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Climate change, wildfires, and environmental justice concerns have drawn increased attention to the impact of air pollution on children's health and development. Children are especially vulnerable to air pollution exposure, as their brains and bodies are still developing. The objective of this systematic review was to synthesize available empirical evidence on the associations between air pollution exposure and brain outcomes in developmental samples (ages 0-18 years old). Studies were identified by searching the PubMed and Web of Science Core Collection databases and underwent a two-phase screening process before inclusion. 40 studies were included in the review, which included measures of air pollution and brain outcomes at various points in development. Results linked air pollution to varied brain outcomes, including structural volumetric and cortical thickness differences, alterations in white matter microstructure, functional network changes, metabolic and molecular effects, as well as tumor incidence. Few studies included longitudinal changes in brain outcomes. This review also suggests methodologies for incorporating air pollution measures in developmental cognitive neuroscience studies and provides specific policy recommendations to reduce air pollution exposure and promote healthy brain development by improving access to clean air.

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p

Childhood adversity is a leading transdiagnostic risk factor for psychopathology, being associated with an estimated 31-62% of childhood-onset disorders and 23-42% of adult-onset disorders (Kessler et al., 2010). Major unresolved theoretical challenges stem from the nonspecific and probabilistic nature of the links between childhood adversity and psychopathology. The links are nonspecific because childhood adversity increases risk, through a range of mechanisms, for diverse forms of psychopathology and are probabilistic because not all individuals exposed to childhood adversity develop psychopathology. In this article, we propose a path forward by focusing on stress phenotypes, defined as biobehavioral patterns activated in response to stressors that can disrupt future functioning when persistent (e.g., reward seeking, social withdrawal, aggression). This review centers on the accumulating evidence that psychopathology appears to be more strongly predicted by behavior and biology during states of stress. Building on this observation, our theoretical framework proposes that we can model pathways from childhood adversity to psychopathology with greater specificity and certainty by understanding stress phenotypes, defined as patterns of behavior and their corresponding biological substrates that are elicited by stressors. This approach aims to advance our conceptualization of mediating pathways from childhood adversity to psychopathology. Understanding stress phenotypes will bring us closer to "precision mental health," a person-centered approach to identifying, preventing, and treating psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

ObjectiveTo explore differences in regional cortical morphometric structure between adolescents at risk for depression or with current depression.MethodsWe analyzed cross-sectional structural neuroimaging data from a sample of 150 Brazilian adolescents classified as low-risk (n=50) or high-risk for depression (n=50) or with current depression (n=50) through a vertex-based approach with measurements of cortical volume, surface area and thickness. Differences between groups in subcortical volumes and in the organization of networks of structural covariance were also explored.ResultsNo significant differences in brain structure between groups were observed in whole-brain vertex-wise cortical volume, surface area or thickness. Also, no significant differences in subcortical volume were observed between risk groups. In relation to the structural covariance network, there was an indication of an increase in the hippocampus betweenness centrality index in the high-risk group network compared to the low-risk and current depression group networks. However, this result was only statistically significant when applying false discovery rate correction for nodes within the affective network.ConclusionIn an adolescent sample recruited using an empirically based composite risk score, no major differences in brain structure were detected according to the risk and presence of depression.

Research in adults suggests that higher peripheral inflammation is associated with increased threat-related amygdala activity and reduced cortico-amygdala connectivity. However, there is limited research in adolescents, which is striking given the major developmental changes that occur in cortico-amygdala circuitry during adolescence. In this study, we examine the association between peripheral inflammation and amygdala activity and connectivity to emotional faces in a community sample of adolescents. Participants included 88 adolescents 12 to 15 years old who provided a blood sample and underwent fMRI scanning while completing a face and shape matching task that included fearful, angry, and happy faces. Blood samples were assayed for interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α); IL-6 and CRP were combined into a composite due to their high correlation and TNF-α was analyzed separately. Results indicated that higher TNF-α, but not the composite of IL-6 and CRP, was associated with increased amygdala activity to threatening (fearful and angry) faces and to happy faces, relative to shape matching. Whole-brain analyses also identified associations between TNF-α and neural activity to angry and happy faces in regions outside of the amygdala. Psychophysiological interaction analysis indicated that higher TNF-α was associated with reduced bilateral amygdala connectivity to the left cuneus, right cuneus/calcarine fissure/precuneus, and left supramarginal gyrus/inferior parietal gyrus during angry and fearful faces > shapes and higher IL-6/CRP was associated with reduced bilateral amygdala connectivity to the right postcentral gyrus and right precuneus. Results suggest that peripheral inflammation is associated with increased amygdala activity to emotional face stimuli and reduced amygdala connectivity with occipital and parietal regions. These findings enhance our understanding of the association between peripheral inflammation and neural response to emotional faces, which could inform the development of interventions targeting inflammation for adolescents.

Although adolescence is a period in which developmental changes occur in brain connectivity, personality formation, and peer interaction, few studies have examined the neural correlates of personality dimensions related to social behavior within adolescent samples. The current study aims to investigate whether adolescents' brain functional connectivity is associated with extraversion and agreeableness, personality dimensions linked to peer acceptance, social network size, and friendship quality. Considering sex-variant neural maturation in adolescence, we also examined sex-specific associations between personality and functional connectivity. Using resting-state functional magnetic resonance imaging (fMRI) data from a community sample of 70 adolescents aged 12-15, we examined associations between self-reported extraversion and agreeableness and seed-to-whole brain connectivity with the amygdala as a seed region of interest. Then, using 415 brain regions that correspond to 8 major brain networks and subcortex, we explored neural connectivity within brain networks and across the whole-brain. We conducted group-level multiple regression analyses with the regressors of extraversion, agreeableness, and their interactions with sex. Results demonstrated that amygdala connectivity with the postcentral gyrus, middle temporal gyrus, and the temporal pole is positively associated with extraversion in girls and negatively associated with extraversion in boys. Agreeableness was positively associated with amygdala connectivity with the middle occipital cortex and superior parietal cortex, in the same direction for boys and girls. Results of the whole-brain connectivity analysis revealed that the connectivity of the postcentral gyrus, located in the dorsal attention network, with regions in default mode network (DMN), salience/ventral attention network, and control network (CON) was associated with extraversion, with most connections showing positive associations in girls and negative associations in boys. For agreeableness, results of the within-network connectivity analysis showed that connections within the limbic network were positively associated with agreeableness in boys while negatively associated with or not associated with agreeableness in girls. Results suggest that intrinsic functional connectivity may contribute to adolescents' individual differences in extraversion and agreeableness and highlights sex-specific neural connectivity patterns associated with the two personality dimensions. This study deepens our understanding of the neurobiological correlates of adolescent personality that may lead to different developmental trajectories of social experience.

Relatively little is known about associations between peripheral inflammation and neural function in humans. Neuroimaging studies in adults have suggested that elevated peripheral inflammatory markers are associated with altered resting state functional connectivity (rsFC) in several brain networks associated with mood and cognition. Few studies have examined these associations in adolescents, yet scarce data from adolescents point to different networks than adult studies. The current study examined the associations between peripheral inflammation and rsFC in a community sample of adolescents (n = 70; age, 12-15 years; 32 female, 36 male, 2 nonbinary). After blood sampling, an fMRI scan was performed to assess rsFC. Assay for serum inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP), was performed. Results indicated that higher TNF-α was associated with altered rsFC between the right amygdala and left striatum and between the right inferior frontal gyrus and left parietal cortex (p

Adolescents comprise one fourth of the world's population, with about 90% of them living in low- and middle-income countries (LMICs). The incidence of depression markedly increases during adolescence, making the disorder a leading cause of disease-related disability in this age group. However, most research on adolescent depression has been performed in high-income countries (HICs). To ascertain the extent to which this disparity operates in neuroimaging research, a systematic review of the literature was performed. A total of 148 studies were identified, with neuroimaging data available for 4,729 adolescents with depression. When stratified by income group, 122 (82%) studies originated from HICs, while 26 (18%) were conducted in LMICs, for a total of 3,705 and 1,024 adolescents with depression respectively. A positive Spearman rank correlation was observed between country per capita income and sample size (rs=0.673, p = 0.023). Our results support the previous reports showing a large disparity between the number of studies and the adolescent population per world region. Future research comparing neuroimaging findings across populations from HICs and LMICs may provide unique insights to enhance our understanding of the neurobiological processes underlying the development of depression.

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS). Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers. Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample. Results: A total of 7,720 adolescents aged 14-16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group. Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence.

ObjectiveAltered activity within reward-related neural regions, including the ventral striatum (VS) and medial prefrontal cortex (mPFC), is associated with concurrent problematic substance use. The aims of the present study were (a) to identify patterns of reward-related neural activity that prospectively predicted changes in alcohol use 2 years after magnetic resonance imaging in a sample of adolescents, and (b) to examine whether these patterns differed by sex. We also tested whether depression symptoms or impulsivity mediated associations between neural activity and future alcohol use.MethodParticipants were 262 adolescents (129 male and 133 female) of Mexican origin who completed the Monetary Incentive Delay task during a functional magnetic resonance imaging scan at age 16. Participants reported on their alcohol use at ages 16 and 18.ResultsResults indicated that different patterns of reward-related neural activity predicted future increases in alcohol use for male and female adolescents. In boys, higher VS activity during reward anticipation and average ventral mPFC activity during reward feedback predicted increases in alcohol use from age 16 to 18 years; in girls, higher dorsal mPFC activity and blunted VS activity during reward anticipation predicted increases in alcohol use from age 16 to 18 years. Depression symptoms or impulsivity did not mediate these associations.ConclusionThe results suggest that different pathways of risk may lead to problematic alcohol use for adolescent boys and girls. These sex differences in neural risk pathways have important implications for prevention and intervention approaches targeting Mexican-origin youth.

BackgroundDepression is a leading contributor to disability-adjusted life-years because of early onset and chronicity throughout the lifecycle. It is crucial to identify early predictors of depression among adolescents and young people to effectively target prevention. A gap in the literature is a comprehensive systematic review of predictors of depression among adolescents around the globe, especially in low- and middle-income countries LMICs. This review aims to identify evidence for biological, psychological, and contextual risk factors for the development of depression among adolescents and young adults (10-24 years of age) in high-income countries (HICs) and LMICs, ultimately contributing to (a) identification of potential mechanisms underlying depression development, (b) selection of common risk and protective factors as targets for detection, and (c) refinement of risk models that can be evaluated through existing cohorts in HICs and LMICs.MethodsThis review will follow the Population, Exposure, Comparison, Outcome (PI(E)CO) model and adheres to the PRISMA-P guidelines. A search strategy was developed by a multidisciplinary research consortium. Seven databases (MEDLINE via Ovid, PsycINFO, Cochrane Database of Systematic Reviews, Web of Science, Lilacs, African Journals Online, Global Health) will be searched to identify articles. Independent raters will screen and retrieve articles for inclusion, conduct quality ratings, and extract data. The Systematic Assessment of Quality in Observational Research adapted for Cultural Psychiatry Epidemiology (SAQOR-CPE) will be used to assess quality of observational studies. We will assess for publication bias using funnel plots and statistical methods. We will use narrative synthesis to present results, addressing the study's objectives following the Cochrane Handbook guidelines. Meta-analyses will be used to report summary statistics for association of risk factors with development of depression.DiscussionThis systematic review will summarize evidence-based research that examines the psychological, biological, and contextual factors contributing to the onset of depression in adolescents across the globe. Results will support the development of a model that can be evaluated in existing cohorts around the world.Systematic review registrationPROSPERO registration CRD42018103973 .

Relational bullying and victimization are common social experiences during adolescence, but relatively little functional magnetic resonance imaging (fMRI) research has examined the neural correlates of bullying and victimization in adolescents. The aim of the present study was to address this gap by examining the association between amygdala activity to angry and fearful faces and peer relational bullying and victimization in a community-based sample of adolescents. Participants included 49 adolescents, 12-15 years old, who underwent fMRI scanning while completing an emotional face matching task. Results indicated that interactions between amygdala activity to angry and fearful faces predicted self-reported relational bullying and victimization. Specifically, a combination of higher amygdala activity to angry faces and lower amygdala activity to fearful faces predicted more bullying behavior, whereas a combination of lower amygdala activity to angry faces and lower amygdala activity to fearful faces predicted less relational victimization. Exploratory whole-brain analyses also suggested that increased rostral anterior cingulate cortex activity to fearful faces was associated with less bullying. These results suggest that relational bullying and victimization are related to different patterns of neural activity to angry and fearful faces, which may help in understanding how patterns of social information processing predict these experiences.

BACKGROUND:Childhood maltreatment is one of the most potent predictors of future psychopathology, including internalizing disorders. It remains unclear whether heightened amygdala reactivity to threat and elevated stress exposure may be implicated in the pathogenesis and maintenance of internalizing disorders among individuals with a history of childhood maltreatment. METHODS:Using data from a sample of 1,144 young adults, we investigated the contribution of baseline threat-related amygdala reactivity and prospective major stressful life events to internalizing symptoms severity 1 year later (on average) in individuals with a history of maltreatment (n = 100) and propensity score matched nonmaltreated peers (n = 96). RESULTS:Even after stringently matching for several potentially confounding variables - including baseline internalizing symptoms, socioeconomic status and IQ - childhood maltreatment status predicted increased amygdala reactivity at baseline, elevated post-baseline exposure to major stressful life events and internalizing symptoms at follow-up. We also showed, for the first time, that amygdala reactivity at baseline and also post-baseline exposure to major stressful life events mediated the association between a history of maltreatment and future internalizing symptoms. CONCLUSIONS:These findings provide support for the view that maltreatment is a potent developmental insult leading to long-lasting neurocognitive recalibrations of the threat processing system. It is possible that such alterations, over time, may impact mental health functioning by compromising the ability to effectively negotiate everyday challenges (stress susceptibility). These alterations were not, however, found to sensitize an individual to the impact of major stressful life events. The results of this study also lend compelling support to the view that increased psychiatric risk, in the context of childhood maltreatment, follows from an increased propensity to experience major stressful life events (stress generation).

Functional connectivity between the amygdala and the prefrontal cortex is critical for socioemotional processing, particularly during face processing. Though processing others' emotions is important for a myriad of complex social behaviors, more research is needed to understand how different types of emotional facial expressions differentially elicit connectivity of the amygdala with widespread neural regions. Moreover, though prior studies have reported cross-sectional associations between altered amygdala-prefrontal cortex functional connectivity and internalizing symptoms (e.g., depression, anxiety), few studies have examined whether amygdala functional connectivity is prospectively related to changes in these symptoms, with little work focusing on low-income men living in stressful contexts. The current study used psycho-physiological interaction analyses at the within-subjects level to examine how amygdala connectivity differed while participants viewed fearful, angry, and neutral faces. We used structural equation modeling at the between-subjects level, using extracted parameter estimates, to test whether amygdala connectivity during face processing predicted increases in internalizing psychopathology over time, controlling for earlier symptoms. An urban sample of 167 young men from low-income families was employed. Results indicated that negative connectivity between the amygdala and prefrontal regions was modulated by emotional face type. Neuronal activity in the cingulate and frontal cortices was connected to amygdala reactivity during fearful and neutral, but not angry, face processing. Moreover, weaker left amygdala-left middle frontal gyrus negative connectivity when viewing fearful faces and stronger right amygdala-left inferior frontal gyrus negative connectivity when viewing neutral faces at age 20 both predicted increases in internalizing behaviors from age 20 to age 22. Our findings show that amygdala-prefrontal cortex connectivity can predict the persistence of internalizing symptoms among high-risk participants over time but suggest that these patterns may differ depending on the emotional stimuli examined.

We have previously reported that threat-related amygdala activity measured during a baseline fMRI scan predicts the experience of depression and anxiety associated with stressful life events years later. Here, we examine whether two broad measures of childhood environmental enrichment, namely parental educational achievement and subjective parental socioeconomic status, buffer against the effects of amygdala activity on future vulnerability to stress. Analyses of data available from 579 young adults revealed that maternal, but not paternal, educational achievement moderates the association between amygdala activity, recent life stress, and changes in mood and anxiety symptoms, even when controlling for participants' current subjective socioeconomic status. Specifically, only participants reporting lower maternal educational achievement exhibited our previously observed interaction between amygdala activity and future life stress predicting increases in depression and anxiety. These results suggest that higher maternal educational achievement may help buffer stress sensitivity associated with heightened threat-related amygdala activity.

Recent neuroimaging studies have suggested divergent relationships between antisocial behavior (AB) and callous-unemotional (CU) traits and amygdala reactivity to fearful and angry facial expressions in adolescents. However, little work has examined if these findings extend to dimensional measures of behavior in ethnically diverse, non-clinical samples, or if participant sex, ethnicity, pubertal stage, and age moderate associations. We examined links between amygdala reactivity and dimensions of AB and CU traits in 220 Hispanic and non-Hispanic Caucasian adolescents (age 11-15; 49.5% female; 38.2% Hispanic), half of whom had a family history for depression and thus were at relatively elevated risk for late starting, emotionally dysregulated AB. We found that AB was significantly related to increased right amygdala reactivity to angry facial expressions independent of sex, ethnicity, pubertal stage, age, and familial risk status for depression. CU traits were not related to fear- or anger-related amygdala reactivity. The present study further demonstrates that AB is related to increased amygdala reactivity to interpersonal threat cues in adolescents, and that this relationship generalizes across sex, ethnicity, pubertal stage, age, and familial risk status for depression.

Increased levels of peripheral inflammatory markers, including C-Reactive Protein (CRP), are associated with increased risk for depression, anxiety, and suicidality. The brain mechanisms that may underlie the association between peripheral inflammation and internalizing problems remain to be determined. The present study examines associations between peripheral CRP concentrations and threat-related amygdala activity, a neural biomarker of depression and anxiety risk, in a sample of 172 young adult undergraduate students. Participants underwent functional MRI scanning while performing an emotional face matching task to obtain a measure of threat-related amygdala activity to angry and fearful faces; CRP concentrations were assayed from dried blood spots. Results indicated a significant interaction between CRP and sex: in men, but not women, higher CRP was associated with higher threat-related amygdala activity. These results add to the literature finding associations between systemic levels of inflammation and brain function and suggest that threat-related amygdala activity may serve as a potential pathway through which heightened chronic inflammation may increase risk for mood and anxiety problems.

BackgroundWilliams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior.MethodsThrough an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students.ResultsThe GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men.ConclusionsA common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety.

Personality traits such as conscientiousness as self-reported by individuals can help predict a range of outcomes, from job performance to longevity. Asking others to rate the personality of their acquaintances often provides even better predictive power than using self-report. Here, we examine whether peer-reported personality can provide a better link between brain function, namely threat-related amygdala activity, and future health-related behavior, namely problem drinking, than self-reported personality. Using data from a sample of 377 young adult university students who were rated on five personality traits by peers, we find that higher threat-related amygdala activity to fearful facial expressions is associated with higher peer-reported, but not self-reported, conscientiousness. Moreover, higher peer-reported, but not self-reported, conscientiousness predicts lower future problem drinking more than one year later, an effect specific to men. Remarkably, relatively higher amygdala activity has an indirect effect on future drinking behavior in men, linked by peer-reported conscientiousness to lower future problem drinking. Our results provide initial evidence that the perceived conscientiousness of an individual by their peers uniquely reflects variability in a core neural mechanism supporting threat responsiveness. These novel patterns further suggest that incorporating peer-reported measures of personality into individual differences research can reveal novel predictive pathways of risk and protection for problem behaviors.

Calculating math problems from memory may seem unrelated to everyday processing of emotions, but they have more in common than one might think. Prior research highlights the importance of the dorsolateral prefrontal cortex (dlPFC) in executive control, intentional emotion regulation, and experience of dysfunctional mood and anxiety. While it has been hypothesized that emotion regulation may be related to 'cold' (ie. not emotion-related) executive control, this assertion has not been tested. We address this gap by providing evidence that greater dlPFC activity during 'cold' executive control is associated with increased use of cognitive reappraisal to regulate emotions in everyday life. We then demonstrate that in the presence of increased life stress, increased dlPFC activity is associated with lower mood and anxiety symptoms and clinical diagnoses. Collectively, our results encourage ongoing efforts to understand prefrontal executive control as a possible intervention target for improving emotion regulation in mood and anxiety disorders.

Common functional polymorphisms in the gene encoding interleukin-18 (IL18), a cytokine belonging to the IL-1 superfamily that can induce synthesis of several other cytokines, have been associated with major depressive episodes following the experience of stressful life events. The neural mechanisms underlying these associations remain unexamined. Here we use an imaging genetics strategy to examine the effects of risk-related IL18 haplotypes comprising rs187238 and rs1946518 on threat-related amygdala reactivity and, through an indirect effect, stress-related symptoms of depression and anxiety in 448 non-Hispanic Caucasian university students. Analyses indicated that women but not men possessing an IL18 haplotype comprising both risk-related alleles evidenced increased threat-related left centromedial amygdala reactivity relative to other haplotype groups. Moreover, in women only, increased threat-related left centromedial amygdala reactivity predicted increased symptoms of depression and anxiety in individuals also reporting higher levels of life stress. Path analyses revealed a significant indirect effect of IL18 risk haplotype on symptoms of depression and anxiety through increased threat-related amygdala reactivity. These results suggest that a common functional IL18 haplotype associated with heightened proinflammatory responses confers susceptibility to stress-related depression and anxiety through effects on threat-related amygdala function, a risk pathway specific to women. If replicated, these patterns can inform the search for personalized interventions targeting neurobiological pathways of risk associated with inflammation.

ObjectiveAlthough heightened amygdala reactivity is observed in patients with major depression, two critical gaps in our knowledge remain. First, it is unclear whether heightened amygdala reactivity is a premorbid vulnerability or a consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The authors sought to address these gaps by evaluating developmental change in threat-related amygdala reactivity in adolescents at high or low risk for depression based on family history, before onset of disorder.MethodAt baseline and again 2 years later, adolescents (initially 11-15 years of age) participated in a functional MRI paradigm that elicited threat-related amygdala reactivity. After quality control, data were available for 232 adolescents at wave 1 and 197 adolescents at wave 2; longitudinal data meeting quality control at both waves were available for 157 of these participants. Change in amygdala reactivity was assessed as a function of family history of depression and severity of stressful life events.ResultsThreat-related amygdala reactivity increased with age in participants with a positive family history regardless of the severity of life stress reported, and it increased in adolescents with a negative family history who reported relatively severe life stress. These changes in amygdala reactivity with age occurred in the absence of clinical disorder or increases in depressive symptoms.ConclusionsThese results suggest that heightened amygdala reactivity emerges during adolescence, prior to the development of depression, as a function of familial risk or, in the absence of familial risk, stressful life events.

We all experience a host of common life stressors such as the death of a family member, medical illness, and financial uncertainty. While most of us are resilient to such stressors, continuing to function normally, for a subset of individuals, experiencing these stressors increases the likelihood of developing treatment-resistant, chronic psychological problems, including depression and anxiety. It is thus paramount to identify predictive markers of risk, particularly those reflecting fundamental biological processes that can be targets for intervention and prevention. Using data from a longitudinal study of 340 healthy young adults, we demonstrate that individual differences in threat-related amygdala reactivity predict psychological vulnerability to life stress occurring as much as 1 to 4 years later. These results highlight a readily assayed biomarker, threat-related amygdala reactivity, which predicts psychological vulnerability to commonly experienced stressors and represents a discrete target for intervention and prevention.

Anxiety disorders are associated with abnormalities in amygdala function and prefrontal cortex-amygdala connectivity. The majority of functional magnetic resonance imaging studies have examined mean group differences in amygdala activation or connectivity in children and adolescents with anxiety disorders relative to controls, but emerging evidence suggests that abnormalities in amygdala function are dependent on the timing of the task and may vary across the course of a scanning session. The goal of the present study was to extend our knowledge of the dynamics of amygdala dysfunction by examining whether changes in amygdala activation and connectivity over scanning differ in pediatric anxiety disorder patients relative to typically developing controls during an emotion processing task. Examining changes in activation over time allows for a comparison of how brain function differs during initial exposure to novel stimuli versus more prolonged exposure. Participants included 34 anxiety disorder patients and 19 controls 7 to 19 years old. Participants performed an emotional face-matching task during functional magnetic resonance imaging scanning, and the task was divided into thirds in order to examine change in activation over time. Results demonstrated that patients exhibited an abnormal pattern of amygdala activation characterized by an initially heightened amygdala response relative to controls at the beginning of scanning, followed by significant decreases in activation over time. In addition, controls evidenced greater context-modulated prefrontal cortex-amygdala connectivity during the beginning of scanning relative to patients. These results indicate that differences in emotion processing between the groups vary from initial exposure to novel stimuli relative to more prolonged exposure. Implications are discussed regarding how this pattern of neural activation may relate to altered early-occurring or anticipatory emotion-regulation strategies and maladaptive later-occurring strategies in children and adolescents with anxiety disorders.

BackgroundPediatric and adult anxiety disorder patients exhibit attention bias to threat and difficulty disengaging attention away from threat. Cognitive frameworks suggest that these patterns are associated with hyperactivation of regions associated with detecting threat, such as the amygdala, and hypoactivation of regions associated with regulating attention, including the lateral prefrontal cortex and rostral anterior cingulate cortex (rACC). The aim of the present study was to examine the neural correlates of these processes in children and adolescents with anxiety disorders.MethodsParticipants with an anxiety disorder 7 to 19 years old (n = 34) and typically developing controls (n = 35) underwent fMRI scanning. During scanning, they completed a task with conditions that manipulated whether participants were instructed to match emotional faces (direct emotion processing) or match shapes in the context of emotional face distractors (attentional control).ResultsResults revealed a significant difference in rACC activation during shape versus face matching, with controls evidencing greater rACC activation relative to patients.ConclusionsThis study identifies abnormalities in rACC activation as a potential neural mediator associated with pediatric anxiety disorders, which can inform frameworks for understanding their development and treatment.

The uncinate fasciculus is a major white matter tract that provides a crucial link between areas of the human brain that underlie emotion processing and regulation. Specifically, the uncinate fasciculus is the major direct fiber tract that connects the prefrontal cortex and the amygdala. The aim of the present study was to use a multi-modal imaging approach in order to simultaneously examine the relation between structural connectivity of the uncinate fasciculus and functional activation of the amygdala in a youth sample (children and adolescents). Participants were 9 to 19years old and underwent diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). Results indicate that greater structural connectivity of the uncinate fasciculus predicts reduced amygdala activation to sad and happy faces. This effect is moderated by age, with younger participants exhibiting a stronger relation. Further, decreased amygdala activation to sad faces predicts lower internalizing symptoms. These results provide important insights into brain structure-function relationships during adolescence, and suggest that greater structural connectivity of the uncinate fasciculus may facilitate regulation of the amygdala, particularly during early adolescence. These findings also have implications for understanding the relation between brain structure, function, and the development of emotion regulation difficulties, such as internalizing symptoms.

Objective: Amygdala habituation, the rapid decrease in amygdala responsiveness to the repeated presentation of stimuli, is fundamental to the nervous system. Habituation is important for maintaining adaptive levels of arousal to predictable social stimuli and decreased habituation is associated with heightened anxiety. Input from the ventromedial prefrontal cortex (vmPFC) regulates amygdala activity. Although previous research has shown abnormal amygdala function in youth with autism spectrum disorders (ASD), no study has examined amygdala habituation in a young sample or whether habituation is related to amygdala connectivity with the vmPFC. Method: Data were analyzed from 32 children and adolescents with ASD and 56 typically developing controls who underwent functional magnetic resonance imaging while performing a gender identification task for faces that were fearful, happy, sad, or neutral. Habituation was tested by comparing amygdala activation to faces during the first half versus the second half of the session. VmPFC-amygdala connectivity was examined through psychophysiologic interaction analysis. Results: Youth with ASD had decreased amygdala habituation to sad and neutral faces compared with controls. Moreover, decreased amygdala habituation correlated with autism severity as measured by the Social Responsiveness Scale. There was a group difference in vmPFC-amygdala connectivity while viewing sad faces, and connectivity predicted amygdala habituation to sad faces in controls. Conclusions: Sustained amygdala activation to faces suggests that repeated face presentations are processed differently in individuals with ASD, which could contribute to social impairments. Abnormal modulation of the amygdala by the vmPFC may play a role in decreased habituation. (Contains 3 figures and 1 table.)

Background: Autism spectrum disorders (ASD) involve a core deficit in social functioning and impairments in the ability to recognize face emotions. In an emotional faces task designed to constrain group differences in attention, the present study used functional MRI to characterize activation in the amygdala, ventral prefrontal cortex (vPFC), and striatum, three structures involved in socio-emotional processing in adolescents with ASD. Methods: Twenty-two adolescents with ASD and 20 healthy adolescents viewed facial expressions (happy, fearful, sad and neutral) that were briefly presented (250 ms) during functional MRI acquisition. To monitor attention, subjects pressed a button to identify the gender of each face. Results: The ASD group showed greater activation to the faces relative to the control group in the amygdala, vPFC and striatum. Follow-up analyses indicated that the ASD relative to control group showed greater activation in the amygdala, vPFC and striatum (p less than 0.05 small volume corrected), particularly to sad faces. Moreover, in the ASD group, there was a negative correlation between developmental variables (age and pubertal status) and mean activation from the whole bilateral amygdala; younger adolescents showed greater activation than older adolescents. There were no group differences in accuracy or reaction time in the gender identification task. Conclusions: When group differences in attention to facial expressions were limited, adolescents with ASD showed greater activation in structures involved in socio-emotional processing.