Background
The COVID‐19 pandemic is the most serious global public health crisis since the 1918 influenza pandemic. This study is the first to assess its mental health impact across the lifespan in ...the United States in adolescents, adults, and health care workers.
Methods
We recruited 4909 participants through an online survey advertising on Facebook and Instagram to assess exposure to COVID‐19 and psychiatric symptoms from April 27 to July 13. We also recruited through the University of Pittsburgh, University of Pittsburgh Medical Center, and other health care systems around Pittsburgh. The primary outcomes were clinically significant depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms, suicidal ideation or behavior, and grief reactions since COVID‐19.
Results
Adolescents were significantly more likely to report moderate to severe symptoms of depression (55% vs. 29%; χ2 = 122, df = 1; p < .001), anxiety (48% vs. 29%; χ2 = 73; df = 1; p < .001), PTSD (45% vs. 33%; χ2 = 12; df = 1; p < .001), suicidal ideation or behavior (38% vs. 16%; χ2 = 117; df = 1; p < .001), and sleep problems (69% vs. 57%; χ2 = 26; df = 1; p < .001) compared to adults. The rates of intense grief reactions among those who lost someone to COVID‐19 was 55%. Loneliness was the most common predictor across outcomes and higher number of hours spent on social media and exposure to media about COVID‐19 predicted depression symptoms and suicidal ideation or behavior in adolescents.
Conclusions
The COVID‐19 pandemic is associated with increased rates of clinically significant psychiatric symptoms. Loneliness could put individuals at increased risk for the onset of psychiatric disorders.
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; MSD age = 16.001.45 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 (β = -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 (β = -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.
•Inflammation is linked to neural correlates of implicit emotion regulation in youth.•Early life stress (ELS) severity moderates this neuroimmune association.•ELS severity moderates the link between ...inflammation and frontoamygdala connectivity.•The results extend current models of neuroimmune relations and the effects of ELS.
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.
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.
•Sleep problems in adolescents are associated with increases in depressive symptoms.•With low early stress, sleep problems increase cingulum cingulate (CGC) integrity.•Increases in CGC integrity are related to increases in depressive symptoms.•Sleep problems reduce uncinate fasciculus integrity in youth with more early stress.•Integrity of uncinate fasciculus is not related to depressive symptoms.
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.
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.
Neighborhood or area-level socioeconomic disadvantage is associated with neural alterations across the lifespan. Few studies, however, 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.
In 200 adolescents (ages 13-20 years; 54.5% female, 4% non-binary) recruited from two 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.
Greater neighborhood socioeconomic disadvantage was associated with lower fractional anisotropy (FA) in the left arcuate fasciculus (β=-0.24, FDR-corrected p=0.035) and right uncinate fasciculus (β=-0.32, FDR-corrected p=0.002), above and beyond the effects of family-level socioeconomic status. Depressive symptoms significantly moderated the association between left arcuate fasciculus FA and both neighborhood (β=0.17, FDR-corrected p=0.026) and unemployment disadvantage (β=0.22, FDR-corrected p=0.004), 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.
Greater neighborhood socioeconomic disadvantage, particularly poverty and education attainment levels, is associated with lower FA in the arcuate fasciculus and uncinate fasciculus, above and beyond family-level measures of socioeconomic status. These patterns were observed only in adolescents with low levels of depression, suggesting that we must be cautious about generalizing these findings to youth who struggle with mental health difficulties.
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 youths 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.
We compared carefully matched youths assessed before the pandemic (n = 81) and after the pandemic-related shutdowns ended (n = 82).
We found that youths 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.
The COVID-19 pandemic not only appears 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.
Abstract
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.
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.
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.
We found that ΔCRP was negatively associated with ΔAmygdala GMV (i.e. increasing CRP levels were associated with decreasing amygdala volume; β=-0.84; p=0.012). This effect was stronger in youth who experienced greater SES disadvantage (β=-0.56; p=0.025).
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.
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