Abstract Background Difficulties in social communication are a defining clinical feature of autism. However, the underlying neurobiological heterogeneity has impeded targeted therapies and requires new approaches to identifying clinically relevant bio-behavioural subgroups. In the largest autism cohort to date, we comprehensively examined difficulties in facial expression recognition, a key process in social communication, as a bio-behavioural stratification biomarker, and validated them against clinical features and neurofunctional responses. Methods Between 255 and 488 participants aged 6–30 years with autism, typical development and/or mild intellectual disability completed the Karolinska Directed Emotional Faces task, the Reading the Mind in the Eyes Task and/or the Films Expression Task. We first examined mean-group differences on each test. Then, we used a novel intersection approach that compares two centroid and connectivity-based clustering methods to derive subgroups based on the combined performance across the three tasks. Measures and subgroups were then related to clinical features and neurofunctional differences measured using fMRI during a fearful face-matching task. Results We found significant mean-group differences on each expression recognition test. However, cluster analyses showed that these were driven by a low-performing autistic subgroup (~ 30% of autistic individuals who performed below 2SDs of the neurotypical mean on at least one test), while a larger subgroup (~ 70%) performed within 1SD on at least 2 tests. The low-performing subgroup also had on average significantly more social communication difficulties and lower activation in the amygdala and fusiform gyrus than the high-performing subgroup. Limitations Findings of autism expression recognition subgroups and their characteristics require independent replication. This is currently not possible, as there is no other existing dataset that includes all relevant measures. However, we demonstrated high internal robustness (91.6%) of findings between two clustering methods with fundamentally different assumptions, which is a critical pre-condition for independent replication. Conclusions We identified a subgroup of autistic individuals with expression recognition difficulties and showed that this related to clinical and neurobiological characteristics. If replicated, expression recognition may serve as bio-behavioural stratification biomarker and aid in the development of targeted interventions for a subgroup of autistic individuals.

Introduction: Habituation and novelty detection are two fundamental and widely studied neurocognitive processes. Whilst neural responses to repetitive and novel sensory input have been well-documented across a range of neuroimaging modalities, it is not yet fully understood how well these different modalities are able to describe consistent neural response patterns. This is particularly true for infants and young children, as different assessment modalities might show differential sensitivity to underlying neural processes across age. Thus far, many neurodevelopmental studies are limited in either sample size, longitudinal scope or breadth of measures employed, impeding investigations of how well common developmental trends can be captured via different methods. Method: This study assessed habituation and novelty detection in N = 204 infants using EEG and fNIRS measured in two separate paradigms, but within the same study visit, at 1, 5 and 18 months of age in an infant cohort in rural Gambia. EEG was acquired during an auditory oddball paradigm during which infants were presented with Frequent, Infrequent and Trial Unique sounds. In the fNIRS paradigm, infants were familiarised to a sentence of infant-directed speech, novelty detection was assessed via a change in speaker. Indices for habituation and novelty detection were extracted for both EEG and NIRS Results: We found evidence for weak to medium positive correlations between responses on the fNIRS and the EEG paradigms for indices of both habituation and novelty detection at most age points. Habituation indices correlated across modalities at 1 month and 5 months but not 18 months of age, and novelty responses were significantly correlated at 5 months and 18 months, but not at 1 month. Infants who showed robust habituation responses also showed robust novelty responses across both assessment modalities. Discussion: This study is the first to examine concurrent correlations across two neuroimaging modalities across several longitudinal age points. Examining habituation and novelty detection, we show that despite the use of two different testing modalities, stimuli and timescale, it is possible to extract common neural metrics across a wide age range in infants. We suggest that these positive correlations might be strongest at times of greatest developmental change.

Abstract Background Neurofibromatosis type 1 (NF1) is a genetic disorder often associated with cognitive dysfunctions, including a high occurrence of deficits in visuoperceptual skills. The neural underpinnings of these visuoperceptual deficits are not fully understood. We used steady-state visual evoked potentials (SSVEPs) to investigate possible alterations in the synchronization of neural activity in the occipital cortex of children with NF1. Methods SSVEPs were measured using electroencephalography and compared between children with NF1 (n = 28) and neurotypical controls (n = 28) aged between 4 and 13 years old. SSVEPs were recorded during visual stimulation with coloured icons flickering at three different frequencies (6 Hz, 10 Hz, and 15 Hz) and analyzed in terms of signal-to-noise ratios. A mixed design ANCOVA was performed to compare SSVEP responses between groups at the three stimulation frequencies. Pearson’s correlations with levels of intellectual functioning as well as with symptoms of ADHD, ASD and emotional/behavioral problems were performed. The impact of psychostimulant medication on the SSVEP responses was analyzed in a subset of the NF1 group (n = 8) with paired t-tests. Results We observed reduced signal-to-noise ratios of the SSVEP responses in children with NF1. The SSVEP responses were negatively correlated with symptoms of inattention and with symptoms of emotional/behavioral problems in the NF1 group. The SSVEP response generated by the lowest stimulation frequency (i.e., 6 Hz) was rescued with the intake of psychostimulant medication. Conclusions Impaired processing of rhythmic visual stimulation was evidenced in children with NF1 through measures of SSVEP responses. Those responses seem to be more reduced in children with NF1 who exhibit more symptoms of inattention and emotional/behavioral problems in their daily life. SSVEPs are potentially sensitive electrophysiological markers that could be included in future studies investigating the impact of medication on brain activity and cognitive functioning in children with NF1.

Abstract Background Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. Methods We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2–32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants’ MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%–30% split). Results In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52–0.62, specificity 0.59–0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. Limitations The statistical power to detect weak effects—of the magnitude of those found in the training dataset—in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset’s effects. Conclusions This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects.

Abstract Attention-deficit/hyperactivity disorder (ADHD) is first diagnosed during middle childhood, when patterns of difficulty are often established. Pre-emptive approaches that strengthen developing cognitive systems could offer an alternative to post-diagnostic interventions. This proof-of-concept randomised controlled trial (RCT) tested whether computerised gaze-based attention training is feasible and improves attention in infants liable to develop ADHD. Forty-three 9- to 16-month-old infants with a first-degree relative with ADHD were recruited (11/2015–11/2018) at two UK sites and randomised with minimisation by site and sex to receive 9 weekly sessions of either (a) gaze-contingent attention training (intervention; n = 20); or (b) infant-friendly passive viewing of videos (control, n = 23). Sessions were delivered at home with blinded outcome assessments. The primary outcome was a composite of attention measures jointly analysed via a multivariate ANCOVA with a combined effect size (ES) from coefficients at baseline, midpoint and endpoint (Registration: ISRCTN37683928 ). Uptake and compliance was good but intention-to-treat analysis showed no significant differences between 20 intervention and 23 control infants on primary (ES −0.4, 95% CI −0.9 to 0.2; Complier-Average-Causal Effect ES −0.6, 95% CI −1.6 to 0.5) or secondary outcomes (behavioural attention). There were no adverse effects on sleep but a small increase in post-intervention session fussiness. Although feasible, there was no support for short-term effects of gaze-based attention training on attention skills in early ADHD. Longer-term outcomes remain to be assessed. The study highlights challenges and opportunities for pre-emptive intervention approaches to the management of ADHD.

Abstract Background ASD and ADHD are prevalent neurodevelopmental disorders that frequently co-occur and have strong evidence for a degree of shared genetic aetiology. Behavioural and neurocognitive heterogeneity in ASD and ADHD has hampered attempts to map the underlying genetics and neurobiology, predict intervention response, and improve diagnostic accuracy. Moving away from categorical conceptualisations of psychopathology to a dimensional approach is anticipated to facilitate discovery of data-driven clusters and enhance our understanding of the neurobiological and genetic aetiology of these conditions. The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project is one of the first large-scale, family-based studies to take a truly transdiagnostic approach to ASD and ADHD. Using a comprehensive phenotyping protocol capturing dimensional traits central to ASD and ADHD, the MAGNET project aims to identify data-driven clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours; investigate the degree of familiality for different dimensional ASD-ADHD phenotypes and clusters; and map the neurocognitive, brain imaging, and genetic correlates of these data-driven symptom-based clusters. Methods The MAGNET project will recruit 1,200 families with children who are either typically developing, or who display elevated ASD, ADHD, or ASD-ADHD traits, in addition to affected and unaffected biological siblings of probands, and parents. All children will be comprehensively phenotyped for behavioural symptoms, comorbidities, neurocognitive and neuroimaging traits and genetics. Conclusion The MAGNET project will be the first large-scale family study to take a transdiagnostic approach to ASD-ADHD, utilising deep phenotyping across behavioural, neurocognitive, brain imaging and genetic measures.

Abstract Background Sensory modulation difficulties are common in children with conditions such as Autism Spectrum Disorder (ASD) and could contribute to other social and non-social symptoms. Positing a causal role for sensory processing differences requires observing atypical sensory reactivity prior to the emergence of other symptoms, which can be achieved through prospective studies. Methods In this longitudinal study, we examined auditory repetition suppression and change detection at 5 and 10 months in infants with and without Neurofibromatosis Type 1 (NF1), a condition associated with higher likelihood of developing ASD. Results In typically developing infants, suppression to vowel repetition and enhanced responses to vowel/pitch change decreased with age over posterior regions, becoming more frontally specific; age-related change was diminished in the NF1 group. Whilst both groups detected changes in vowel and pitch, the NF1 group were largely slower to show a differentiated neural response. Auditory responses did not relate to later language, but were related to later ASD traits. Conclusions These findings represent the first demonstration of atypical brain responses to sounds in infants with NF1 and suggest they may relate to the likelihood of later ASD.

Natasha Bertelsen et al. develop a computational model to categorize patients with autism spectrum disorder (ASD) into distinct subgroups, based on social-communicative or restricted repetitive behaviors. By integrating publicly available neuroimaging and genetic data, they report neural and molecular signatures in two of these subgroups, altogether highlighting subtle differences in neural circuitry and genomic networks that could underlie phenotypic differences among ASD patients.

Abstract Backgrounds Atypicalities in tactile processing are reported in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) but it remains unknown if they precede and associate with the traits of these disorders emerging in childhood. We investigated behavioural and neural markers of tactile sensory processing in infants at elevated likelihood of ASD and/or ADHD compared to infants at typical likelihood of the disorders. Further, we assessed the specificity of associations between infant markers and later ASD or ADHD traits. Methods Ninety-one 10-month-old infants participated in the study (n = 44 infants at elevated likelihood of ASD; n = 20 infants at elevated likelihood of ADHD; n = 9 infants at elevated likelihood of ASD and ADHD; n = 18 infants at typical likelihood of the disorders). Behavioural and EEG responses to pairs of tactile stimuli were experimentally recorded and concurrent parental reports of tactile responsiveness were collected. ASD and ADHD traits were measured at 24 months through standardized assessment (ADOS-2) and parental report (ECBQ), respectively. Results There was no effect of infants’ likelihood status on behavioural markers of tactile sensory processing. Conversely, increased ASD likelihood associated with reduced neural repetition suppression to tactile input. Reduced neural repetition suppression at 10 months significantly predicted ASD (but not ADHD) traits at 24 months across the entire sample. Elevated tactile sensory seeking at 10 months moderated the relationship between early reduced neural repetition suppression and later ASD traits. Conclusions Reduced tactile neural repetition suppression is an early marker of later ASD traits in infants at elevated likelihood of ASD or ADHD, suggesting that a common pathway to later ASD traits exists despite different familial backgrounds. Elevated tactile sensory seeking may act as a protective factor, mitigating the relationship between early tactile neural repetition suppression and later ASD traits.

Abstract Childhood screen time is associated with both attentional difficulties (for television viewing) and benefits (in action video gamers), but few studies have investigated today’s pervasive touchscreen devices (e.g. smartphones and tablets), which combine salient features, interactive content, and accessibility from toddlerhood (a peak period of cognitive development). We tested exogenous and endogenous attention, following forty children who were stable high (HU) or low (LU) touchscreen users from toddlerhood to pre-school. HUs were slower to disengage attention, relative to their faster baseline orienting ability. In an infant anti-saccade task, HUs displayed more of a corrective strategy of orienting faster to distractors before anticipating the target. Results suggest that long-term high exposure to touchscreen devices is associated with faster exogenous attention and concomitant decreases in endogenous attention control. Future work is required to demonstrate causality, dissociate variants of use, and investigate how attention behaviours found in screen-based contexts translate to real-world settings.

The Developing Human Connectome Project has created a large open science resource which provides researchers with data for investigating typical and atypical brain development across the perinatal period. It has collected 1228 multimodal magnetic resonance imaging (MRI) brain datasets from 1173 fetal and/or neonatal participants, together with collateral demographic, clinical, family, neurocognitive and genomic data from 1173 participants, together with collateral demographic, clinical, family, neurocognitive and genomic data. All subjects were studied in utero and/or soon after birth on a single MRI scanner using specially developed scanning sequences which included novel motion-tolerant imaging methods. Imaging data are complemented by rich demographic, clinical, neurodevelopmental, and genomic information. The project is now releasing a large set of neonatal data; fetal data will be described and released separately. This release includes scans from 783 infants of whom: 583 were healthy infants born at term; as well as preterm infants; and infants at high risk of atypical neurocognitive development. Many infants were imaged more than once to provide longitudinal data, and the total number of datasets being released is 887. We now describe the dHCP image acquisition and processing protocols, summarize the available imaging and collateral data, and provide information on how the data can be accessed.

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the “social brain,” a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. Methods As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. Results We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. Conclusions Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition.

The first 1000 days from conception to two-years of age are a critical period in brain development, and there is an increasing drive for developing technologies to help advance our understanding of neurodevelopmental processes during this time. Functional near-infrared spectroscopy (fNIRS) has enabled longitudinal infant brain function to be studied in a multitude of settings. Conventional fNIRS analyses tend to occur in the channel-space, where data from equivalent channels across individuals are combined, which implicitly assumes that head size and source-detector positions (i.e. array position) on the scalp are constant across individuals. The validity of such assumptions in longitudinal infant fNIRS analyses, where head growth is most rapid, has not previously been investigated. We employed an image reconstruction approach to analyse fNIRS data collected from a longitudinal cohort of infants in The Gambia aged 5- to 12-months. This enabled us to investigate the effect of variability in both head size and array position on the anatomical and statistical inferences drawn from the data at both the group- and the individual-level. We also sought to investigate the impact of group size on inferences drawn from the data. We found that variability in array position was the driving factor between differing inferences drawn from the data at both the individual- and group-level, but its effect was weakened as group size increased towards the full cohort size (N = 53 at 5-months, N = 40 at 8-months and N = 45 at 12-months). We conclude that, at the group sizes in our dataset, group-level channel-space analysis of longitudinal infant fNIRS data is robust to assumptions about head size and array position given the variability in these parameters in our dataset. These findings support a more widespread use of image reconstruction techniques in longitudinal infant fNIRS studies.

Across cultures, imitation provides a crucial route to learning during infancy. However, neural predictors which would enable early identification of infants at risk of suboptimal developmental outcomes are still rare. In this paper, we examine associations between ERP markers of habituation and novelty detection measured at 1 and 5 months of infant age in the UK (n = 61) and rural Gambia (n = 214) and infants’ responses on a deferred imitation task at 8 and 12 months. In both cohorts, habituation responses at 5 months significantly predicted deferred imitation responses at 12 months of age in both cohorts. Furthermore, ERP habituation responses explained a unique proportion of variance in deferred imitation scores which could not be accounted for by a neurobehavioural measure (Mullen Scales of Early Learning) conducted at 5 months of age. Our findings highlight the potential for ERP markers of habituation and novelty detection measured before 6 months of age to provide insight into later imitation abilities and memory development across diverse settings.

Introduction: Infants and children in low- and middle-income countries are frequently exposed to a range of poverty-related risk factors, increasing their likelihood of poor neurodevelopmental outcomes. There is a need for culturally objective markers, which can be used to study infants from birth, thereby enabling early identification and ultimately intervention during a critical time of neurodevelopment. Method: In this paper, we investigate developmental changes in auditory event related potentials (ERP) associated with habituation and novelty detection in infants between 1 and 5 months living in the United Kingdom and The Gambia, West Africa. Previous research reports that whereas newborns’ ERP responses are increased when presented with stimuli of higher intensity, this sensory driven response decreases over the first few months of life, giving rise to a cognitively driven, novelty-based response. Anthropometric measures were obtained concurrently with the ERP measures at 1 and 5 months of age. Neurodevelopmental outcome was measured using the Mullen Scales of Early Learning (MSEL) at 5 months of age. Results: The described developmental change was observed in the UK cohort, who exhibited an intensity-based response at 1 month and a novelty-based response at 5 months of age. This change was accompanied by greater habituation to stimulus intensity at 5 compared to 1 month. In the Gambian cohort we did not see a change from an intensity-to a novelty-based response, and no change in habituation to stimulus intensity across the two age points. The degree of change from an intensity towards a novelty-based response was further found to be associated with MSEL scores at 5 months of infant age, whereas infants’ growth between 1 and 5 months was not. Discussion: Our study highlights the utility of ERP-based markers to study young infants in rural Africa. By implementing a well-established paradigm in a previously understudied population we have demonstrated its use as a culturally objective tool to better understand early learning in diverse settings world-wide. Results offer insight into the neurodevelopmental processes underpinning early neurocognitive development, which may in the future contribute to early identification of infants at heightened risk of adverse neurodevelopmental outcome.

Abstract Background The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. Methods LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. Results Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some ‘lessons learnt’. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). Conclusion We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

Abstract Background The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. Methods From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. Results The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. Conclusions The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials.

Infants and children in low- and middle-income countries (LMICs) are frequently exposed to a range of environmental risk factors which may negatively affect their neurocognitive development. The mechanisms by which factors such as undernutrition and poverty impact development and cognitive outcomes in early childhood are poorly understood. This lack of knowledge is due in part to a paucity of objective assessment tools which can be implemented across different cultural settings and in very young infants. Over the last decade, technological advances, particularly in neuroimaging, have opened new avenues for research into the developing human brain, allowing us to investigate novel biological associations. This paper presents functional near-infrared spectroscopy (fNIRS), electroencephalography (EEG) and eye tracking (ET) as objective, cross-cultural methods for studying infant neurocognitive development in LMICs, and specifically their implementation in rural Gambia, West Africa. These measures are currently included, as part of a broader battery of assessments, in the Brain Imaging for Global Health (BRIGHT) project, which is developing brain function for age curves in Gambian and UK infants from birth to 24 months of age. The BRIGHT project combines fNIRS, EEG and ET with behavioural, growth, health and sociodemographic measures. The implementation of these measures in rural Gambia are discussed, including methodological and technical challenges that needed to be addressed to ensure successful data acquisition. The aim is to provide guidance to other groups seeking to implement similar methods in their research in other LMICs to better understand associations between environmental risk and early neurocognitive development.

Mapping infant neurocognitive differences that precede later ADHD-related behaviours is critical for designing early interventions. In this study, we investigated (1) group differences in a battery of measures assessing aspects of attention and activity level in infants with and without a family history of ADHD or related conditions (ASD), and (2) longitudinal associations between the infant measures and preschool ADHD traits at 3 years. Participants (N = 151) were infants with or without an elevated likelihood for ADHD (due to a family history of ADHD and/or ASD). A multi-method assessment protocol was used to assess infant attention and activity level at 10 months of age that included behavioural, cognitive, physiological and neural measures. Preschool ADHD traits were measured at 3 years of age using the Child Behaviour Checklist (CBCL) and the Child Behaviour Questionnaire (CBQ). Across a broad range of measures, we found no significant group differences in attention or activity level at 10 months between infants with and without a family history of ADHD or ASD. However, parent and observer ratings of infant activity level at 10 months were positively associated with later preschool ADHD traits at 3 years. Observable behavioural differences in activity level (but not attention) may be apparent from infancy in children who later develop elevated preschool ADHD traits.

Alterations in the development of attention control and learning have been associated with autism and can be measured using the "antisaccade task," which assesses a child's ability to make an oculomotor response away from a distracting stimulus, and learn to instead anticipate a later reward. We aimed to assess these cognitive processes using portable eye-tracking in an understudied population of pre-school children with and without a diagnosis of autism spectrum disorder in community settings in New Delhi, India. The eye-tracking antisaccade task was presented to children in three groups (n = 104) (children with a clinical diagnosis of autism spectrum disorder or intellectual disability and children meeting developmental milestones). In accordance with findings from high-income, laboratory-based environments, children learnt to anticipate looks towards a reward, as well as inhibit eye-movements towards a distractor stimulus. We also provide novel evidence that while differences in inhibition responses might be applicable to multiple developmental conditions, a reduced learning to anticipate looks towards a target in this age group may be specific to autism. This eye-tracking task may, therefore, have the potential to identify and assess autism specific traits across development, and be used in longitudinal research studies such as investigating response to intervention in low-resource settings.