Leveraging multivariate approaches to advance the science of early-life adversity.

Since the landmark Adverse Childhood Experiences (ACEs) study, adversity research has expanded to more precisely account for the multifaceted nature of adverse experiences. The complex data structures and interrelated nature of adversity data require robust multivariate statistical methods, and recent methodological and statistical innovations have facilitated advancements in research on childhood adversity. Here, we provide an overview of a subset of multivariate methods that we believe hold particular promise for advancing the field's understanding of early-life adversity, and discuss how these approaches can be practically applied to explore different research questions. This review covers data-driven or unsupervised approaches (including dimensionality reduction and person-centered clustering/subtype identification) as well as supervised/prediction-based approaches (including linear and tree-based models and neural networks). For each, we highlight studies that have effectively applied the method to provide novel insight into early-life adversity. Taken together, we hope this review serves as a resource to adversity researchers looking to expand upon the cumulative approach described in the original ACEs study, thereby advancing the field's understanding of the complexity of adversity and related developmental consequences.

Neighborhood Socioeconomic Disadvantage and White Matter Microstructure of the Arcuate Fasciculus and Uncinate Fasciculus in Adolescents.

Background: Neighborhood- or area-level socioeconomic disadvantage is associated with neural alterations across the life span. However, few studies have examined the effects of neighborhood disadvantage on white matter microstructure during adolescence, an important period of development that coincides with increased risk for psychopathology. Methods: In 200 adolescents (ages 13-20 years; 54.5% female, 4% nonbinary) recruited from 2 studies enriched for early adversity and depression, we examined whether neighborhood socioeconomic disadvantage derived from census tract data was related to white matter microstructure in several major white matter tracts. We also examined whether depressive symptoms and sex moderated these associations. Results: Greater neighborhood socioeconomic disadvantage was associated with lower fractional anisotropy (FA) in the left arcuate fasciculus (ß = -0.24, false discovery rate [FDR]-corrected p = .035) and right uncinate fasciculus (ß = -0.32, FDR-corrected p = .002) above and beyond the effects of family-level socioeconomic status. Depressive symptoms significantly moderated the association between left arcuate fasciculus FA and both neighborhood (ß = 0.17, FDR-corrected p = .026) and unemployment (ß = 0.22, FDR-corrected p = .004) disadvantage such that these associations were only significant in adolescents who reported less severe depression. Sex did not moderate the association between socioeconomic disadvantage and FA in these tracts. Conclusions: Greater neighborhood socioeconomic disadvantage, particularly poverty and educational attainment levels, was associated with lower FA in the arcuate fasciculus and uncinate fasciculus above and beyond the effects of family-level measures of socioeconomic status. These patterns were only observed in adolescents with low levels of depression, suggesting that we must be cautious about generalizing these findings to youths who struggle with mental health difficulties.

Multivariate links between the developmental timing of adversity exposure and white matter tract integrity in adulthood.

Early-life adversity is pervasive worldwide and represents a potent risk factor for increased mental health burden across the lifespan. However, there is substantial individual heterogeneity in associations between adversity exposure, neurobiological changes, and mental health problems. Accounting for key features of adversity such as the developmental timing of exposure may clarify associations between adversity, neurodevelopment, and mental health. The present study leverages sparse canonical correlation analysis to characterize modes of covariation between age of adversity exposure and the integrity of white matter tracts throughout the brain in a sample of 107 adults. We find that adversity exposure during middle childhood (ages 5-6 and 8-9 in particular) is consistently linked with alterations in white matter tract integrity, such that tracts supporting sensorimotor functions display higher integrity in relation to adversity exposure while tracts supporting cortico-cortical communication display lower integrity. Further, latent patterns of tract integrity linked with adversity experienced across preschool age and middle childhood (ages 4-9) were associated with trauma-related symptoms in adulthood. Our findings underscore that adversity exposure may differentially affect white matter in a function- and developmental-timing specific manner and suggest that adversity experienced between ages 4-9 may shape the development of global white matter tracts in ways that are relevant for adult mental health.

Characterizing experiential elements of early-life stress to inform resilience: Buffering effects of controllability and predictability and the importance of their timing.

Key theoretical frameworks have proposed that examining the impact of exposure to specific dimensions of stress at specific developmental periods is likely to yield important insight into processes of risk and resilience. Utilizing a sample of N = 549 young adults who provided a detailed retrospective history of their lifetime exposure to numerous dimensions of traumatic stress and ratings of their current trauma-related symptomatology via completion of an online survey, here we test whether an individual's perception of their lifetime stress as either controllable or predictable buffered the impact of exposure on trauma-related symptomatology assessed in adulthood. Further, we tested whether this moderation effect differed when evaluated in the context of early childhood, middle childhood, adolescence, and young adulthood stress. Consistent with hypotheses, results highlight both stressor controllability and stressor predictability as buffering the impact of traumatic stress exposure on trauma-related symptomatology and suggest that the potency of this buffering effect varies across unique developmental periods. Leveraging dimensional ratings of lifetime stress exposure to probe heterogeneity in outcomes following stress - and, critically, considering interactions between dimensions of exposure and the developmental period when stress occurred - is likely to yield increased understanding of risk and resilience following traumatic stress.

Associations among Household and Neighborhood Socioeconomic Disadvantages, Resting-state Frontoamygdala Connectivity, and Internalizing Symptoms in Youth.

Exposure to socioeconomic disadvantages (SED) can have negative impacts on mental health, yet SED are a multifaceted construct and the precise processes by which SED confer deleterious effects are less clear. Using a large and diverse sample of preadolescents (ages 9-10 years at baseline, n = 4038, 49% female) from the Adolescent Brain Cognitive Development Study, we examined associations among SED at both household (i.e., income-needs and material hardship) and neighborhood (i.e., area deprivation and neighborhood unsafety) levels, frontoamygdala resting-state functional connectivity, and internalizing symptoms at baseline and 1-year follow-up. SED were positively associated with internalizing symptoms at baseline and indirectly predicted symptoms 1 year later through elevated symptoms at baseline. At the household level, youth in households characterized by higher disadvantage (i.e., lower income-to-needs ratio) exhibited more strongly negative frontoamygdala coupling, particularly between the bilateral amygdala and medial OFC (mOFC) regions within the frontoparietal network. Although more strongly positive amygdala-mOFC coupling was associated with higher levels of internalizing symptoms at baseline and 1-year follow-up, it did not mediate the association between income-to-needs ratio and internalizing symptoms. However, at the neighborhood level, amygdala-mOFC functional coupling moderated the effect of neighborhood deprivation on internalizing symptoms. Specifically, higher neighborhood deprivation was associated with higher internalizing symptoms for youth with more strongly positive connectivity, but not for youth with more strongly negative connectivity, suggesting a potential buffering effect. Findings highlight the importance of capturing multilevel socioecological contexts in which youth develop to identify youth who are most likely to benefit from early interventions.

Genetic variation in endocannabinoid signaling is associated with differential network-level functional connectivity in youth.

The endocannabinoid system is an important regulator of emotional responses such as fear, and a number of studies have implicated endocannabinoid signaling in anxiety. The fatty acid amide hydrolase (FAAH) C385A polymorphism, which is associated with enhanced endocannabinoid signaling in the brain, has been identified across species as a potential protective factor from anxiety. In particular, adults with the variant FAAH 385A allele have greater fronto-amygdala connectivity and lower anxiety symptoms. Whether broader network-level differences in connectivity exist, and when during development this neural phenotype emerges, remains unknown and represents an important next step in understanding how the FAAH C385A polymorphism impacts neurodevelopment and risk for anxiety disorders. Here, we leveraged data from 3,109 participants in the nationwide Adolescent Brain Cognitive Development Study℠ (10.04 ± 0.62 years old; 44.23% female, 55.77% male) and a cross-validated, data-driven approach to examine associations between genetic variation and large-scale resting-state brain networks. Our findings revealed a distributed brain network, comprising functional connections that were both significantly greater (95% CI for p values = [<0.001, <0.001]) and lesser (95% CI for p values = [0.006, <0.001]) in A-allele carriers relative to non-carriers. Furthermore, there was a significant interaction between genotype and the summarized connectivity of functional connections that were greater in A-allele carriers, such that non-carriers with connectivity more similar to A-allele carriers (i.e., greater connectivity) had lower anxiety symptoms (ß = -0.041, p = 0.030). These findings provide novel evidence of network-level changes in neural connectivity associated with genetic variation in endocannabinoid signaling and suggest that genotype-associated neural differences may emerge at a younger age than genotype-associated differences in anxiety.

Stress and adolescence: vulnerability and opportunity during a sensitive window of development.

Adolescence is a period of dynamic change across multiple systems. Concurrent maturation of neural, biological, and psychosocial functioning renders adolescence a time of heightened sensitivity to both negative and positive experiences. Here, we review recent literature across these domains, discuss risk and opportunity in the context of ongoing neural development, and highlight promising directions for future research. Finally, we propose that conceptualizing adolescence as a sensitive window during which plasticity across multiple systems is enhanced may support the identification of links between experience, neurodevelopment, and psychopathology.

Inflammatory cytokines and callosal white matter microstructure in adolescents.

Adolescent depression is characterized by heightened inflammation and altered connectivity of fronto-cingulate-limbic tracts, including the genu of the corpus callosum (CCG) and the uncinate fasciculus (UF). No studies, however, have yet examined the association between inflammation, measured by peripheral levels of cytokines, and white matter connectivity of fronto-cingulate-limbic tracts in adolescents. Here, 56 depressed adolescents (32 females, 3 non-binary; 16.23 ± 1.28 years) and 19 controls (10 females; 15.72 ± 1.17 years) completed a diffusion-weighted MRI scan at 3 Tesla. We conducted deterministic tractography to segment bilateral corpus callosum (genu and splenium) and UF and computed mean fractional anisotropy (FA) in each tract. A subset of participants (43 depressed and 17 healthy controls) also provided dried blood spot samples from which we assayed interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-ɑ) using a Luminex multiplex array. Depressed participants did not differ from controls in FA of the corpus callosum or UF (all FDR-corrected ps > 0.056) but exhibited higher levels of inflammation than did controls (IL-6: ß = 0.91, FDR-corrected p = 0.006; TNF-α: ß = 0.76, FDR-corrected p = 0.006). Although diagnostic group did not moderate the associations between inflammatory cytokines and FA in the CCG and UF, across both groups, greater peripheral inflammation was associated with lower FA in the CCG (IL-6: ß = -0.38; FDR-corrected p = 0.044; TNF-ɑ: ß = -0.41, FDR-corrected p = 0.044). This study is the first to examine associations between peripheral inflammation and white matter microstructure of fronto-cingulate-limbic tracts in depressed and nondepressed adolescents. Future mechanistic studies are needed to confirm our findings; nevertheless, our results suggest that heightened inflammation is an important component of neurophenotypes that are relevant to adolescent depression.

Associations among negative life events, changes in cortico-limbic connectivity, and psychopathology in the ABCD Study.

Adversity exposure is a risk factor for psychopathology, which most frequently onsets during adolescence, and prior research has demonstrated that alterations in cortico-limbic connectivity may account in part for this association. In a sample of youth from the Adolescent Brain Cognitive Development (ABCD) Study (N = 4006), we tested a longitudinal structural equation model to examine the indirect effect of adversity exposure (negative life events) on later psychopathology via changes in cortico-limbic resting-state functional connectivity (rsFC). We also examined the potential protective effects of parental acceptance. Generally, cortico-limbic connectivity became more strongly negative between baseline and year 2 follow-up, suggesting that stronger negative correlations within these cortico-limbic networks may reflect a more mature phenotype. Exposure to a greater number of negative life events was associated with stronger negative cortico-limbic rsFC which, in turn, was associated with lower internalizing (but not externalizing) symptoms. The indirect effect of negative life events on internalizing symptoms via cortico-limbic rsFC was significant. Parental acceptance did not moderate the association between negative life events and rsFC. Our findings highlight how stressful childhood experiences may accelerate neurobiological maturation in specific cortico-limbic connections, potentially reflecting an adaptive process that protects against internalizing problems in the context of adversity.

Migration-related trauma and mental health among migrant children emigrating from Mexico and Central America to the United States: Effects on developmental neurobiology and implications for policy.

Children make up over half of the world's migrants and refugees and face a multitude of traumatic experiences prior to, during, and following migration. Here, we focus on migrant children emigrating from Mexico and Central America to the United States and review trauma related to migration, as well as its implications for the mental health of migrant and refugee children. We then draw upon the early adversity literature to highlight potential behavioral and neurobiological sequalae of migration-related trauma exposure, focusing on attachment, emotion regulation, and fear learning and extinction as transdiagnostic mechanisms underlying the development of internalizing and externalizing symptomatology following early-life adversity. This review underscores the need for interdisciplinary efforts to both mitigate the effects of trauma faced by migrant and refugee youth emigrating from Mexico and Central America and, of primary importance, to prevent child exposure to trauma in the context of migration. Thus, we conclude by outlining policy recommendations aimed at improving the mental health of migrant and refugee youth.

Sex differences in myelin content of white matter tracts in adolescents with depression.

Depression is a chronic and debilitating condition that often emerges during adolescence, a period of significant brain maturation. Few studies, however, have examined how mechanisms of neuroplasticity, including myelination, are affected by adolescent-onset depression. Here, we used multimodal MR imaging to characterize myelin, indexed by R1, in white matter tracts previously associated with depression and compare 48 adolescents with lifetime depression (45 with current depression, 3 remitted) and 35 healthy controls in R1. Compared to healthy controls, R1 was higher in adolescents with lifetime depression in the uncinate fasciculus and corpus callosum genu (all ßs > 0.42; all ps < 0.037). Sex significantly moderated the association between depression and R1 in the left uncinate fasciculus and corpus callosum genu (all ßs > 0.86; all ps < 0.02), such that depressed female adolescents had significantly higher R1 in these tracts than did healthy female adolescents (all ßs > 0.82; all ps < 0.0012). In contrast, depressed and non-depressed male adolescents did not differ in R1 in these tracts (all ps > 0.32). While fractional anisotropy (FA), a commonly examined measure of white matter organization based on diffusion-weighted MRI, in the left uncinate was positively associated with lifetime depression in our sample (ß = 0.56; p = 0.016), we found no evidence of sex-specific effects of depression in FA. Our results suggest that R1 is more sensitive to sex-specific effects of depression than FA, particularly in female adolescents. Given evidence that myelin inhibits synapse formation and reduces brain plasticity, our findings implicate experience-driven regional myelination as a mechanism underlying depression during periods of significant neural maturation such as adolescence.

Decomposing complex links between the childhood environment and brain structure in school-aged youth.

Childhood experiences play a profound role in conferring risk and resilience for brain and behavioral development. However, how different facets of the environment shape neurodevelopment remains largely unknown. Here we sought to decompose heterogeneous relationships between environmental factors and brain structure in 989 school-aged children from the Adolescent Brain Cognitive Development Study. We applied a cross-modal integration and clustering approach called 'Similarity Network Fusion', which combined two brain morphometrics (i.e., cortical thickness and myelin-surrogate markers), and key environmental factors (i.e., trauma exposure, neighborhood safety, school environment, and family environment) to identify homogeneous subtypes. Depending on the subtyping resolution, results identified two or five subgroups, each characterized by distinct brain structure-environment profiles. Notably, more supportive caregiving and school environments were associated with greater myelination, whereas less supportive caregiving, higher family conflict and psychopathology, and higher perceived neighborhood safety were observed with greater cortical thickness. These subtypes were highly reproducible and predicted externalizing symptoms and overall mental health problems. Our findings support the theory that distinct environmental exposures are differentially associated with alterations in structural neurodevelopment. Delineating more precise associations between risk factors, protective factors, and brain development may inform approaches to enhance risk identification and optimize interventions targeting specific experiences.

Sex differences in the effects of gonadal hormones on white matter microstructure development in adolescence.

Adolescence is characterized by rapid brain development in white matter (WM) that is attributed in part to surges in gonadal hormones. To date, however, there have been few longitudinal investigations relating changes in gonadal hormones and WM development in adolescents. We acquired diffusion-weighted MRI to estimate mean fractional anisotropy (FA) from 10 WM tracts and salivary testosterone from 51 females and 29 males (ages 9-14 years) who were matched on pubertal stage and followed, on average, for 2 years. We tested whether interactions between sex and changes in testosterone levels significantly explained changes in FA. We found positive associations between changes in testosterone and changes in FA within the corpus callosum, cingulum cingulate, and corticospinal tract in females (all ps<0.05, corrected) and non-significant associations in males. We also collected salivary estradiol from females and found that increases in estradiol were associated with increases in FA in the left uncinate fasciculus (p = 0.04, uncorrected); however, this effect was no longer significant after accounting for changes in testosterone. Our findings indicate there are sex differences in how changes in testosterone relate to changes in WM microstructure of tracts that support impulse control and emotion regulation across the pubertal transition.

Cerebral blood flow in 5- to 8-month-olds: Regional tissue maturity is associated with infant affect.

Infancy is marked by rapid neural and emotional development. The relation between brain function and emotion in infancy, however, is not well understood. Methods for measuring brain function predominantly rely on the BOLD signal; however, interpretation of the BOLD signal in infancy is challenging because the neuronal-hemodynamic relation is immature. Regional cerebral blood flow (rCBF) provides a context for the infant BOLD signal and can yield insight into the developmental maturity of brain regions that may support affective behaviors. This study aims to elucidate the relations among rCBF, age, and emotion in infancy. One hundred and seven mothers reported their infants' (infant age M ± SD = 6.14 ± 0.51 months) temperament. A subsample of infants completed MRI scans, 38 of whom produced usable perfusion MRI during natural sleep to quantify rCBF. Mother-infant dyads completed the repeated Still-Face Paradigm, from which infant affect reactivity and recovery to stress were quantified. We tested associations of infant age at scan, temperament factor scores, and observed affect reactivity and recovery with voxel-wise rCBF. Infant age was positively associated with CBF in nearly all voxels, with peaks located in sensory cortices and the ventral prefrontal cortex, supporting the formulation that rCBF is an indicator of tissue maturity. Temperamental Negative Affect and recovery of positive affect following a stressor were positively associated with rCBF in several cortical and subcortical limbic regions, including the orbitofrontal cortex and inferior frontal gyrus. This finding yields insight into the nature of affective neurodevelopment during infancy. Specifically, infants with relatively increased prefrontal cortex maturity may evidence a disposition toward greater negative affect and negative reactivity in their daily lives yet show better recovery of positive affect following a social stressor.

Depressive Symptoms Predict Change in Telomere Length and Mitochondrial DNA Copy Number Across Adolescence.

OBJECTIVE: Several studies have found associations between a diagnosis or symptoms of major depressive disorder and markers of cellular aging and dysfunction. These investigations, however, are predominantly cross-sectional and focus on adults. In the present study, we used a prospective longitudinal design to test the cross-sectional association between depressive symptoms in adolescents and telomere length (TL) as well as mitochondrial DNA copy number (mtDNA-cn). METHOD: A total of 121 adolescents (mean age = 11.38 years, SD = 1.03; 39% male adolescents and 61% female adolescents) were followed for approximately 2 years. At baseline and follow-up, participants provided saliva for DNA extraction, from which measures of TL and mtDNA-cn were obtained. Depressive symptoms were obtained via the Children's Depression Inventory. RESULTS: There was no association between depressive symptoms and markers of cellular aging at baseline; however, depressive symptoms at baseline predicted higher rates of telomere erosion (ß = -0.201, p = .016) and greater increases in mtDNA-cn (ß = 0.190, p = .012) over the follow-up period. Markers of cellular aging at baseline did not predict subsequent changes in depressive symptoms. Furthermore, including the number of stressful life events did not alter these patterns of findings. CONCLUSION: These results indicate that depressive symptoms precede changes in cellular aging and dysfunction, rather than the reverse.

Early life stress, cortisol, frontolimbic connectivity, and depressive symptoms during puberty.

Early life stress (ELS) is a risk factor for the development of depression in adolescence; the mediating neurobiological mechanisms, however, are unknown. In this study, we examined in early pubertal youth the associations among ELS, cortisol stress responsivity, and white matter microstructure of the uncinate fasciculus and the fornix, two key frontolimbic tracts; we also tested whether and how these variables predicted depressive symptoms in later puberty. A total of 208 participants (117 females; M age = 11.37 years; M Tanner stage = 2.03) provided data across two or more assessment modalities: ELS; salivary cortisol levels during a psychosocial stress task; diffusion magnetic resonance imaging; and depressive symptoms. In early puberty there were significant associations between higher ELS and decreased cortisol production, and between decreased cortisol production and increased fractional anisotropy in the uncinate fasciculus. Further, increased fractional anisotropy in the uncinate fasciculus predicted higher depressive symptoms in later puberty, above and beyond earlier symptoms. In post hoc analyses, we found that sex moderated several additional associations. We discuss these findings within a broader conceptual model linking ELS, emotion dysregulation, and depression across the transition through puberty, and contend that brain circuits implicated in the control of hypothalamic-pituitary-adrenal axis function should be a focus of continued research.