Effects of Pollution Burden on Neural Function During Implicit Emotion Regulation and Longitudinal Changes in Depressive Symptoms in Adolescents.

Background: Exposure to environmental pollutants early in life has been associated with increased prevalence and severity of depression in adolescents; however, the neurobiological mechanisms underlying this association are not well understood. In the current longitudinal study, we investigated whether pollution burden in early adolescence (9-13 years) was associated with altered brain activation and connectivity during implicit emotion regulation and changes in depressive symptoms across adolescence. Methods: One hundred forty-five participants (n = 87 female; 9-13 years) provided residential addresses, from which we determined their relative pollution burden at the census tract level, and performed an implicit affective regulation task in the scanner. Participants also completed questionnaires assessing depressive symptoms at 3 time points, each approximately 2 years apart, from which we calculated within-person slopes of depressive symptoms. We conducted whole-brain activation and connectivity analyses to examine whether pollution burden was associated with alterations in brain function during implicit emotion regulation of positively and negatively valenced stimuli and how these effects were related to slopes of depressive symptoms across adolescence. Results: Greater pollution burden was associated with greater bilateral medial prefrontal cortex activation and stronger bilateral medial prefrontal cortex connectivity with regions within the default mode network (e.g., temporoparietal junction, posterior cingulate cortex, precuneus) during implicit regulation of negative emotions, which was associated with greater increases in depressive symptoms across adolescence in those exposed to higher pollution burden. Conclusions: Adolescents living in communities characterized by greater pollution burden showed altered default mode network functioning during implicit regulation of negative emotions that was associated with increases in depressive symptoms across adolescence.

Exposure to environmental pollution is related to increased risk for depression in youth; however, the neurobiological mechanisms underlying this association are unknown. We found that adolescents living in neighborhoods with greater census tract­level pollution burden had stronger functional connectivity between the medial prefrontal cortex and regions within the default mode network during implicit regulation of negative emotions, which in turn was associated with greater increases in depressive symptoms across adolescence in these pollution-exposed youths.

Task-Rest Reconfiguration Efficiency of the Reward Network Across Adolescence and Its Association With Early Life Stress and Depressive Symptoms.

OBJECTIVE: Adolescents face significant changes in many domains of their daily lives that require them to flexibly adapt to changing environmental demands. To shift efficiently among various goals, adolescents must reconfigure their brains, disengaging from previous tasks and engaging in new activities. METHOD: To examine this reconfiguration, we obtained resting-state and task-based functional magnetic resonance imaging (fMRI) scans in a community sample of 164 youths. We assessed the similarity of functional connectivity (FC) of the reward network between resting state and a reward-processing state, indexing the degree of reward network reconfiguration required to meet task demands. Given research documenting relations among reward network function, early life stress (ELS), and adolescent depression, we examined the association of reconfiguration efficiency with age across adolescence, the moderating effect of ELS on this association, and the relation between reconfiguration efficiency and depressive symptoms. RESULTS: We found that older adolescents showed greater reconfiguration efficiency than younger adolescents and, furthermore, that this age-related association was moderated by the experience of ELS. CONCLUSION: These findings suggest that reconfiguration efficiency of the reward network increases over adolescence, a developmental pattern that is attenuated in adolescents exposed to severe ELS. In addition, even after controlling for the effects of age and exposure to ELS, adolescents with higher levels of depressive symptoms exhibited greater reconfiguration efficiency, suggesting that they have brain states at rest that are more strongly optimized for reward processing than do asymptomatic youth. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science.

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.

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.

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.

An exploration of dimensions of early adversity and the development of functional brain network connectivity during adolescence: Implications for trajectories of internalizing symptoms.

Different dimensions of adversity may affect mental health through distinct neurobiological mechanisms, though current supporting evidence consists largely of cross-sectional associations between threat or deprivation and fronto-limbic circuitry. In this exploratory three-wave longitudinal study spanning ages 9-19 years, we examined the associations between experiences of unpredictability, threat, and deprivation with the development of functional connectivity within and between three brain networks implicated in psychopathology: the salience (SAL), default mode (DMN), and fronto-parietal (FPN) networks, and tested whether network trajectories moderated associations between adversity and changes in internalizing symptoms. Connectivity decreased with age on average; these changes differed by dimension of adversity. Whereas family-level deprivation was associated with lower initial levels and more stability across most networks, unpredictability was associated with stability only in SAL connectivity, and threat was associated with stability in FPN and DMN-SAL connectivity. In youth exposed to higher levels of any adversity, lower initial levels and more stability in connectivity were related to smaller increases in internalizing symptoms. Our findings suggest that whereas deprivation is associated with widespread neurodevelopmental differences in cognitive and emotion processing networks, unpredictability is related selectively to salience detection circuitry. Studies with wider developmental windows should examine whether these neurodevelopmental alterations are adaptive or serve to maintain internalizing symptoms.

Reduced anxiety and changes in amygdala network properties in adolescents with training for awareness, resilience, and action (TARA).

Mindfulness-based approaches show promise to improve emotional health in youth and may help treat and prevent adolescent depression and anxiety. However, there is a fundamental gap in understanding the neural reorganization that takes place as a result of such interventions. The Training for Awareness, Resilience, and Action (TARA) program, initially developed for depressed adolescents, uses a framework drawn from neuroscience, mindfulness, yoga, and modern psychotherapeutic techniques to promote emotional health. The goal of this study was to assess the effects of the TARA training on emotional health and structural white matter brain networks in healthy youth. We analyzed data from 23 adolescents who underwent the 12-week TARA training in a controlled within-subject study design and whose brain networks were assessed using diffusion MRI connectomics. Compared to the control time period, adolescents showed a significant decrease in anxiety symptoms with TARA (Cohen's d = -0.961, p = 0.006); moreover, the node strength of the Right Amygdala decreased significantly after TARA (Cohen's d = -1.026, p = 0.004). Post-hoc analyses indicated that anxiety at baseline before TARA was positively correlated with Right Amygdala node strength (r = 0.672, p = 0.001). While change in Right Amygdala node strength with TARA was not correlated with change in anxiety (r = 0.146, p = 0.51), it was associated with change in depression subscale of Anhedonia / Negative Affect (r = 0.575, p = 0.004, exploratory analysis), possibly due to overlapping constructs captured in our anxiety and depression scales. Our results suggest that increased structural connectivity of Right Amygdala may underlie increased anxiety in adolescents and be lowered through anxiety-reducing training such as TARA. The results of this study contribute to our understanding of the neural mechanisms of TARA and may facilitate neuroscience-based prevention and treatment of adolescent anxiety and depression.

Neural Correlates of Smartphone Dependence in Adolescents.

Increases in depressive and suicide-related symptoms among United States adolescents have been recently linked to increased use of smartphones. Understanding of the brain mechanisms that underlie the potential smartphone dependence may help develop interventions to address this important problem. In this exploratory study, we investigated the neural mechanisms underlying potential smartphone dependence in a sample of 19 adolescent volunteers who completed self-assessments of their smartphone dependence, depressive symptoms, and sleep problems. All 19 adolescents underwent diffusion MRI that allowed for assessment of white matter structural connectivity within the framework of connectomics. Based on previous literature on the neurobiology of addiction, we hypothesized a disruption of network centrality of three nodes in the mesolimbic network: Nucleus Accumbens, anterior cingulate cortex, and amygdala. Our results showed positive correlations between the node centrality of the right amygdala and self-reported smartphone dependence, between smartphone dependence and sleep problems, and between sleep problems and depressive symptoms. A higher phone dependence was observed in females compared to males. Supported by these results, we propose a model of how smartphone dependence can be linked to aberrations in brain networks, sex, sleep disturbances, and depression in adolescents.

Gray Matter Changes in Adolescents Participating in a Meditation Training.

Meditation has shown to benefit a wide range of conditions and symptoms, but the neural mechanisms underlying the practice remain unclear. Magnetic resonance imaging (MRI) studies have investigated the structural brain changes due to the practice by examining volume, density, or cortical thickness changes. However, these studies have focused on adults; meditation's structural effects on the adolescent brain remain understudied. In this study, we investigated how meditation training affects the structure of the adolescent brain by scanning a group of 38 adolescents (16.48 ± 1.29 years) before and after participating in a 12-week meditation training. Subjects underwent Training for Awareness, Resilience, and Action (TARA), a program that mainly incorporates elements from mindfulness meditation and yoga-based practices. A subset of the adolescents also received an additional control scan 12 weeks before TARA. We conducted voxel-based morphometry (VBM) to assess gray matter volume changes pre- to post-training and during the control period. Subjects showed significant gray matter (GM) volume decreases in the left posterior insula and to a lesser extent in the left thalamus and left putamen after meditation training. There were no significant changes during the control period. Our results support previous findings that meditation affects regions associated with physical and emotional awareness. However, our results are different from previous morphometric studies in which meditation was associated with structural increases. We posit that this discrepancy may be due to the differences between the adolescent brain and the adult brain.

Application of machine learning to structural connectome to predict symptom reduction in depressed adolescents with cognitive behavioral therapy (CBT).

PURPOSE: Adolescent major depressive disorder (MDD) is a highly prevalent, incapacitating and costly illness. Many depressed teens do not improve with cognitive behavioral therapy (CBT), a first-line treatment for adolescent MDD, and face devastating consequences of increased risk of suicide and many negative health outcomes. "Who will improve with CBT?" is a crucial question that remains unanswered, and treatment planning for adolescent depression remains biologically unguided. The purpose of this study was to utilize machine learning applied to patients' brain imaging data in order to help predict depressive symptom reduction with CBT. METHODS: We applied supervised machine learning to diffusion MRI-based structural connectome data in order to predict symptom reduction in 30 depressed adolescents after three months of CBT. A set of 21 attributes was chosen, including the baseline depression score, age, gender, two global network properties, and node strengths of brain regions previously implicated in depression. The practical and robust J48 pruned tree classifier was utilized with a 10-fold cross-validation. RESULTS: The classification resulted in an 83% accuracy of predicting depressive symptom reduction. The resulting tree of size seven with only three attributes highlights the role of the right thalamus in predicting depressive symptom reduction with CBT. Additional analysis showed a significant negative correlation between the change in the depressive symptoms and the node strength of the right thalamus. CONCLUSIONS: Our results demonstrate that a machine learning algorithm that exclusively uses structural connectome data and the baseline depression score can predict with a high accuracy depressive symptom reduction in adolescent MDD with CBT. This knowledge can help improve treatment planning for adolescent depression.

Test-Retest Reliability of Graph Theoretic Metrics in Adolescent Brains.

Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate (1) the effects of edge weighting schemes and (2) the effects of varying interscan periods on graph metrics within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count, and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62 ± 1.10 years) or within the same scanning session (30 min apart) (16.65 ± 1.14 years). The intraclass correlation coefficient was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA weights are more suited for DTI connectome studies in adolescents.

High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression.

BACKGROUND: Adolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group. METHODS: The first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents. RESULTS: There were no diagnosis-specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto-occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn. LIMITATIONS: Undifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations. CONCLUSIONS: The results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population.