Purpose of review

Much of our understanding of early development in children with autism spectrum disorder (ASD) comes from studies of children with a family history of autism. We reviewed the current literature on neurodevelopmental profiles and autism prevalence from other high-risk infant groups to expose gaps and inform next steps. We focused on infants with early medical risk (e.g., preterm birth) and genetic risk (tuberous sclerosis complex [TSC]).

Recent findings

About 7% of very preterm infants are later diagnosed with ASD. Prospective studies of early development outside of familial-risk infants are rare; however, recent work within preterm and TSC infants suggests interesting similarities and differences from infants with a family history of ASD. It is essential that we extend our knowledge of early markers of ASD beyond familial-risk infants to expand our knowledge of autism as it emerges in order to develop better, more individualized early interventions.

BACKGROUND: The TAND (Tuberous Sclerosis Complex [TSC]-Associated Neuropsychiatric Disorders) Checklist was developed as a clinical screener for neurodevelopmental disorders in TSC. Most studies have described patterns in older children and adults. This study sought to better understand behavioral concerns as measured by the TAND Checklist in young children with TSC. METHODS: We examined patterns of caregiver responses to the TAND Checklist in 90 toddlers with TSC (12 to 23 months n = 60; 24 to 36 months n = 30) through data collected during baseline visits across two TSC early intervention studies. RESULTS: Over 90% of caregivers reported at least one behavioral concern related to TAND. The number of concerns increased with age. Delayed language was the most frequently reported concern across ages (12 to 23 months: 58.3%, 24 to 36 months: 86.7%). Questions related to behavioral concerns were largely relevant in this age range, but questions in other areas, such as neuropsychological or academic function, were not. CONCLUSIONS: TAND symptoms are very common in toddlers with TSC, and these symptoms may increase with age. The TAND Checklist is a useful tool for identifying behavioral concerns efficiently, but several items and sections are not suited to younger children. Results support the development of an abbreviated form of the TAND Checklist for toddlers.

Postpartum depression (PPD) can interfere with the establishment of affective bonds between infant and mother, which is important for the cognitive, social-emotional, and physical development of the child. Rates of PPD have increased during the COVID-19 pandemic, likely due to the added stress and limited support available to new parents. The present study examined whether parenting-related stress, perceived bonding impairments, the quality of observed mother-infant interactions, and salivary oxytocin levels differ between depressed and non-depressed mothers, along with differential impacts of COVID-19 on depressed mothers. Participants included 70 mothers (45 depressed, 25 controls) with infants aged 2-6 months. All data were collected remotely to ease participant burden during the pandemic. Depression was associated with experiences of heightened parenting-related stress and bonding difficulties. These differences were not observed during mother-infant interactions or in salivary oxytocin levels. Differences in COVID-19-related experiences were minimal, though depressed mothers rated slightly higher stress associated with returning to work and financial impacts of the pandemic. Findings highlight the importance of early intervention for PPD to mitigate long-term effects on mothers, children, and families. Additionally, they underscore the need for early intervention to support the developing mother-infant dyad relationship during this crucial time.

Background

Research in rare genetic syndromes associated with ASD is often hampered by the wide geographic distribution of families and the presence of medical comorbidities, such as epilepsy, that may preclude travel to clinical sites. These challenges can limit the sample size and generalizability of the cohorts included in both natural history studies and clinical trials. Tuberous sclerosis complex (TSC) is a rare genetic syndrome that confers an elevated risk for autism spectrum disorder (ASD), with social communication delays identified in this population as early as 12 months of age. Early identification of risk necessitates parallel testing of early intervention, prompting the first randomized controlled clinical trial of behavioral intervention for infants with TSC (NCT03422367). However, considerable early recruitment challenges have mandated the systematic identification of enrollment barriers followed by modification of the study design to address these barriers.

Methods

Caregivers were interviewed regarding barriers to enrollment (phase 1). Adaptations to the intervention were made to address these barriers (phase 2). Outcomes based on this modification to the study design were defined by enrollment rate and participant demographics.

Results

Qualitative reports from caregivers indicated that distance and time were the primary barriers to clinical trial enrollment. The intervention was then modified to a remote model, with at-home, parent-delivered intervention, and weekly video conferencing with interventionists at the study sites. Enrollment increased 10-fold (from 3 to 30 participants) within 1 year and included a more diverse and clinically representative cohort of infants.

Conclusion

The design and implementation of more scalable methods to disseminate research remotely can substantially improve access to clinical trials in rare neurodevelopmental disorders. The lessons learned from this trial can serve as a model for future studies not only in rare conditions, but in other populations that lack adequate access, such as families with limited financial or clinical resources. Continued efforts will further refine delivery methods to enhance efficiency and ease of these delivery systems for families.

Background

Functional brain connectivity is altered in children and adults with autism spectrum disorder (ASD). Functional disruption during infancy could provide earlier markers of ASD, thus providing a crucial opportunity to improve developmental outcomes. Using a whole-brain multivariate approach, we asked whether electroencephalography measures of neural connectivity at 3 months of age predict autism symptoms at 18 months.

Methods

Spontaneous electroencephalography data were collected from 65 infants with and without familial risk for ASD at 3 months of age. Neural connectivity patterns were quantified using phase coherence in the alpha range (6-12 Hz). Support vector regression analysis was used to predict ASD symptoms at age 18 months, with ASD symptoms quantified by the Toddler Module of the Autism Diagnostic Observation Schedule, Second Edition.

Results

Autism Diagnostic Observation Schedule scores predicted by support vector regression algorithms trained on 3-month electroencephalography data correlated highly with Autism Diagnostic Observation Schedule scores measured at 18 months (r = .76, p = .02, root-mean-square error = 2.38). Specifically, lower frontal connectivity and higher right temporoparietal connectivity at 3 months predicted higher ASD symptoms at 18 months. The support vector regression model did not predict cognitive abilities at 18 months (r = .15, p = .36), suggesting specificity of these brain patterns to ASD.

Conclusions

Using a data-driven, unbiased analytic approach, neural connectivity across frontal and temporoparietal regions at 3 months predicted ASD symptoms at 18 months. Identifying early neural differences that precede an ASD diagnosis could promote closer monitoring of infants who show signs of neural risk and provide a crucial opportunity to mediate outcomes through early intervention.

Tuberous sclerosis complex (TSC) is a rare genetic syndrome that confers risk for neurodevelopmental disorders, including autism spectrum disorder and intellectual disability. Delays in social communication and early cognitive abilities are observable as early as 9 months of age in children with TSC; however, there have been no studies of early behavioral intervention in TSC. We conducted a pilot study of an evidence-based, parent-mediated behavioral intervention focused on improving early social communication and play skills in 5 children with TSC (aged 1-3 years). Participants showed maintenance and sometimes gains in developmental abilities, relative to peers, following intervention. Parents generally found the intervention to be helpful and were able to administer the intervention with fidelity. Preliminary results demonstrate initial feasibility of an early play-based, parent-mediated intervention and support the need for a large-scale, randomized clinical trial in TSC.

Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic syndrome that confers significantly increased risk for autism spectrum disorder (ASD), with 50-60% of infants with TSC meeting criteria for ASD by 3 years of age. In a previous study of the current longitudinal cohort, we found that infants with TSC who develop ASD (TSC/ASD) evidence decreased cognitive abilities that diverge from infants with TSC and no ASD (TSC/no ASD). We extended this work by asking whether TSC/ASD infants (n = 13) differed from TSC/no ASD infants (n = 10) and infants with low developmental risk and no ASD (LR; n = 21) in their social communication functioning during the first year of life. We measured early ASD symptoms with the Autism Observation Scale for Infants (AOSI) at 9 and 12 months of age. At both ages, infants in the TSC/ASD group had significantly higher AOSI total scores than infants in the TSC/no ASD and LR groups, which were not fully explained by differences in cognitive abilities. Several items on the AOSI at both ages were predictive of ASD outcome, particularly those representing core social communication deficits (e.g., social referencing). Our findings signal the need for further study of this population within the first year and provide strong justification for early identification and early intervention targeting social communication skills in infants with TSC. Autism Res 2017, 10: 1981-1990. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Lay summary

We examined early signs of autism spectrum disorder (ASD) in infants with tuberous sclerosis complex (TSC), approximately 50% of whom will meet criteria for ASD by age 3. Infants with TSC and ASD showed deficits in social communication behaviors by 9 months of age that were clearly distinguishable from behaviors in infants with TSC who do not develop ASD and low risk infants. Results support the importance of early ASD screening and intervention for infants with TSC.

Despite growing evidence implicating thalamic functional connectivity atypicalities in autism spectrum disorder (ASD), it remains unclear how such alterations emerge early in human development. Because the thalamus plays a critical role in sensory processing and neocortical organization early in life, its connectivity with other cortical regions could be key for studying the early onset of core ASD symptoms. Here, we investigated emerging thalamocortical functional connectivity in infants at high (HL) and typical (TL) familial likelihood for ASD in early and late infancy. We report significant thalamo-limbic hyperconnectivity in 1.5-month-old HL infants, and thalamo-cortical hypoconnectivity in prefrontal and motor regions in 9-month-old HL infants. Importantly, early sensory over-responsivity (SOR) symptoms in HL infants predicted a direct trade-off in thalamic connectivity whereby stronger thalamic connectivity with primary sensory regions and basal ganglia was inversely related to connectivity with higher order cortices. This trade-off suggests that ASD may be characterized by early differences in thalamic gating. The patterns reported here could directly underlie atypical sensory processing and attention to social vs. nonsocial stimuli observed in ASD. These findings lend support to a theoretical framework of ASD whereby early disruptions in sensorimotor processing and attentional biases early in life may cascade into core ASD symptomatology.

BACKGROUND: While the cerebellum is traditionally known for its role in sensorimotor control, emerging research shows that particular subregions, such as right Crus I (RCrusI), support language and social processing. Indeed, cerebellar atypicalities are commonly reported in autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by socio-communicative impairments. However, the cerebellums contribution to early socio-communicative development remains virtually unknown. METHODS: Here, we characterized functional connectivity within cerebro-cerebellar networks implicated in language/social functions in 9-month-old infants who exhibit distinct 3-year socio-communicative developmental profiles. We employed a data-driven clustering approach to stratify our sample of infants at high (n = 82) and low (n = 37) familial risk for ASD into three cohorts-Delayed, Late-Blooming, and Typical-who showed unique socio-communicative trajectories. We then compared the cohorts on indices of language and social development. Seed-based functional connectivity analyses with RCrusI were conducted on infants with fMRI data (n = 66). Cohorts were compared on connectivity estimates from a-priori regions, selected on the basis of reported coactivation with RCrusI during language/social tasks. RESULTS: The three trajectory-based cohorts broadly differed in social communication development, as evidenced by robust differences on numerous indices of language and social skills. Importantly, at 9 months, the cohorts showed striking differences in cerebro-cerebellar circuits implicated in language/social functions. For all regions examined, the Delayed cohort exhibited significantly weaker RCrusI connectivity compared to both the Late-Blooming and Typical cohorts, with no significant differences between the latter cohorts. CONCLUSIONS: We show that hypoconnectivity within distinct cerebro-cerebellar networks in infancy predicts altered socio-communicative development before delays overtly manifest, which may be relevant for early detection and intervention. As the cerebellum is implicated in prediction, our findings point to probabilistic learning as a potential intermediary mechanism that may be disrupted in infancy, cascading into alterations in social communication.

Objectives

Autism spectrum disorder (ASD) is estimated to be ∼10 times higher in children with versus without an autistic sibling in population-based studies. Prospective studies of infant siblings have revealed even higher familial recurrence rates. In the current prospective longitudinal study, we provide updated estimates of familial ASD recurrence using a multinational database of infants with older autistic siblings.

Methods

Data were collated across 18 sites of the Baby Siblings Research Consortium, an international network studying the earliest manifestations of ASD. A total of 1605 infants with an older autistic sibling were followed from early in life to 3 years, when they were classified as ASD or non-ASD. Hierarchical generalized linear modeling, with site as a random effect, was used to examine predictors of recurrence in families and calculate likelihood ratios.

Results

A total of 20.2% of siblings developed ASD, which is not significantly higher than the previously reported rate of 18.7%. Male infant sex and >1 older affected sibling were significant predictors of familial recurrence. Proband sex also influenced recurrence rates, with siblings of female probands significantly more likely to develop ASD than siblings of male probands. Race and maternal education were also associated with recurrence in families.

Conclusions

The familial recurrence rate of ASD, as measured in infant sibling studies, has not changed appreciably since previous estimates were made in 2011. Younger siblings of autistic children, particularly those who are male, have an affected female sibling, multiple affected siblings, or are impacted by social inequities, should be closely monitored and promptly referred for diagnostic evaluation.