HighlightsProspective studies of infants at familial risk are characterizing developmental pathways to ASD.Children with ASD show social and communication difficulties in the second year of life.Early neurocognitive markers include atypical neural response to gaze and slowed disengagement.Mapping how ASD unfolds from birth is central to early identification and intervention.

Objective A previously published randomized clinical trial indicated that a developmental behavioral intervention, the Early Start Denver Model (ESDM), resulted in gains in IQ, language, and adaptive behavior of children with autism spectrum disorder. This report describes a secondary outcome measurement from this trial, EEG activity. Method Forty-eight 18- to 30-month-old children with autism spectrum disorder were randomized to receive the ESDM or referral to community intervention for 2 years. After the intervention (age 48 to 77 months), EEG activity (event-related potentials and spectral power) was measured during the presentation of faces versus objects. Age-matched typical children were also assessed. Results The ESDM group exhibited greater improvements in autism symptoms, IQ, language, and adaptive and social behaviors than the community intervention group. The ESDM group and typical children showed a shorter Nc latency and increased cortical activation (decreased α power and increased θ power) when viewing faces, whereas the community intervention group showed the opposite pattern (shorter latency event-related potential [ERP] and greater cortical activation when viewing objects). Greater cortical activation while viewing faces was associated with improved social behavior. Conclusions This was the first trial to demonstrate that early behavioral intervention is associated with normalized patterns of brain activity, which is associated with improvements in social behavior, in young children with autism spectrum disorder.

SummaryBackgroundRisk markers for later autism identified in the first year of life present plausible intervention targets during early development. We aimed to assess the effect of a parent-mediated intervention for infants at high risk of autism on these markers.MethodsWe did a two-site, two-arm assessor-blinded randomised controlled trial of families with an infant at familial high risk of autism aged 7–10 months, testing the adapted Video Interaction to Promote Positive Parenting (iBASIS-VIPP) versus no intervention. Families were randomly assigned to intervention or no intervention groups using a permuted block approach stratified by centre. Assessors, but not families or therapists, were masked to group assignment. The primary outcome was infant attentiveness to parent. Regression analysis was done on an intention-to-treat basis. This trial is registered with ISCRTN Registry, number ISRCTN87373263.FindingsWe randomly assigned 54 families between April 11, 2011, and Dec 4, 2012 (28 to intervention, 26 to no intervention). Although CIs sometimes include the null, point estimates suggest that the intervention increased the primary outcome of infant attentiveness to parent (effect size 0·29, 95% CI −0·26 to 0·86, thus including possibilities ranging from a small negative treatment effect to a strongly positive treatment effect). For secondary outcomes, the intervention reduced autism-risk behaviours (0·50, CI −0·15 to 1·08), increased parental non-directiveness (0·81, 0·28 to 1·52), improved attention disengagement (0·48, −0·01 to 1·02), and improved parent-rated infant adaptive function (χ2[2] 15·39, p=0·0005). There was a possibility of nil or negative effect in language and responsivity to vowel change (P1: ES–0·62, CI −2·42 to 0·31; P2: −0·29, −1·55 to 0·71).InterpretationWith the exception of the response to vowel change, our study showed positive estimates across a wide range of behavioural and brain function risk-markers and developmental outcomes that are consistent with a moderate intervention effect to reduce the risk for later autism. However, the estimates have wide CIs that include possible nil or small negative effects. The results are encouraging for development and prevention science, but need larger-scale replication to improve precision.FundingAutistica, Waterloo Foundation, Autism Speaks, and the UK Medical Research Council.

BackgroundThere has been increasing interest in the potential for pre‐emptive interventions in the prodrome of autism, but little investigation as to their effect.MethodsA two‐site, two‐arm assessor‐blinded randomised controlled trial (RCT) of a 12‐session parent‐mediated social communication intervention delivered between 9 and 14 months of age (Intervention in the British Autism Study of Infant Siblings‐Video Interaction for Promoting Positive Parenting), against no intervention. Fifty‐four infants (28 intervention, 26 nonintervention) at familial risk of autism but not otherwise selected for developmental atypicality were assessed at 9‐month baseline, 15‐month treatment endpoint, and 27‐ and 39‐month follow‐up. Primary outcome: severity of autism prodromal symptoms, blind‐rated on Autism Observation Schedule for Infants or Autism Diagnostic Observation Schedule 2nd Edition across the four assessment points. Secondary outcomes: blind‐rated parent–child interaction and child language; nonblind parent‐rated communication and socialisation. Prespecified intention‐to‐treat analysis combined estimates from repeated measures within correlated regressions to estimate the overall effect of the infancy intervention over time.ResultsEffect estimates in favour of intervention on autism prodromal symptoms, maximal at 27 months, had confidence intervals (CIs) at each separate time point including the null, but showed a significant overall effect over the course of the intervention and follow‐up period (effect size [ES] = 0.32; 95% CI 0.04, 0.60; p = .026). Effects on proximal intervention targets of parent nondirectiveness/synchrony (ES = 0.33; CI 0.04, 0.63; p = .013) and child attentiveness/communication initiation (ES = 0.36; 95% CI 0.04, 0.68; p = .015) showed similar results. There was no effect on categorical diagnostic outcome or formal language measures.ConclusionsFollow‐up to 3 years of the first RCT of a very early social communication intervention for infants at familial risk of developing autism has shown a treatment effect, extending 24 months after intervention end, to reduce the overall severity of autism prodromal symptoms and enhance parent–child dyadic social communication over this period. We highlight the value of extended follow‐up and repeat assessment for early intervention trials.

BackgroundThe 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.MethodsLEAP 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.ResultsHere, 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).ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0146-8) contains supplementary material, which is available to authorized users.