Consortium Profile: The Methylation, Imaging and NeuroDevelopment (MIND) Consortium.

Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (Npooled DNAm = 11,299; Npooled neuroimaging = 10,133; Npooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.

Functional brain connectivity predictors of prospective substance use initiation and their environmental correlates.

Background: Early substance use initiation (SUI) places youth at substantially higher risk for later substance use disorders. Furthermore, adolescence is a critical period for the maturation of brain networks, the pace and magnitude of which are susceptible to environmental influences and may shape risk for SUI. Methods: We examined whether patterns of functional brain connectivity during rest (rsFC), measured longitudinally in pre-and-early adolescence, can predict future SUI. In an independent sub-sample, we also tested whether these patterns are associated with key environmental factors, specifically neighborhood pollution and socioeconomic dimensions. We utilized data from the Adolescent Brain Cognitive Development (ABCD) Study®. SUI was defined as first-time use of at least one full dose of alcohol, nicotine, cannabis, or other drugs. We created a control group (N = 228) of participants without SUI who were matched with the SUI group (N = 233) on age, sex, race/ethnicity, and parental income and education. Results: Multivariate analysis showed that whole-brain rsFC prior to SUI during 9-10 and 11-12 years of age successfully differentiated the prospective SUI and control groups. This rsFC signature was expressed more at older ages in both groups, suggesting a pattern of accelerated maturation in the SUI group in the years prior to SUI. In an independent sub-sample (N = 2,854) and adjusted for family socioeconomic factors, expression of this rsFC pattern was associated with higher pollution, but not neighborhood disadvantage. Conclusion: Brain functional connectivity patterns in early adolescence that are linked to accelerated maturation and environmental exposures can predict future SUI in youth.

Exposure to community violence as a mechanism linking neighborhood socioeconomic disadvantage and neural responses to reward.

A growing literature links socioeconomic disadvantage and adversity to brain function, including disruptions in reward processing. Less research has examined exposure to community violence (ECV) as a specific adversity related to differences in reward-related brain activation, despite the prevalence of community violence exposure for those living in disadvantaged contexts. The current study tested whether ECV was associated with reward-related ventral striatum (VS) activation after accounting for familial factors associated with differences in reward-related activation (e.g. parenting and family income). Moreover, we tested whether ECV is a mechanism linking socioeconomic disadvantage to reward-related activation in the VS. We utilized data from 444 adolescent twins sampled from birth records and residing in neighborhoods with above-average levels of poverty. ECV was associated with greater reward-related VS activation, and the association remained after accounting for family-level markers of disadvantage. We identified an indirect pathway in which socioeconomic disadvantage predicted greater reward-related activation via greater ECV, over and above family-level adversity. These findings highlight the unique impact of community violence exposure on reward processing and provide a mechanism through which socioeconomic disadvantage may shape brain function.

The future of neuroscience in developmental psychopathology.

Developmental psychopathology started as an intersection of fields and is now a field itself. As we contemplate the future of this field, we consider the ways in which a newer, interdisciplinary field - human developmental neuroscience - can inform, and be informed by, developmental psychopathology. To do so, we outline principles of developmental psychopathology and how they are and/or can be implemented in developmental neuroscience. In turn, we highlight how the collaboration between these fields can lead to richer models and more impactful translation. In doing so, we describe the ways in which models from developmental psychopathology can enrich developmental neuroscience and future directions for developmental psychopathology.

Exposure to community violence as a mechanism linking neighborhood disadvantage to amygdala reactivity and the protective role of parental nurturance.

Emerging literature links neighborhood disadvantage to altered neural function in regions supporting socioemotional and threat processing. Few studies, however, have examined the proximal mechanisms through which neighborhood disadvantage is associated with neural functioning. In a sample of 7- to 19-year-old twins recruited from disadvantaged neighborhoods (354 families, 708 twins; 54.5% boys; 78.5% White, 13.0% Black, 8.5% other racial/ethnic group membership), we found that exposure to community violence was related to increased amygdala reactivity during socioemotional processing and may be one mechanism linking neighborhood disadvantage to amygdala functioning. Importantly, parenting behavior appeared to modulate these effects, such that high parental nurturance buffered the effect of exposure to community violence on amygdala reactivity. These findings elucidate the potential impact of exposure to community violence on brain function and highlight the role parents can play in protecting youth from the neural effects of exposure to adversity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Associations of depression and anxiety symptoms in childhood and adolescence with epigenetic aging.

BACKGROUND: Childhood anxiety and depression symptoms are potential risk factors for accelerated biological aging. In child and adolescent twins, we tested whether these symptoms were associated with DNA methylation (DNAm) aging, a measure of biological aging. METHODS: 276 twins (135 pairs, 6 singletons) had DNAm assayed from saliva in middle childhood (mean = 7.8 years). Residuals of five different DNAm age estimates regressed on chronological age were used to indicate accelerated aging. Anxiety and depression symptoms were assessed in middle childhood and early adolescence using the Child Behavior Checklist. Mixed effect regression was used to examine potential relationships between anxiety or depression symptoms, and accelerated DNAm age. MZ twin difference analysis was then utilized to determine if associations were environmentally-driven or due to genetic or shared-environment confounding. RESULTS: Anxiety and depression symptoms were not associated with accelerated DNAm aging in middle childhood. In early adolescence, only the Wu clock was significant and indicated that each one symptom increase in anxiety symptoms had an associated age acceleration of 0.03 years (~0.4 months; p = 0.019). MZ twin difference analysis revealed non-significant within-pair effects, suggesting genetic and shared environmental influences. LIMITATIONS: Sample is predominantly male and white. Generalizability to other populations may be limited. CONCLUSION: Accelerated DNAm aging of the Wu clock in middle childhood is associated with anxiety, but not depression, symptoms in early adolescence. Further, this association may be the result of shared genetic and environmental influences. Accelerated DNAm aging may serve as an early risk factor or predictor of later anxiety symptoms.

Parental Nurturance Moderates the Etiology of Youth Resilience.

Parenting behaviors are among the most robust predictors of youth resilience to adversity. Critically, however, very few studies examining these effects have been genetically-informed, and none have considered parenting as an etiologic moderator of resilience. What's more, despite the multidimensionality of resilience, extant etiologic literature has largely focused on a single domain. The current study sought to fill these respective gaps in the literature by examining whether and how parental nurturance shapes the etiology of academic, social, and psychological resilience, respectively. We employed a unique sample of twins (N = 426 pairs; ages 6-11) exposed to moderate-to-severe levels of environmental adversity (i.e., family poverty, neighborhood poverty, community violence) from the Twin Study of Behavioral and Emotional Development in Children. As expected, parental nurturance was positively correlated with all forms of resilience. Extended univariate genotype-by-environment interaction models revealed that parental nurturance significantly moderated genetic influences on all three domains of resilience (academic resilience A1= -0.53, psychological resilience A1= -1.22, social resilience A1= -0.63; all p < .05), such that as parental nurturance increased, genetic influences on youth resilience decreased. Put another way, children experiencing high levels of parental nurturance were more resilient to disadvantage, regardless of their genetic predisposition towards resilience. In the absence of nurturing parenting, however, genetic influences played an outsized role in the origins of resilience. Such findings indicate that parental nurturance may serve as a malleable protective factor that increases youth resilience regardless of genetic influences.

Relationship between COVID-related stressors and internalizing symptoms: Gendered neuroendocrine risk profiles.

The COVID-19 pandemic generated significant life stress and increases in internalizing disorders. Moreover, COVID-related stressors disproportionately impacted women, consistent with outcomes showing a gender gap in stress-related disorders. Gender-related stress vulnerability emerges in adolescence alongside gender-specific changes in neuroendocrine signaling. Most research on the neuroendocrinology of stress-related disorders has focused on differences in the hypothalamic-pituitary-adrenal (HPA) axis effector hormone cortisol. More recent studies, however, emphasize dehydroepiandrosterone (DHEA), a neuroprotective and neuroactive hormone released concurrently with cortisol that balances its biobehavioral actions during stress. Notably, women show lower cortisol responses and higher DHEA responses to stress. However, lower cortisol and higher DHEA are associated with internalizing disorders in women, while those associations are opposite in men. Thus, gender-specific factors perhaps result in a neuroendocrine profile that places women at greater risk for stress-related disorders. The current study prospectively examined socially evaluated cold-pressor task (SECPT) induced neuroendocrine responses at age 15 and internalizing symptoms during the COVID-19 pandemic at age 21 in a cohort of 175 primarily Black low-socioeconomic status participants, while controlling for internalizing symptoms at age 15. The association between COVID-related stress and internalizing symptoms was not stronger in women. Lower DHEA-cortisol ratios were associated with a weaker relationship between COVID-related stress and internalizing symptoms in women, while higher ratios were associated with a weaker relationship in men. These findings suggest gender differences in the relationship between DHEA and cortisol and internalizing outcomes during a stressful period, and support differential neuroendocrine protective and risk pathways for young men and women.

Parent Mental Health Before and During the COVID-19 Pandemic.

Although extant cross-sectional data suggest that parents have experienced numerous challenges (e.g., homeschooling, caregiver burden) and mental health consequences during the COVID-19 pandemic, longitudinal data are needed to confirm mental health changes relative to pre-pandemic levels and identify which specific pandemic-related changes most highly predict mental health during the pandemic. In two longitudinal subsamples (N = 299 and N = 175), we assessed change in anxiety, depression, and stress before and during the pandemic and whether the accumulation of pandemic-related changes predicted observed mental health changes. On average, parents reported increased depression and anxiety, but no significant changes in reported stress. Moreover, increased interpersonal conflict, difficulty managing work and caregiving responsibilities, and increased economic challenges were the types of pandemic-related changes that most strongly predicted worse mental health, highlighting that juggling caregiving responsibilities and economic concerns, along with the pandemic's impact on interpersonal family relationships are key predictors of worsening parental mental illness symptoms.

Socioeconomic resources in youth are linked to divergent patterns of network integration and segregation across the brain's transmodal axis.

Socioeconomic resources (SER) calibrate the developing brain to the current context, which can confer or attenuate risk for psychopathology across the lifespan. Recent multivariate work indicates that SER levels powerfully influence intrinsic functional connectivity patterns across the entire brain. Nevertheless, the neurobiological meaning of these widespread alterations remains poorly understood, despite its translational promise for early risk identification, targeted intervention, and policy reform. In the present study, we leverage the resources of graph theory to precisely characterize multivariate and univariate associations between household SER and the functional integration and segregation (i.e., participation coefficient, within-module degree) of brain regions across major cognitive, affective, and sensorimotor systems during the resting state in 5,821 youth (ages 9-10 years) from the Adolescent Brain Cognitive Development (ABCD) Study. First, we establish that decomposing the brain into profiles of integration and segregation captures more than half of the multivariate association between SER and functional connectivity with greater parsimony (100-fold reduction in number of features) and interpretability. Second, we show that the topological effects of SER are not uniform across the brain; rather, higher SER levels are related to greater integration of somatomotor and subcortical systems, but greater segregation of default mode, orbitofrontal, and cerebellar systems. Finally, we demonstrate that the effects of SER are spatially patterned along the unimodal-transmodal gradient of brain organization. These findings provide critical interpretive context for the established and widespread effects of SER on brain organization, indicating that SER levels differentially configure the intrinsic functional architecture of developing unimodal and transmodal systems. This study highlights both sensorimotor and higher-order networks that may serve as neural markers of environmental stress and opportunity, and which may guide efforts to scaffold healthy neurobehavioral development among disadvantaged communities of youth.

Neighborhood poverty during childhood prospectively predicts adolescent functional brain network architecture.

Family poverty has been associated with altered brain structure, function, and connectivity in youth. However, few studies have examined how disadvantage within the broader neighborhood may influence functional brain network organization. The present study leveraged a longitudinal community sample of 538 twins living in low-income neighborhoods to evaluate the prospective association between exposure to neighborhood poverty during childhood (6-10 y) with functional network architecture during adolescence (8-19 y). Using resting-state and task-based fMRI, we generated two latent measures that captured intrinsic brain organization across the whole-brain and network levels - network segregation and network segregation-integration balance. While age was positively associated with network segregation and network balance overall across the sample, these associations were moderated by exposure to neighborhood poverty. Specifically, these positive associations were observed only in youth from more, but not less, disadvantaged neighborhoods. Moreover, greater exposure to neighborhood poverty predicted reduced network segregation and network balance in early, but not middle or late, adolescence. These effects were detected both across the whole-brain system as well as specific functional networks, including fronto-parietal, default mode, salience, and subcortical systems. These findings indicate that where children live may exert long-reaching effects on the organization and development of the adolescent brain.

Elucidating the role of negative parenting in the genetic v. environmental influences on adult psychopathic traits.

BACKGROUND: Psychopathic traits involve interpersonal manipulation, callous affect, erratic lifestyle, and antisocial behavior. Though adult psychopathic traits emerge from both genetic and environmental risk, no studies have examined etiologic associations between adult psychopathic traits and experiences of parenting in childhood, or the extent to which parenting practices may impact the heritability of adult psychopathic traits using a genetically-informed design. METHODS: In total, 1842 adult twins from the community reported their current psychopathic traits and experiences of negative parenting during childhood. We fit bivariate genetic models to the data, decomposing the variance within, and the covariance between, psychopathic traits and perceived negative parenting into their genetic and environmental components. We then fit a genotype × environment interaction model to evaluate whether negative parenting moderated the etiology of psychopathic traits. RESULTS: Psychopathic traits were moderately heritable with substantial non-shared environmental influences. There were significant associations between perceived negative parenting and three of four psychopathy facets (interpersonal manipulation, erratic lifestyle, antisocial tendencies, but not callous affect). These associations were attributable to a common non-shared environmental pathway and not to overlapping genetic effects. Additionally, we found that primarily shared environmental influences were stronger on psychopathic traits for individuals with a history of greater negative parenting. CONCLUSIONS: Utilizing a genetically-informed design, we found that both genetic and non-shared environmental factors contribute to the emergence of psychopathic traits. Moreover, perceptions of negative parenting emerged as a clear environmental influence on the development of interpersonal, lifestyle, and antisocial features of psychopathy.

Early childhood household instability, adolescent structural neural network architecture, and young adulthood depression: A 21-year longitudinal study.

Unstable and unpredictable environments are linked to risk for psychopathology, but the underlying neural mechanisms that explain how instability relate to subsequent mental health concerns remain unclear. In particular, few studies have focused on the association between instability and white matter structures despite white matter playing a crucial role for neural development. In a longitudinal sample recruited from a population-based study (N = 237), household instability (residential moves, changes in household composition, caregiver transitions in the first 5 years) was examined in association with adolescent structural network organization (network integration, segregation, and robustness of white matter connectomes; Mage = 15.87) and young adulthood anxiety and depression (six years later). Results indicate that greater instability related to greater global network efficiency, and this association remained after accounting for other types of adversity (e.g., harsh parenting, neglect, food insecurity). Moreover, instability predicted increased depressive symptoms via increased network efficiency even after controlling for previous levels of symptoms. Exploratory analyses showed that structural connectivity involving the left fronto-lateral and temporal regions were most strongly related to instability. Findings suggest that structural network efficiency relating to household instability may be a neural mechanism of risk for later depression and highlight the ways in which instability modulates neural development.

Antisocial behavior is associated with reduced frontoparietal network efficiency in youth.

Youth antisocial behavior (AB) is associated with deficits in socioemotional processing, reward and threat processing and executive functioning. These deficits are thought to emerge from differences in neural structure, functioning and connectivity, particularly within the default, salience and frontoparietal networks. However, the relationship between AB and the organization of these networks remains unclear. To address this gap, the current study applied unweighted, undirected graph analyses to resting-state functional magnetic resonance imaging data in a cohort of 161 adolescents (95 female) enriched for exposure to poverty, a risk factor for AB. As prior work indicates that callous-unemotional (CU) traits may moderate the neurocognitive profile of youth AB, we examined CU traits as a moderator. Using multi-informant latent factors, AB was found to be associated with less efficient frontoparietal network topology, a network associated with executive functioning. However, this effect was limited to youth at low or mean levels of CU traits, indicating that these neural differences were specific to those high on AB but not CU traits. Neither AB, CU traits nor their interaction was significantly related to default or salience network topologies. Results suggest that AB, specifically, may be linked with shifts in the architecture of the frontoparietal network.

Why weight? Analytic approaches for large-scale population neuroscience data.

Population-based neuroimaging studies that feature complex sampling designs enable researchers to generalize their results more widely. However, several theoretical and analytical questions pose challenges to researchers interested in these data. The following is a resource for researchers interested in using population-based neuroimaging data. We provide an overview of sampling designs and describe the differences between traditional model-based analyses and survey-oriented design-based analyses. To elucidate key concepts, we leverage data from the Adolescent Brain Cognitive Development℠ Study (ABCD Study®), a population-based sample of 11,878 9-10-year-olds in the United States. Analyses revealed modest sociodemographic discrepancies between the target population of 9-10-year-olds in the U.S. and both the recruited ABCD sample and the analytic sample with usable structural and functional imaging data. In evaluating the associations between socioeconomic resources (i.e., constructs that are tightly linked to recruitment biases) and several metrics of brain development, we show that model-based approaches over-estimated the associations of household income and under-estimated the associations of caregiver education with total cortical volume and surface area. Comparable results were found in models predicting neural function during two fMRI task paradigms. We conclude with recommendations for ABCD Study® users and users of population-based neuroimaging cohorts more broadly.

School connectedness as a protective factor against childhood exposure to violence and social deprivation: A longitudinal study of adaptive and maladaptive outcomes.

School connectedness, a construct indexing supportive school relationships, has been posited to promote resilience to environmental adversity. Consistent with prominent calls in the field, we examined the protective nature of school connectedness against two dimensions of early adversity that index multiple levels of environmental exposure (violence exposure, social deprivation) when predicting both positive and negative outcomes in longitudinal data from 3,246 youth in the Fragile Families and Child Wellbeing Study (48% female, 49% African American). Child and adolescent school connectedness were promotive, even when accounting for the detrimental effects of early adversity. Additionally, childhood school connectedness had a protective but reactive association with social deprivation, but not violence exposure, when predicting externalizing symptoms and positive function. Specifically, school connectedness was protective against the negative effects of social deprivation, but the effect diminished as social deprivation became more extreme. These results suggest that social relationships at school may compensate for low levels of social support in the home and neighborhood. Our results highlight the important role that the school environment can play for youth who have been exposed to adversity in other areas of their lives and suggest specific groups that may especially benefit from interventions that boost school connectedness.

Antisocial behavior is associated with reduced frontoparietal activity to loss in a population-based sample of adolescents.

BACKGROUND: Adolescent antisocial behavior (AB) is a public health concern due to the high financial and social costs of AB on victims and perpetrators. Neural systems involved in reward and loss processing are thought to contribute to AB. However, investigations into these processes are limited: few have considered anticipatory and consummatory components of reward, response to loss, nor whether associations with AB may vary by level of callous-unemotional (CU) traits. METHODS: A population-based community sample of 128 predominantly low-income youth (mean age = 15.9 years; 42% male) completed a monetary incentive delay task during fMRI. A multi-informant, multi-method latent variable approach was used to test associations between AB and neural response to reward and loss anticipation and outcome and whether CU traits moderated these associations. RESULTS: AB was not associated with neural response to reward but was associated with reduced frontoparietal activity during loss outcomes. This association was moderated by CU traits such that individuals with higher levels of AB and CU traits had the largest reductions in frontoparietal activity. Co-occurring AB and CU traits were also associated with increased precuneus response during loss anticipation. CONCLUSIONS: Findings indicate that AB is associated with reduced activity in brain regions involved in cognitive control, attention, and behavior modification during negative outcomes. Moreover, these reductions are most pronounced in youth with co-occurring CU traits. These findings have implications for understanding why adolescents involved in AB continue these behaviors despite severe negative consequences (e.g. incarceration).

Adolescent functional network connectivity prospectively predicts adult anxiety symptoms related to perceived COVID-19 economic adversity.

BACKGROUND: Stressful events, such as the COVID-19 pandemic, are major contributors to anxiety and depression, but only a subset of individuals develop psychopathology. In a population-based sample (N = 174) with a high representation of marginalized individuals, this study examined adolescent functional network connectivity as a marker of susceptibility to anxiety and depression in the context of adverse experiences. METHODS: Data-driven network-based subgroups were identified using an unsupervised community detection algorithm within functional neural connectivity. Neuroimaging data collected during emotion processing (age 15) were extracted from a priori regions of interest linked to anxiety and depression. Symptoms were self-reported at ages 15, 17, and 21 (during COVID-19). During COVID-19, participants reported on pandemic-related economic adversity. Differences across subgroup networks were first examined, then subgroup membership and subgroup-adversity interaction were tested to predict change in symptoms over time. RESULTS: Two subgroups were identified: Subgroup A, characterized by relatively greater neural network variation (i.e., heterogeneity) and density with more connections involving the amygdala, subgenual cingulate, and ventral striatum; and the more homogenous Subgroup B, with more connections involving the insula and dorsal anterior cingulate. Accounting for initial symptoms, subgroup A individuals had greater increases in symptoms across time (ß = .138, p = .042), and this result remained after adjusting for additional covariates (ß = .194, p = .023). Furthermore, there was a subgroup-adversity interaction: compared with Subgroup B, Subgroup A reported greater anxiety during the pandemic in response to reported economic adversity (ß = .307, p = .006), and this remained after accounting for initial symptoms and many covariates (ß = .237, p = .021). CONCLUSIONS: A subgrouping algorithm identified young adults who were susceptible to adversity using their personalized functional network profiles derived from a priori brain regions. These results highlight potential prospective neural signatures involving heterogeneous emotion networks that predict individuals at the greatest risk for anxiety when experiencing adverse events.

Socioeconomic resources are associated with distributed alterations of the brain's intrinsic functional architecture in youth.

Little is known about how exposure to limited socioeconomic resources (SER) in childhood gets "under the skin" to shape brain development, especially using rigorous whole-brain multivariate methods in large, adequately powered samples. The present study examined resting state functional connectivity patterns from 5821 youth in the Adolescent Brain Cognitive Development (ABCD) study, employing multivariate methods across three levels: whole-brain, network-wise, and connection-wise. Across all three levels, SER was associated with widespread alterations across the connectome. However, critically, we found that parental education was the primary driver of neural associations with SER. These parental education associations with the developing connectome exhibited notable concentrations in somatosensory and subcortical regions, and they were partially accounted for by home enrichment activities, child's cognitive abilities, and child's grades, indicating interwoven links between parental education, child stimulation, and child cognitive performance. These results add a new data-driven, multivariate perspective on links between household SER and the child's developing functional connectome.