Socioeconomic Disadvantage Moderates the Association of Systemic Inflammation with Amygdala Volume in Adolescents Over a Two-Year Interval: An Exploratory Study.

BACKGROUND: Research has demonstrated an association between elevated systemic inflammation and changes in brain function. Affective areas of the brain involved in processing threat (e.g., amygdala) and reward (e.g., nucleus accumbens [NAcc]) appear to be sensitive to inflammation. Early life stress (ELS), such as experiencing low socioeconomic status (SES), may also potentiate this association, but relevant evidence has come primarily from cross-sectional studies of brain function. It is unclear whether similar associations are present between ELS, inflammation, and brain structure, particularly in typically developing populations. METHODS: We recruited and assessed 50 adolescents (31F/19M) from the community (M±SD age=15.5±1.1; range=13.1-17.5 years ) and in exploratory analyses examined whether changes in C-reactive protein (ΔCRP) from blood spots predict changes in gray matter volumes (ΔGMV) in the bilateral amygdala and NAcc over a two-year period. We also investigated whether experiencing ELS, operationalized using a comprehensive composite score of SES disadvantage at the family and neighborhood levels, significantly moderated the association between ΔCRP and ΔGMV. RESULTS: We found that ΔCRP was negatively associated with ΔAmygdala GMV (i.e. increasing CRP levels were associated with decreasing amygdala volume; ß=-0.84; p=0.012). This effect was stronger in youth who experienced greater SES disadvantage (ß=-0.56; p=0.025). CONCLUSIONS: These findings suggest that increases in systemic inflammation are associated with reductions in amygdala GMV in adolescents, potentially signaling accelerated maturation, and that these neuroimmune processes are compounded in adolescents who experienced greater SES disadvantage. Our findings are consistent with theoretical frameworks of neuroimmune associations and suggest they may influence adolescent neurodevelopment.

Sex-Specific Vulnerability to Externalizing Problems: Sensitivity to Early Stress and Nucleus Accumbens Activation Over Adolescence.

BACKGROUND: Exposure and sensitivity to early-life stress (ELS) are related to increased risk for psychopathology in adolescence. While cross-sectional studies have reported blunted nucleus accumbens (NAcc) activation in the context of these associations, researchers have not yet assessed the effects of ELS on developmental trajectories of activation. We examined whether trajectories are affected by stress and the moderating role of biological sex in predicting vulnerability to symptoms of psychopathology. METHODS: Adolescents (n = 173) completed 3 assessments at 2-year intervals across puberty (ages 9-18 years). At baseline, we assessed objective ELS and stress sensitivity using the Traumatic Events Screening Inventory for Children. At all time points, we assessed NAcc activation using the Monetary Incentive Delay task and externalizing, internalizing, and total problems using the Youth Self-Report. We examined correlations between NAcc trajectories (extracted using linear mixed-effects models) with ELS and stress sensitivity and conducted multivariate regression analysis to examine the interaction of NAcc trajectories and biological sex in predicting symptoms of psychopathology. RESULTS: Symptoms increased over adolescence. Stress sensitivity, but not objective ELS, was associated with decreasing trajectories of NAcc activation. Biological sex interacted with NAcc trajectories to predict psychopathology; boys, but not girls, with decreasing NAcc activation had more severe externalizing problems in adolescence. These findings were replicated in the putamen and caudate but not in the medial prefrontal cortex or control brain regions. CONCLUSIONS: NAcc activation may be a sex-specific marker of externalizing problems in adolescence. Efforts to reduce stress sensitivity may help to decrease symptoms of psychopathology in adolescent boys.

Protocol for teen inflammation glutamate emotion research (TIGER): Toward predictors of treatment response and clinical course in depressed adolescents.

Adolescent-onset depression is a prevalent and debilitating condition commonly associated with treatment refractory depression and non-response to first-line antidepressants. There are, however, no objective tests to determine who may or may not respond to antidepressants. As depressed adolescents are especially vulnerable to the lifelong consequences of ineffectively-treated depression, it is critical to identify neurobiological predictors of treatment non-response in this population. Here, we describe the scientific rationale and protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) study, a prospective 18-month investigation of 160 depressed adolescents who will be assessed before and after treatment with selective serotonin reuptake inhibitors. TIGER will be using ultra-high field imaging to test the effects of acute stress and antidepressant treatment on inflammatory and glutamatergic processes hypothesized to underlie depression maintenance. Results from this work will motivate future studies testing alternative therapeutics for depressed adolescents at risk for treatment resistant depression. ClinicalTrials.gov Identifier: NCT05329441.

Early life stress moderates the relation between systemic inflammation and neural activation to reward in adolescents both cross-sectionally and longitudinally.

Elevated levels of systemic inflammation are associated with altered reward-related brain function in ventral striatal areas of the brain like the nucleus accumbens (NAcc). In adolescents, cross-sectional research indicates that exposure to early life stress (ELS) can moderate the relation between inflammation and neural activation, which may contribute to atypical reward function; however, no studies have tested whether this moderation by ELS of neuroimmune associations persists over time. Here, we conducted a cross-sectional analysis and the first exploratory longitudinal analysis testing whether cumulative severity of ELS moderates the association of systemic inflammation with reward-related processing in the NAcc in adolescents (n = 104; 58F/46M; M[SD] age = 16.00[1.45] years; range = 13.07-19.86 years). For the cross-sectional analysis, we modeled a statistical interaction between ELS and levels of C-reactive protein (CRP) predicting NAcc activation during the anticipation and outcome phases of a monetary reward task. We found that higher CRP was associated with blunted NAcc activation during the outcome of reward in youth who experienced higher levels of ELS (ß = -0.31; p = 0.006). For the longitudinal analysis, we modeled an interaction between ELS and change in CRP predicting change in NAcc activation across 2 years. This analysis similarly showed that increasing CRP over time was associated with decreasing NAcc during reward outcomes in youth who experienced higher levels of ELS (ß = -0.47; p = 0.022). Both findings support contemporary theoretical frameworks involving associations among inflammation, reward-related brain function, and ELS exposure, and suggest that experiencing ELS can have significant and enduring effects on neuroimmune function and adolescent neurodevelopment.

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.

Early life stress predicts trajectories of emotional problems and hippocampal volume in adolescence.

Exposure to early life stress (ELS) has been consistently associated with adverse emotional and neural consequences in youth. The development of brain structures such as the hippocampus, which plays a significant role in stress and emotion regulation, may be particularly salient in the development of psychopathology. Prior work has documented smaller hippocampal volume (HCV) in relation to both ELS exposure and risk for psychopathology. We used longitudinal k-means clustering to identify simultaneous trajectories of HCV and emotional problems in 155 youth across three assessments conducted approximately two years apart (mean baseline age = 11.33 years, 57% female). We also examined depressive symptoms and resilience approximately two years after the third timepoint. We identified three clusters of participants: a cluster with high HCV and low emotional problems; a cluster with low HCV and high emotional problems; and a cluster with low HCV and low emotional problems. Importantly, severity of ELS was associated with greater likelihood of belonging to the low HCV/high symptom cluster than to the low HCV/low symptom cluster. Further, low HCV/high symptom participants had more depressive symptoms and lower resilience scores than did participants in the low HCV/low symptom, but not than in the high HCV/low symptom cluster. Our findings suggest that smaller HCV indexes biological sensitivity to stress. This adds to our understanding of the ways in which ELS can affect hippocampal and emotional development in young people and points to hippocampal volume as a marker of susceptibility to context.

Preparation and processing of dried blood spots for microRNA sequencing.

Dried blood spots (DBS) are biological samples commonly collected from newborns and in geographic areas distanced from laboratory settings for the purposes of disease testing and identification. MicroRNAs (miRNAs)-small non-coding RNAs that regulate gene activity at the post-transcriptional level-are emerging as critical markers and mediators of disease, including cancer, infectious diseases, and mental disorders. This protocol describes optimized procedural steps for utilizing DBS as a reliable source of biological material for obtaining peripheral miRNA expression profiles. We outline key practices, such as the method of DBS rehydration that maximizes RNA extraction yield, and the use of degenerate oligonucleotide adapters to mitigate ligase-dependent biases that are associated with small RNA sequencing. The standardization of miRNA readout from DBS offers numerous benefits: cost-effectiveness in sample collection and processing, enhanced reliability and consistency of miRNA profiling, and minimal invasiveness that facilitates repeated testing and retention of participants. The use of DBS-based miRNA sequencing is a promising method to investigate disease mechanisms and to advance personalized medicine.

Early life stress, sleep disturbances, and depressive symptoms during adolescence: The role of the cingulum bundle.

Adolescence is often characterized by sleep disturbances that can affect the development of white matter tracts implicated in affective and cognitive regulation, including the cingulate portion of the cingulum bundle (CGC) and the uncinate fasciculus (UF). These effects may be exacerbated in adolescents exposed to early life adversity (ELA). We examined the longitudinal relations between sleep problems and CGC and UF microstructure during adolescence and their relation to depressive symptoms as a function of exposure to ELA. We assessed self-reported sleep disturbances and depressive symptoms and acquired diffusion-weighted MRI scans twice: in early adolescence (9-13 years) and four years later (13-17 years) (N = 72 complete cases). Independent of ELA, higher initial levels and increases in sleep problems were related to increases in depressive symptoms. Further, increases in right CGC fractional anisotropy (FA) mediated the association between sleep problems and depressive symptoms for youth who experienced lower, but not higher, levels of ELA. In youth with higher ELA, higher initial levels of and steeper decreases in sleep problems were associated with greater decreases in right UF FA, but were unrelated to depressive symptoms. Our findings highlight the importance of sleep quality in shaping fronto-cingulate-limbic tract development and depressive symptoms during adolescence.

Objective and subjective sleep health in adolescence: Associations with puberty and affect.

Sleep health tends to worsen during adolescence, partially due to pubertal-related changes that, in combination with social and psychological factors, can lead to long-lasting impairments in sleep health and affective functioning. Discrepant findings between subjective and objective measures of sleep in relation to affect have been reported in studies of adults; however, few investigations have assessed both subjective and objective sleep quality in a single sample, and fewer have examined this in the context of pubertal development. We aimed to (1) characterise pubertal associations with subjective sleep satisfaction, objective sleep efficiency, and objective and subjective sleep duration in adolescents; (2) examine the longitudinal association between daily affect and sleep metrics; and (3) test whether pubertal stage moderated this association. Eighty-nine participants (64% female, ages 13-20) completed an ecological momentary assessment (EMA) and actigraphy protocol. Independent of age, advanced pubertal stage was associated with lower subjective sleep satisfaction but not with objective sleep indices. Subjective sleep satisfaction was associated with within-person trajectories of negative affect, but not with positive affect. Pubertal stage and sleep satisfaction did not interact to predict within-day negative or positive affect. These findings are consistent with previous reports showing that objective and subjective sleep health are associated differently with puberty, and that subjective sleep health is associated with daily affect. Pubertal stage may be a more important indicator of subjective sleep quality in adolescence than is chronological age, most likely due to hormonal changes and psychological adjustment to the physical changes associated with the pubertal transition.

Effects of the COVID-19 Pandemic on Mental Health and Brain Maturation in Adolescents: Implications for Analyzing Longitudinal Data.

Background: The COVID-19 pandemic has caused significant stress and disruption for young people, likely leading to alterations in their mental health and neurodevelopment. In this context, it is not clear whether youth who lived through the pandemic and its shutdowns are comparable psychobiologically to their age- and sex-matched peers assessed before the pandemic. This question is particularly important for researchers who are analyzing longitudinal data that span the pandemic. Methods: In this study we compared carefully matched youth assessed before the pandemic (n=81) and after the pandemic-related shutdowns ended (n=82). Results: We found that youth assessed after the pandemic shutdowns had more severe internalizing mental health problems, reduced cortical thickness, larger hippocampal and amygdala volume, and more advanced brain age. Conclusions: Thus, not only does the COVID-19 pandemic appear to have led to poorer mental health and accelerated brain aging in adolescents, but it also poses significant challenges to researchers analyzing data from longitudinal studies of normative development that were interrupted by the pandemic.

Early life stress, systemic inflammation, and neural correlates of implicit emotion regulation in adolescents.

Exposure to early life stress (ELS) increases the risk for developing psychopathology; however, the mechanisms underlying this association are not clear. In this study we examined systemic inflammation as a pathway that may link exposure to stress to altered neural correlates of implicit emotion regulation in adolescents with varying levels of exposure to ELS (n = 83; 52 females, 31 males; 15.63 ± 1.10 years). We measured ventrolateral prefrontal cortex (vlPFC) activation and functional connectivity (FC) between the bilateral amygdala and the vlPFC as adolescents completed an affect labeling task in the scanner and assessed concentrations of C-reactive protein (CRP) using a dried blood spot protocol. We found that CRP levels were negatively associated with vlPFC activation during implicit regulation of negatively-valenced stimuli, and that cumulative severity of ELS exposure moderated this neuroimmune association. Severity of ELS also significantly moderated the association between CRP levels and FC between the bilateral amygdala and l-vlPFC during implicit emotion regulation: in adolescents who had been exposed to more severe ELS, higher CRP was associated with more negative frontoamygdala FC during implicit regulation of negatively-valenced stimuli. Thus, ELS may disrupt the normative association between the immune system and the neural processes that underlie socioemotional functioning potentially increasing adolescents' risk for maladaptive outcomes.

Correlates and predictors of the severity of suicidal ideation in adolescence: an examination of brain connectomics and psychosocial characteristics.

BACKGROUND: Suicidal ideation (SI) typically emerges during adolescence but is challenging to predict. Given the potentially lethal consequences of SI, it is important to identify neurobiological and psychosocial variables explaining the severity of SI in adolescents. METHODS: In 106 participants (59 female) recruited from the community, we assessed psychosocial characteristics and obtained resting-state fMRI data in early adolescence (baseline: aged 9-13 years). Across 250 brain regions, we assessed local graph theory-based properties of interconnectedness: local efficiency, eigenvector centrality, nodal degree, within-module z-score, and participation coefficient. Four years later (follow-up: ages 13-19 years), participants self-reported their SI severity. We used least absolute shrinkage and selection operator (LASSO) regressions to identify a linear combination of psychosocial and brain-based variables that best explain the severity of SI symptoms at follow-up. Nested-cross-validation yielded model performance statistics for all LASSO models. RESULTS: A combination of psychosocial and brain-based variables explained subsequent severity of SI (R2 = .55); the strongest was internalizing and externalizing symptom severity at follow-up. Follow-up LASSO regressions of psychosocial-only and brain-based-only variables indicated that psychosocial-only variables explained 55% of the variance in SI severity; in contrast, brain-based-only variables performed worse than the null model. CONCLUSIONS: A linear combination of baseline and follow-up psychosocial variables best explained the severity of SI. Follow-up analyses indicated that graph theory resting-state metrics did not increase the prediction of the severity of SI in adolescents. Attending to internalizing and externalizing symptoms is important in early adolescence; resting-state connectivity properties other than local graph theory metrics might yield a stronger prediction of the severity of SI.