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BACKGROUND: Although investigations have begun to differentiate biological and neurobiological responses to a variety of adversities, studies considering both endocrine and immune function in the same datasets are limited. METHODS: Associations between proximal (family functioning, caregiver depression, and anxiety) and distal (SES-D; socioeconomic disadvantage) early-life adversities with salivary inflammatory biomarkers (IL-1β, IL-6, IL-8, and TNF-α) and hair HPA markers (cortisol, cortisone, and dehydroepiandrosterone) were examined in two samples of young U.S. children (N = 142; N = 145). RESULTS: Children exposed to higher SES-D had higher levels of TNF-α (B = 0.13, p = 0.011), IL-1β (B = 0.10, p = 0.033), and DHEA (B = 0.16, p = 0.011). Higher family dysfunction was associated with higher cortisol (B = 0.08, p = 0.033) and cortisone (B = 0.05, p = 0.003). An interaction between SES-D and family dysfunction was observed for cortisol levels (p = 0.020) whereby children exposed to lower/average levels of SES-D exhibited a positive association between family dysfunction and cortisol levels, whereas children exposed to high levels of SES-D did not. These findings were partially replicated in the second sample. CONCLUSIONS: Our results indicate that these biological response systems may react differently to different forms of early-life adversity. IMPACT: Different forms of early-life adversity have varied stress signatures, and investigations of early-life adversities with inflammation and HPA markers are lacking. Children with higher socioeconomic disadvantage had higher TNF-α, IL-1β, and DHEA. Higher family dysfunction was associated with higher hair cortisol and cortisone levels, and the association between family dysfunction and cortisol was moderated by socioeconomic disadvantage. Biological response systems (immune and endocrine) were differentially associated with distinct forms of early-life adversities.

Visual exploration paradigms involving object arrays have been used to examine salience of social stimuli such as faces in ASD. Recent work suggests performance on these paradigms may associate with clinical features of ASD. We evaluate metrics from a visual exploration paradigm in 4-to-11-year-old children with ASD (n = 23; 18 males) and typical development (TD; n = 23; 13 males). Presented with arrays containing faces and nonsocial stimuli, children with ASD looked less at (p = 0.002) and showed fewer fixations to (p = 0.022) faces than TD children, and spent less time looking at each object on average (p = 0.004). Attention to the screen and faces correlated positively with social and cognitive skills in the ASD group (ps < 0.05). This work furthers our understanding of objective measures of visual exploration in ASD and its potential for quantifying features of ASD.

Institutional rearing negatively impacts the development of children's social skills and executive functions (EF). However, little is known about whether childhood social skills mediate the effects of the foster care intervention (FCG) and foster caregiving quality following early institutional rearing on EF and social skills in adolescence. We examined (a) whether children's social skills at 8 years mediate the impact of the FCG on the development of EF at ages 12 and 16 years, and (b) whether social skills and EF at ages 8 and 12 mediate the relation between caregiving quality in foster care at 42 months and subsequent social skills and EF at age 16. Participants included abandoned children from Romanian institutions, who were randomly assigned to a FCG (n = 68) or care as usual (n = 68), and a never-institutionalized group (n = 135). At ages 8, 12, and 16, social skills were assessed via caregiver and teacher reports and EF were assessed via the Cambridge Neuropsychological Test Automated Battery. Caregiving quality of foster caregivers was observed at 42 months. FCG predicted better social skills at 8 years, which in turn predicted better EF in adolescence. Higher caregiver quality in foster care at 42 months predicted better social skills at 8 and 12 years, and better EF at 12 years, which in turn predicted 16-year EF and social skills. These findings suggest that interventions targeting caregiving quality within foster care home environments may have long-lasting positive effects on children's social skills and EF.

We examined whether family care following early-life deprivation buffered the association between stressful life events (SLEs) and executive functioning (EF) in adolescence. In early childhood, 136 institutionally reared children were randomly assigned to foster care or care-as-usual; 72 never-institutionalized children served as a comparison group. At age 16 years, adolescents (n = 143; 54% female; 67.1% Romanian) self-reported recent SLEs, completed a battery of memory and EF tasks, and completed a go/nogo task in which mediofrontal theta power (MFTP) was measured using electroencephalogram. More independent SLEs predicted lower EF and more dependent SLEs predicted lower MFTP, but only among adolescents with prolonged early deprivation. Findings provide preliminary evidence that family care following early deprivation may facilitate resilience against stress during adolescence on EF.

Frontal asymmetry (FA), the difference in brain activity between the left versus right frontal areas, is thought to reflect approach versus avoidance motivation. This study (2012-2021) used functional near-infrared spectroscopy to investigate if infant (M[subscript age] = 7.63 months; N = 90; n = 48 male; n = 75 White) FA in the dorsolateral prefrontal cortex relates to psychopathology in later childhood (M[subscript age] = 62.05 months). Greater right FA to happy faces was associated with increased internalizing ([eta][superscript 2] = 0.09) and externalizing ([eta][superscript 2] = 0.06) problems at age 5 years. Greater right FA to both happy and fearful faces was associated with an increased likelihood of a lifetime anxiety diagnosis (R[superscript 2] > 0.13). FA may be an informative and early-emerging marker for psychopathology.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

There is strong support for the view that children growing up in low-income homes typically evince poorer performance on tests of inhibitory control compared to those growing up in higher income homes. Unfortunately, the vast majority of the work documenting this association has been conducted in high-income countries. It is not yet known whether the mechanisms found to mediate this association would generalize to children in low- and middle-income countries, where the risks of exposure to extreme poverty and a wide range of both biological and psychosocial hazards may be greater. We examined relations among early adversity, neural correlates of inhibitory control, and cognitive outcomes in 154 5-year-old children living in Dhaka, Bangladesh, an area with a high prevalence of poverty. Participants completed a go/no-go task assessing inhibitory control and their behavioral and event-related potential responses were assessed. Cortical source analysis was performed. We collected measures of poverty, malnutrition, maternal mental health, psychosocial adversity, and cognitive skills. Supporting studies in high-income countries, children in this sample exhibited a longer N2 latency and higher P3 amplitude to the no-go versus go condition. Unexpectedly, children had a more pronounced N2 amplitude during go trials than no-go trials. The N2 latency was related to their behavioral accuracy on the go/no-go task. The P3 mean amplitude, behavioral accuracy, and reaction time during the task were all associated with intelligence-quotient (IQ) scores. Children who experienced higher levels of psychosocial adversity had lower accuracy on the task and lower IQ scores.

Over the last 20 years, we have learned much about the extent to which early-life deprivation affects the mental health of children and adolescents. This body of evidence comes predominantly from studies of children raised in institutional care. The Bucharest Early Intervention Project (BEIP) is the only randomized controlled trial designed to evaluate whether the transition to family-based foster care early in development can ameliorate the long-term impact of institutional deprivation on psychopathology during vulnerable developmental windows such as adolescence. In this review, we detail the extent to which early deprivation affects mental health during this period, the capacity of family-based care to facilitate recovery from early deprivation, and the mechanisms underpinning these effects spanning social-emotional, cognitive, stress, and neurobiological domains. We end by discussing the implications and directions for the BEIP and other studies of youth raised in institutions.

BackgroundPostnatal maternal anxiety is common (estimates as high as 40% prevalence) and is associated with altered mother-infant interactions (e.g., reduced maternal emotional expression and engagement). Neural circuitry supporting infants' face and emotion processing develops in their first year. Thus, early exposure to maternal anxiety may impact infants' developing understanding of emotional displays. We examine whether maternal anxiety is associated with individual differences in typically developing infants' neural responses to emotional faces.MethodsOne hundred and forty two mother-infant dyads were assessed when infants were 5, 7, or 12 months old. Infants' electroencephalographic (EEG) data were recorded while passively viewing female happy, fearful, and angry faces. Three event-related potential (ERP) components, each linked to face and emotion processing, were evaluated: NC, N290, and P400. Infant ERP amplitude was related to concurrent maternal-report anxiety assessed with the Spielberger State-Trait Anxiety Inventory (Trait form).ResultsGreater maternal anxiety predicted more negative NC amplitude for happy and fearful faces in left and mid-central scalp regions, beyond covarying influences of maternal depression symptoms, infant negative emotionality, and infant age.ConclusionsPostnatal maternal anxiety is related to infants' neural processing of emotional expressions. Infants of mothers endorsing high trait anxiety may need additional attentional resources to process happy and fearful faces (expressions less likely experienced in mother-infant interactions). Future research should investigate mechanisms underlying this association, given possibilities include experiential, genetic, and prenatal factors.

In this study we investigated the impact of parental language input on language development and associated neuroscillatory patterns in toddlers at risk of Autism Spectrum Disorder (ASD). Forty-six mother-toddler dyads at either high (n = 22) or low (n = 24) familial risk of ASD completed a longitudinal, prospective study including free-play, resting electroencephalography, and standardized language assessments. Input quantity/quality at 18 months positively predicted expressive language at 24 months, and relationships were stronger for high-risk toddlers. Moderated mediations revealed that input-language relationships were explained by 24-month frontal and temporal gamma power (30-50 Hz) for high-risk toddlers who would later develop ASD. Results suggest that high-risk toddlers may be cognitively and neurally more sensitive to their language environments, which has implications for early intervention.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

We examined the communicative intentions behind parents' deictic gesture use with high-risk infants later diagnosed with autism spectrum disorder (ASD; n = 17), high-risk infants who were not diagnosed with ASD (n = 25), and low-risk infants (n = 28) at 12 months and assessed the extent to which the parental deictic gesture intentions predicted infants' later vocabulary development. We found that parents in the three groups produced similar numbers of declarative and imperative gestures during a 10-minute parent-child interaction in the lab at 12 months and that 12-month parental declarative gesture use was significantly, positively associated with children's 36-month vocabulary scores. Encouraging parental use of declarative gestures with infants could have important implications for language development.

BackgroundResearch 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.MethodsCaregivers 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.ResultsQualitative 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.ConclusionThe 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.

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.

Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8-17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.

Autism is hypothesized to be in part driven by a reduced sensitivity to the inherently rewarding nature of social stimuli. Previous neuroimaging studies have indicated that autistic males do indeed display reduced neural activity to social rewards, but it is unknown whether this finding extends to autistic females, particularly as behavioral evidence suggests that affected females may not exhibit the same reduction in social motivation as their male peers. We therefore used functional magnetic resonance imaging to examine social reward processing during an instrumental implicit learning task in 154 children and adolescents (ages 8-17): 39 autistic girls, 43 autistic boys, 33 typically developing girls, and 39 typically developing boys. We found that autistic girls displayed increased activity to socially rewarding stimuli, including greater activity in the nucleus accumbens relative to autistic boys, as well as greater activity in lateral frontal cortices and the anterior insula compared with typically developing girls. These results demonstrate for the first time that autistic girls do not exhibit the same reduction in activity within social reward systems as autistic boys. Instead, autistic girls display increased neural activation to such stimuli in areas related to reward processing and salience detection. Our findings indicate that a reduced sensitivity to social rewards, as assessed with a rewarded instrumental implicit learning task, does not generalize to affected female youth and highlight the importance of studying potential sex differences in autism to improve our understanding of the condition and its heterogeneity.

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.

Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short periods is critically important. In the field of autism spectrum disorder (ASD), resting electroencephalography (EEG) power spectral densities (PSD) are well-studied for their potential as biomarkers. Classically, such data have been decomposed into pre-specified frequency bands (e.g., delta, theta, alpha, beta, and gamma). Recent technical advances, such as the Fitting Oscillations and One-Over-F (FOOOF) algorithm, allow for targeted characterization of the features that naturally emerge within an EEG PSD, permitting a more detailed characterization of the frequency band-agnostic shape of each individual's EEG PSD. Here, using two resting EEGs collected a median of 6 days apart from 22 children with ASD and 25 typically developing (TD) controls during the Feasibility Visit of the Autism Biomarkers Consortium for Clinical Trials, we estimate test-retest reliability based on the characterization of the PSD shape in two ways: (1) Using the FOOOF algorithm we estimate six parameters (offset, slope, number of peaks, and amplitude, center frequency and bandwidth of the largest alpha peak) that characterize the shape of the EEG PSD; and (2) using nonparametric functional data analyses, we decompose the shape of the EEG PSD into a reduced set of basis functions that characterize individual power spectrum shapes. We show that individuals exhibit idiosyncratic PSD signatures that are stable over recording sessions using both characterizations. Our data show that EEG activity from a brief 2-min recording provides an efficient window into characterizing brain activity at the single-subject level with desirable psychometric characteristics that persist across different analytical decomposition methods. This is a necessary step towards analytical validation of biomarkers based on the EEG PSD and provides insights into parameters of the PSD that offer short-term reliability (and thus promise as potential biomarkers of trait or diagnosis) vs. those that are more variable over the short term (and thus may index state or other rapidly dynamic measures of brain function). Future research should address the longer-term stability of the PSD, for purposes such as monitoring development or response to treatment.