Multilayer network associations between the exposome and childhood brain development.

Growing up in a high poverty neighborhood is associated with elevated risk for academic challenges and health problems. Here, we take a data-driven approach to exploring how measures of children's environments relate to the development of their brain structure and function in a community sample of children between the ages of 4 and 10 years. We constructed exposomes including measures of family socioeconomic status, children's exposure to adversity, and geocoded measures of neighborhood socioeconomic status, crime, and environmental toxins. We connected the exposome to two structural measures (cortical thickness and surface area, n = 170) and two functional measures (participation coefficient and clustering coefficient, n = 130). We found dense connections within exposome and brain layers and sparse connections between exposome and brain layers. Lower family income was associated with thinner visual cortex, consistent with the theory that accelerated development is detectable in early-developing regions. Greater neighborhood incidence of high blood lead levels was associated with greater segregation of the default mode network, consistent with evidence that toxins are deposited into the brain along the midline. Our study demonstrates the utility of multilayer network analysis to bridge environmental and neural explanatory levels to better understand the complexity of child development.

Developmental Correlates of Accelerated Molar Eruption in Early Childhood.

Background: Adversity has been linked to accelerated maturation. Molar eruption is a simple and scalable way to identify early maturation, but its developmental correlates remain unexplored. Thus, we examined whether accelerated maturation as indexed by molar eruption is associated with children's mental health or cognitive skills. Methods: Molar eruption was evaluated from T2-weighted magnetic resonance imaging in 117 children (63 female; ages 4-7 years). Parents reported on child mental health with the Child Behavior Checklist. Children completed standardized assessments of fluid reasoning, working memory, processing speed, crystallized knowledge, and math performance. Relationships between molar eruption and developmental outcomes were examined using linear models, with age, gender, and stress risk as covariates. Results: Earlier molar eruption was positively associated with children's externalizing symptoms (false discovery rate-corrected p [pFDR] = .027) but not internalizing symptoms, and the relationship with externalizing symptoms did not hold when controlling for stress risk. Earlier molar eruption was negatively associated with fluid reasoning (pFDR < .001), working memory (pFDR = .033), and crystallized knowledge (pFDR = .001). The association between molar eruption and both reasoning and crystallized knowledge held when controlling for stress risk. Molar eruption also partially mediated associations between stress risk and both reasoning (proportion mediated = 0.273, p = .004) and crystallized knowledge (proportion mediated = 0.126, p = .016). Conclusions: Accelerated maturation, as reflected in early molar eruption, may have consequences for cognitive development, perhaps because it constrains brain plasticity. Knowing the pace of a child's maturation may provide insight into the impact of a child's stress history on their cognitive development.

A systematic review of interventions to ameliorate the impact of adversity on brain development.

Adversity, including abuse, neglect, and poverty, impacts child brain development. However, the developing brain is highly plastic, and some of the impacts of childhood adversity may be mitigated by psychosocial interventions. The purpose of this review is to synthesize literature on neural outcomes of childhood interventions among individuals exposed to adversity. A systematic literature search identified 36 reports of 13 interventions. Overall, these studies provide evidence for experience-dependent plasticity in the developing brain. We synthesize studies in light of three themes. First, there was mixed evidence for a benefit of a younger age at intervention. Second, interventions tended to accelerate functional brain development, but the impact of interventions on the pace of structural brain development was less clear. Third, individual differences in intervention response were difficult to predict, in part due to small samples. However, there was significant variability in intervention type and timing, neuroimaging outcomes, and follow-up timing. Together, the studies reviewed here hold promise for the role of psychosocial interventions in ameliorating the neurodevelopmental consequences of childhood adversity.

Individual differences in T1w/T2w ratio development during childhood.

Myelination is a key developmental process that promotes rapid and efficient information transfer. Myelin also stabilizes existing brain networks and thus may constrain neuroplasticity, defined here as the brain's potential to change in response to experiences rather than the canonical definition as the process of change. Characterizing individual differences in neuroplasticity may shed light on mechanisms by which early experiences shape learning, brain and body development, and response to interventions. The T1-weighted/T2-weighted (T1w/T2w) MRI signal ratio is a proxy measure of cortical microstructure and thus neuroplasticity. Here, in pre-registered analyses, we investigated individual differences in T1w/T2w ratios in children (ages 4-10, n = 157). T1w/T2w ratios were positively associated with age within early-developing sensorimotor and attention regions. We also tested whether socioeconomic status, cognition (crystallized knowledge or fluid reasoning), and biological age (as measured with molar eruption) were related to T1w/T2w signal but found no significant effects. Associations among T1w/T2w ratios, early experiences, and cognition may emerge later in adolescence and may not be strong enough to detect in moderate sample sizes.

To Proceed Via Telehealth or Not? Considerations for Pediatric Anxiety and Related Disorders Beyond COVID-19.

The COVID-19 pandemic accelerated a widespread shift to telehealth among mental health professionals to prioritize both providers' and clients' safety. Telehealth is likely here to stay; however, there is limited practical guidance for clinicians about how to make decisions regarding who should proceed with care via telehealth versus in-person. There also is virtually no data on the effectiveness of hybrid approaches to care; yet this can be an attractive option with potential clinical benefit. This paper provides practice-informed guidance to support shared clinical decision-making between clinicians and families to decide whether to engage in therapy services in-person or via telehealth. We specifically focus on decision-making guidance relevant for youth with anxiety or related disorders, given the unique implications of telehealth for these youth. Guided by the three-legged stool of evidence-based practice, we discuss how clinicians can use principles of shared decision-making to inform clinical recommendations about treatment modality.

The Age of Reason: Functional Brain Network Development during Childhood.

Human childhood is characterized by dramatic changes in the mind and brain. However, little is known about the large-scale intrinsic cortical network changes that occur during childhood because of methodological challenges in scanning young children. Here, we overcome this barrier by using sophisticated acquisition and analysis tools to investigate functional network development in children between the ages of 4 and 10 years ([Formula: see text]; 50 female, 42 male). At multiple spatial scales, age is positively associated with brain network segregation. At the system level, age was associated with segregation of systems involved in attention from those involved in abstract cognition, and with integration among attentional and perceptual systems. Associations between age and functional connectivity are most pronounced in visual and medial prefrontal cortex, the two ends of a gradient from perceptual, externally oriented cortex to abstract, internally oriented cortex. These findings suggest that both ends of the sensory-association gradient may develop early, in contrast to the classical theories that cortical maturation proceeds from back to front, with sensory areas developing first and association areas developing last. More mature patterns of brain network architecture, controlling for age, were associated with better visuospatial reasoning abilities. Our results suggest that as cortical architecture becomes more specialized, children become more able to reason about the world and their place in it.SIGNIFICANCE STATEMENT Anthropologists have called the transition from early to middle childhood the "age of reason", when children across cultures become more independent. We employ cutting-edge neuroimaging acquisition and analysis approaches to investigate associations between age and functional brain architecture in childhood. Age was positively associated with segregation between cortical systems that process the external world and those that process abstract phenomena like the past, future, and minds of others. Surprisingly, we observed pronounced development at both ends of the sensory-association gradient, challenging the theory that sensory areas develop first and association areas develop last. Our results open new directions for research into how brains reorganize to support rapid gains in cognitive and socioemotional skills as children reach the age of reason.

Early stressful experiences are associated with reduced neural responses to naturalistic emotional and social content in children.

How do children's experiences relate to their naturalistic emotional and social processing? Because children can struggle with tasks in the scanner, we collected fMRI data while 4-to-11-year-olds watched a short film with positive and negative emotional events, and rich parent-child interactions (n = 70). We captured broad, normative stressful experiences by examining socioeconomic status (SES) and stressful life events, as well as children's more proximal experiences with their parents. For a sub-sample (n = 30), parenting behaviors were measured during a parent-child interaction, consisting of a picture book, a challenging puzzle, and free play with novel toys. We characterized positive parenting behaviors (e.g., warmth, praise) and negative parenting behaviors (e.g., harsh tone, physical control). We found that higher SES was related to greater activity in medial orbitofrontal cortex during parent-child interaction movie events. Negative parenting behaviors were associated with less activation of the ventral tegmental area and cerebellum during positive emotional events. In a region-of-interest analysis, we found that stressful life events and negative parenting behaviors were associated with less activation of the amygdala during positive emotional events. These exploratory results demonstrate the promise of using movie fMRI to study how early experiences may shape emotional, social, and motivational processes.

Regional White Matter Scaling in the Human Brain.

Anatomical organization of the primate cortex varies as a function of total brain size, where possession of a larger brain is accompanied by disproportionate expansion of associative cortices alongside a relative contraction of sensorimotor systems. However, equivalent scaling maps are not yet available for regional white matter anatomy. Here, we use three large-scale neuroimaging datasets to examine how regional white matter volume (WMV) scales with interindividual variation in brain volume among typically developing humans (combined N = 2391: 1247 females, 1144 males). We show that WMV scaling is regionally heterogeneous: larger brains have relatively greater WMV in anterior and posterior regions of cortical white matter, as well as the genu and splenium of the corpus callosum, but relatively less WMV in most subcortical regions. Furthermore, regions of positive WMV scaling tend to connect previously-defined regions of positive gray matter scaling in the cortex, revealing a coordinated coupling of regional gray and white matter organization with naturally occurring variations in human brain size. However, we also show that two commonly studied measures of white matter microstructure, fractional anisotropy (FA) and magnetization transfer (MT), scale negatively with brain size, and do so in a manner that is spatially unlike WMV scaling. Collectively, these findings provide a more complete view of anatomic scaling in the human brain, and offer new contexts for the interpretation of regional white matter variation in health and disease.SIGNIFICANCE STATEMENT Recent work has shown that, in humans, regional cortical and subcortical anatomy show systematic changes as a function of brain size variation. Here, we show that regional white matter structures also show brain-size related changes in humans. Specifically, white matter regions connecting higher-order cortical systems are relatively expanded in larger human brains, while subcortical and cerebellar white matter tracts responsible for unimodal sensory or motor functions are relatively contracted. This regional scaling of white matter volume (WMV) is coordinated with regional scaling of cortical anatomy, but is distinct from scaling of white matter microstructure. These findings provide a more complete view of anatomic scaling of the human brain, with relevance for evolutionary, basic, and clinical neuroscience.

Early life stress is associated with earlier emergence of permanent molars.

Exposure to adversity can accelerate biological aging. However, existing biomarkers of early aging are either costly and difficult to collect, like epigenetic signatures, or cannot be detected until late childhood, like pubertal onset. We evaluated the hypothesis that early adversity is associated with earlier molar eruption, an easily assessed measure that has been used to track the length of childhood across primates. In a preregistered analysis (n = 117, ages 4 to 7 y), we demonstrate that lower family income and exposure to adverse childhood experiences (ACEs) are significantly associated with earlier eruption of the first permanent molars, as rated in T2-weighted magnetic resonance images (MRI). We replicate relationships between income and molar eruption in a population-representative dataset (National Health and Nutrition Examination Survey; n = 1,973). These findings suggest that the impact of stress on the pace of biological development is evident in early childhood, and detectable in the timing of molar eruption.

Morphological integration of the human brain across adolescence and adulthood.

Brain structural covariance norms capture the coordination of neurodevelopmental programs between different brain regions. We develop and apply anatomical imbalance mapping (AIM), a method to measure and model individual deviations from these norms, to provide a lifespan map of morphological integration in the human cortex. In cross-sectional and longitudinal data, analysis of whole-brain average anatomical imbalance reveals a reproducible tightening of structural covariance by age 25 y, which loosens after the seventh decade of life. Anatomical imbalance change in development and in aging is greatest in the association cortex and least in the sensorimotor cortex. Finally, we show that interindividual variation in whole-brain average anatomical imbalance is positively correlated with a marker of human prenatal stress (birthweight disparity between monozygotic twins) and negatively correlated with general cognitive ability. This work provides methods and empirical insights to advance our understanding of coordinated anatomical organization of the human brain and its interindividual variation.

Early childhood stress is associated with blunted development of ventral tegmental area functional connectivity.

Early life stress increases risk for later psychopathology, due in part to changes in dopaminergic brain systems that support reward processing and motivation. Work in animals has shown that early life stress has a profound impact on the ventral tegmental area (VTA), which provides dopamine to regions including nucleus accumbens (NAcc), anterior hippocampus, and medial prefrontal cortex (mPFC), with cascading effects over the course of development. However, little is known about how early stress exposure shifts the developmental trajectory of mesocorticolimbic circuitry in humans. In the current study, 88 four- to nine-year-old children participated in resting-state fMRI. Parents completed questionnaires on their children's chronic stress exposure, including socioeconomic status (SES) and adverse childhood experiences (ACEs). We found an age x SES interaction on VTA connectivity, such that children from higher SES backgrounds showed a positive relationship between age and VTA-mPFC connectivity. Similarly, we found an age x ACEs exposure interaction on VTA connectivity, such that children with no ACEs exposure showed a positive relationship between age and VTA-mPFC connectivity. Our findings suggest that early stress exposure relates to the blunted maturation of VTA connectivity in young children, which may lead to disrupted reward processing later in childhood and beyond.

Neural evidence for cognitive reappraisal as a strategy to alleviate the effects of math anxiety.

Math anxiety (MA) describes feelings of tension, apprehension and fear that interfere with math performance. High MA (HMA) is correlated with negative consequences, including lower math grades, and ultimately an avoidance of quantitative careers. Given these adverse consequences, it is essential to explore effective intervention strategies to reduce MA. In the present functional magnetic resonance imaging (fMRI) study, we investigated the efficacy of cognitive reappraisal as a strategy to alleviate the effects of MA. Cognitive reappraisal, an emotion regulation strategy, has been shown to decrease negative affect and amygdala responsivity to stimuli that elicit negative emotion. We compared a reappraisal strategy to participants' natural strategy for solving math problems and analogies. We found that HMA individuals showed an increase in accuracy and a decrease in negative affect during the reappraisal condition as compared to the control condition. During math reappraise trials, increased activity in a network of regions associated with arithmetic correlated with improved performance for HMA individuals. These results suggest that increased engagement of arithmetic regions underlies the performance increases we identify in HMA students when they use reappraisal to augment their math performance. Overall, cognitive reappraisal is a promising strategy for enhancing math performance and reducing anxiety in math anxious individuals.

Sex-biased trajectories of amygdalo-hippocampal morphology change over human development.

The amygdala and hippocampus are two adjacent allocortical structures implicated in sex-biased and developmentally-emergent psychopathology. However, the spatiotemporal dynamics of amygdalo-hippocampal development remain poorly understood in healthy humans. The current study defined trajectories of volume and shape change for the amygdala and hippocampus by applying a multi-atlas segmentation pipeline (MAGeT-Brain) and semi-parametric mixed-effects spline modeling to 1,529 longitudinally-acquired structural MRI brain scans from a large, single-center cohort of 792 youth (403 males, 389 females) between the ages of 5 and 25 years old. We found that amygdala and hippocampus volumes both follow curvilinear and sexually dimorphic growth trajectories. These sex-biases were particularly striking in the amygdala: males showed a significantly later and slower adolescent deceleration in volume expansion (at age 20 years) than females (age 13 years). Shape analysis localized significant hot-spots of sex-biased anatomical development in sub-regional territories overlying rostral and caudal extremes of the CA1/2 in the hippocampus, and the centromedial nuclear group of the amygdala. In both sexes, principal components analysis revealed close integration of amygdala and hippocampus shape change along two main topographically-organized axes - low vs. high areal expansion, and early vs. late growth deceleration. These results (i) bring greater resolution to our spatiotemporal understanding of amygdalo-hippocampal development in healthy males and females, and (ii) uncover focal sex-differences in the structural maturation of the brain components that may contribute to differences in behavior and psychopathology that emerge during adolescence.

Longitudinally Mapping Childhood Socioeconomic Status Associations with Cortical and Subcortical Morphology.

Childhood socioeconomic status (SES) impacts cognitive development and mental health, but its association with human structural brain development is not yet well characterized. Here, we analyzed 1243 longitudinally acquired structural MRI scans from 623 youth (299 female/324 male) to investigate the relation between SES and cortical and subcortical morphology between ages 5 and 25 years. We found positive associations between SES and total volumes of the brain, cortical sheet, and four separate subcortical structures. These associations were stable between ages 5 and 25. Surface-based shape analysis revealed that higher SES is associated with areal expansion of lateral prefrontal, anterior cingulate, lateral temporal, and superior parietal cortices and ventrolateral thalamic, and medial amygdalo-hippocampal subregions. Meta-analyses of functional imaging data indicate that cortical correlates of SES are centered on brain systems subserving sensorimotor functions, language, memory, and emotional processing. We further show that anatomical variation within a subset of these cortical regions partially mediates the positive association between SES and IQ. Finally, we identify neuroanatomical correlates of SES that exist above and beyond accompanying variation in IQ. Although SES is clearly a complex construct that likely relates to development through diverse, nondeterministic processes, our findings elucidate potential neuroanatomical mediators of the association between SES and cognitive outcomes.SIGNIFICANCE STATEMENT Childhood socioeconomic status (SES) has been associated with developmental disparities in mental health, cognitive ability, and academic achievement, but efforts to understand underlying SES-brain relationships are ongoing. Here, we leverage a unique developmental neuroimaging dataset to longitudinally map the associations between SES and regional brain anatomy at high spatiotemporal resolution. We find widespread associations between SES and global cortical and subcortical volumes and surface area and localize these correlations to a distributed set of cortical, thalamic, and amygdalo-hippocampal subregions. Anatomical variation within a subset of these regions partially mediates the positive relationship between SES and IQ. Our findings help to localize cortical and subcortical systems that represent candidate biological substrates for the known relationships between SES and cognition.

Carriage of Supernumerary Sex Chromosomes Decreases the Volume and Alters the Shape of Limbic Structures.

Sex chromosome aneuploidy (SCA) increases risk for several psychiatric disorders associated with the limbic system, including mood and autism spectrum disorders. Thus, SCA offers a genetics-first model for understanding the biological basis of psychopathology. Additionally, the sex-biased prevalence of many psychiatric disorders could potentially reflect sex chromosome dosage effects on brain development. To clarify how limbic anatomy varies across sex and sex chromosome complement, we characterized amygdala and hippocampus structure in a uniquely large sample of patients carrying supernumerary sex chromosomes (n = 132) and typically developing controls (n = 166). After adjustment for sex-differences in brain size, karyotypically normal males (XY) and females (XX) did not differ in volume or shape of either structure. In contrast, all SCAs were associated with lowered amygdala volume relative to gonadally-matched controls. This effect was robust to three different methods for total brain volume adjustment, including an allometric analysis that derived normative scaling rules for these structures in a separate, typically developing population (n = 79). Hippocampal volume was insensitive to SCA after adjustment for total brain volume. However, surface-based analysis revealed that SCA, regardless of specific karyotype, was consistently associated with a spatially specific pattern of shape change in both amygdala and hippocampus. In particular, SCA was accompanied by contraction around the basomedial nucleus of the amygdala and an area crossing the hippocampal tail. These results demonstrate the power of SCA as a model to understand how copy number variation can precipitate changes in brain systems relevant to psychiatric disease.