Multivariate Assessment of Inhibitory Control in Youth: Links With Psychopathology and Brain Function.

Inhibitory control is central to many theories of cognitive and brain development, and impairments in inhibitory control are posited to underlie developmental psychopathology. In this study, we tested the possibility of shared versus unique associations between inhibitory control and three common symptom dimensions in youth psychopathology: attention-deficit/hyperactivity disorder (ADHD), anxiety, and irritability. We quantified inhibitory control using four different experimental tasks to estimate a latent variable in 246 youth (8-18 years old) with varying symptom types and levels. Participants were recruited from the Washington, D.C., metro region. Results of structural equation modeling integrating a bifactor model of psychopathology revealed that inhibitory control predicted a shared or general psychopathology dimension, but not ADHD-specific, anxiety-specific, or irritability-specific dimensions. Inhibitory control also showed a significant, selective association with global efficiency in a frontoparietal control network delineated during resting-state functional magnetic resonance imaging. These results support performance-based inhibitory control linked to resting-state brain function as an important predictor of comorbidity in youth psychopathology.

Sleepless nights, sour moods: daily sleep-irritability links in a pediatric clinical sample.

BACKGROUND: Sleep, or a lack thereof, is strongly related to mood dysregulation. Although considerable research uses symptom scales to examine this relation, few studies use longitudinal, real-time methods focused on pediatric irritability. This study leveraged an ecological momentary assessment (EMA) protocol, assessing bidirectional associations between momentary irritability symptoms and daily sleep duration in a transdiagnostic pediatric sample enriched for irritability. METHODS: A total of N = 125 youth (Mage = 12.58 years, SD = 2.56 years; 74% male; 68.8% White) completed digital, in vivo surveys three times a day for 7 days. For a subset of youth, their parents also completed the EMA protocol. Trait irritability was measured using youth-, parent-, and clinician-report to test its potential moderating effect on the association between sleep duration and momentary irritability. RESULTS: Results from multilevel modeling dynamically linked sleep to irritability. Specifically, according to youth- and parent-report, decreased sleep duration was associated with increased morning irritability (bs ≤ -.09, ps < .049). A bidirectional association between parent-reported nightly sleep duration and anger was found-increased evening anger related to decreased nightly sleep duration, and decreased sleep duration related to increased morning anger (bs ≤ -.17, ps < .019). Trait irritability moderated this association, which was stronger for more irritable youth (b = -.03, p < .027). CONCLUSIONS: This study adds to the literature and suggests sleep-irritability dynamics as a potential treatment target.

Selecting an Ecological Momentary Assessment Platform: Tutorial for Researchers.

BACKGROUND: Although ecological momentary assessment (EMA) has been applied in psychological research for decades, delivery methods have evolved with the proliferation of digital technology. Technological advances have engendered opportunities for enhanced accessibility, convenience, measurement precision, and integration with wearable sensors. Notwithstanding, researchers must navigate novel complexities in EMA research design and implementation. OBJECTIVE: In this paper, we aimed to provide guidance on platform selection for clinical scientists launching EMA studies. METHODS: Our team includes diverse specialties in child and adolescent behavioral and mental health with varying expertise on EMA platforms (eg, users and developers). We (2 research sites) evaluated EMA platforms with the goal of identifying the platform or platforms with the best fit for our research. We created a list of extant EMA platforms; conducted a web-based review; considered institutional security, privacy, and data management requirements; met with developers; and evaluated each of the candidate EMA platforms for 1 week. RESULTS: We selected 2 different EMA platforms, rather than a single platform, for use at our 2 research sites. Our results underscore the importance of platform selection driven by individualized and prioritized laboratory needs; there is no single, ideal platform for EMA researchers. In addition, our project generated 11 considerations for researchers in selecting an EMA platform: (1) location; (2) developer involvement; (3) sample characteristics; (4) onboarding; (5) survey design features; (6) sampling scheme and scheduling; (7) viewing results; (8) dashboards; (9) security, privacy, and data management; (10) pricing and cost structure; and (11) future directions. Furthermore, our project yielded a suggested timeline for the EMA platform selection process. CONCLUSIONS: This study will guide scientists initiating studies using EMA, an in vivo, real-time research tool with tremendous promise for facilitating advances in psychological assessment and intervention.

Network analysis of ecological momentary assessment identifies frustration as a central node in irritability.

BACKGROUND: Irritability presents transdiagnostically, commonly occurring with anxiety and other mood symptoms. However, little is known about the temporal and dynamic interplay among irritability-related clinical phenomena. Using a novel network analytic approach with smartphone-based ecological momentary assessment (EMA), we examined how irritability and other anxiety and mood symptoms were connected. METHODS: Sample included 152 youth ages 8-18 years (M ± SD = 12.28 ± 2.53; 69.74% male; 65.79% White) across several diagnostic groups enriched for irritability including disruptive mood dysregulation disorder (n = 34), oppositional defiant disorder (n = 9), attention-deficit/hyperactivity disorder (n = 47), anxiety disorder (n = 29), and healthy comparisons (n = 33). Participants completed EMA on irritability-related constructs and other mood and anxiety symptoms three times a day for 7 days. EMA probed symptoms on two timescales: "since the last prompt" (between-prompt) versus "at the time of the prompt" (momentary). Irritability was also assessed using parent-, child- and clinician-reports (Affective Reactivity Index; ARI), following EMA. Multilevel vector autoregressive (mlVAR) models estimated a temporal, a contemporaneous within-subject and a between-subject network of symptoms, separately for between-prompt and momentary symptoms. RESULTS: For between-prompt symptoms, frustration emerged as the most central node in both within- and between-subject networks and predicted more mood changes at the next timepoint in the temporal network. For momentary symptoms, sadness and anger emerged as the most central node in the within- and between-subject network, respectively. While anger was positively related to sadness within individuals and measurement occasions, anger was more broadly positively related to sadness, mood lability, and worry between/across individuals. Finally, mean levels, not variability, of EMA-indexed irritability were strongly related to ARI scores. CONCLUSIONS: This study advances current understanding of symptom-level and temporal dynamics of irritability. Results suggest frustration as a potential clinically relevant treatment target. Future experimental work and clinical trials that systematically manipulate irritability-related features (e.g. frustration, unfairness) will elucidate the causal relations among clinical variables.

Parenting and childhood irritability: Negative emotion socialization and parental control moderate the development of irritability.

Irritability, characterized by anger in response to frustration, is normative in childhood. While children typically show a decline in irritability from toddlerhood to school age, elevated irritability throughout childhood may predict later psychopathology. The current study (n = 78) examined associations between trajectories of irritability in early childhood (ages 2-7) and irritability in adolescence (age 12) and tested whether these associations are moderated by parenting behaviors. Results indicate that negative emotion socialization moderated trajectories of irritability - relative to children with low stable irritability, children who exhibited high stable irritability in early childhood and who had parents that exhibited greater negative emotion socialization behaviors had higher irritability in adolescence. Further, negative parental control behavior moderated trajectories of irritability - relative to children with low stable irritability, children who had high decreasing irritability in early childhood and who had parents who exhibited greater negative control behaviors had higher irritability in adolescence. In contrast, positive emotion socialization and control behaviors did not moderate the relations between early childhood irritability and later irritability in adolescence. These results suggest that both irritability in early childhood and negative parenting behaviors may jointly influence irritability in adolescence. The current study underscores the significance of negative parenting behaviors and could inform treatment.

An Exposure-Based Cognitive-Behavioral Therapy for Youth with Severe Irritability: Feasibility and Preliminary Efficacy.

OBJECTIVE: Clinically impairing irritability and temper outbursts are among the most common psychiatric problems in youth and present transdiagnostically; however, few mechanistically informed treatments have been developed. Here, we test the acceptability, feasibility, and preliminary efficacy of a novel exposure-based treatment with integrated parent management skills for youth with severe irritability using a randomized between-subjects multiple baseline design. METHOD: N = 41 patients (Age, Mean (SD) = 11.23 years (1.85), 62.5% male, 77.5% white) characterized by severe and impairing temper outbursts and irritability were randomized to different baseline observation durations (2, 4, or 6 weeks) prior to active treatment; 40 participants completed the 12 session treatment of exposure-based cognitive-behavioral therapy for irritability with integrated parent management skills. Masked clinician ratings were acquired throughout baseline and treatment phases, as well as 3- and 6-months post-treatment. To examine acceptability and feasibility, drop-out rates and adverse events were examined. Primary clinical outcome measures included clinician-administered measures of irritability severity and improvement. Secondary clinical outcome measures included multi-informant measures of irritability, depression, anxiety, and attention-deficit/hyperactivity disorder symptoms. RESULTS: No patients dropped out once treatment began, and no adverse events were reported. Irritability symptoms improved during the active phase of treatment across all measurements (all ßs > -0.04, ps < .011, Cohen's d range: -0.33 to -0.98). Treatment gains were maintained at follow-up (all ßs(39) < -0.001, ps > .400). Sixty-five percent of patients were considered significantly improved or recovered post-treatment based on the primary clinician-rated outcome measure. CONCLUSIONS: Results support acceptability, feasibility, and preliminary efficacy of this novel treatment for youth with severe irritability. Limitations and future directions are also discussed.

Real-time assessment of positive and negative affective fluctuations and mood lability in a transdiagnostic sample of youth.

BACKGROUND: Emotional lability, defined as rapid and/or intense affect fluctuations, is associated with pediatric psychopathology. Although numerous studies have examined labile mood in clinical groups, few studies have used real-time assessments in a well-characterized transdiagnostic sample, and no prior study has included participants with disruptive mood dysregulation disorder (DMDD). The present study leverages ecological momentary assessment (EMA) to assess emotional lability in a transdiagnostic pediatric sample. METHODS: One hundred thirty participants ages 8-18 with primary diagnoses of DMDD, attention-deficit/hyperactivity disorder (ADHD), an anxiety disorder (ANX), or healthy volunteers completed a previously validated 1-week EMA protocol. Clinicians determined diagnoses based on semi-structured interviews and assessed levels of functional impairment. Participants reported momentary affective states and mood change. Composite scores of fluctuations in positive and negative affect were generated. Affect fluctuations were compared between diagnostic groups and tested for their association with functional impairment. RESULTS: Diagnostic groups differed in levels of negative and positive emotional lability. DMDD patients demonstrated the highest level of labile mood compared with other groups. Emotional lability was associated with global impairment in the whole sample. CONCLUSIONS: Both positive and negative emotional lability is salient in pediatric psychopathology and is associated with functional impairment, particularly in DMDD youth.

Validation of an irritability measure in preschoolers in school-based and clinical Brazilian samples.

The Affective Reactivity Index (ARI) is an irritability measure with good psychometric properties. However, there are no published studies in preschool children, an important population in which to differentiate normative from non-normative irritability. The goal of this study was to validate the ARI in preschoolers. Two samples were included: a school-based sample (N = 487, mean age = 57.80 ± 7.23 months, 52.8% male) and a clinical sample of children with Attention Deficit Hyperactivity Disorder (ADHD; N = 153, mean age = 60.5 ± 7.6 months, 83.7% males). Confirmatory factor analysis assessed ARI unidimensionality. ARI criterion validity was tested through comparison to other scales measuring irritability, related constructs, and other aspects of psychopathology. Test-retest reliability was assessed in the school-based sample. Analyses confirmed a single-factor structure and good internal consistency. The ARI showed stronger correlations with irritability measures than with measures of other constructs. In the clinical sample, ADHD children with comorbid disruptive behavior disorders had higher ARI scores than those without this comorbidity. In the school-based sample, test-retest reliability was moderate. This is the first study to demonstrate ARI validity and reliability in preschoolers. The scale performed well in both school-based and clinical samples. Having a concise and validated irritability measure for preschoolers may facilitate both clinical assessment and research on early irritability.

A computational network perspective on pediatric anxiety symptoms.

BACKGROUND: While taxonomy segregates anxiety symptoms into diagnoses, patients typically present with multiple diagnoses; this poses major challenges, particularly for youth, where mixed presentation is particularly common. Anxiety comorbidity could reflect multivariate, cross-domain interactions insufficiently emphasized in current taxonomy. We utilize network analytic approaches that model these interactions by characterizing pediatric anxiety as involving distinct, inter-connected, symptom domains. Quantifying this network structure could inform views of pediatric anxiety that shape clinical practice and research. METHODS: Participants were 4964 youths (ages 5-17 years) from seven international sites. Participants completed standard symptom inventory assessing severity along distinct domains that follow pediatric anxiety diagnostic categories. We first applied network analytic tools to quantify the anxiety domain network structure. We then examined whether variation in the network structure related to age (3-year longitudinal assessments) and sex, key moderators of pediatric anxiety expression. RESULTS: The anxiety network featured a highly inter-connected structure; all domains correlated positively but to varying degrees. Anxiety patients and healthy youth differed in severity but demonstrated a comparable network structure. We noted specific sex differences in the network structure; longitudinal data indicated additional structural changes during childhood. Generalized-anxiety and panic symptoms consistently emerged as central domains. CONCLUSIONS: Pediatric anxiety manifests along multiple, inter-connected symptom domains. By quantifying cross-domain associations and related moderation effects, the current study might shape views on the diagnosis, treatment, and study of pediatric anxiety.

Levels of early-childhood behavioral inhibition predict distinct neurodevelopmental pathways to pediatric anxiety.

BACKGROUND: Anxiety symptoms gradually emerge during childhood and adolescence. Individual differences in behavioral inhibition (BI), an early-childhood temperament, may shape developmental paths through which these symptoms arise. Cross-sectional research suggests that level of early-childhood BI moderates associations between later anxiety symptoms and threat-related amygdala-prefrontal cortex (PFC) circuitry function. However, no study has characterized these associations longitudinally. Here, we tested whether level of early-childhood BI predicts distinct evolving associations between amygdala-PFC function and anxiety symptoms across development. METHODS: Eighty-seven children previously assessed for BI level in early childhood provided data at ages 10 and/or 13 years, consisting of assessments of anxiety and an fMRI-based dot-probe task (including threat, happy, and neutral stimuli). Using linear-mixed-effects models, we investigated longitudinal changes in associations between anxiety symptoms and threat-related amygdala-PFC connectivity, as a function of early-childhood BI. RESULTS: In children with a history of high early-childhood BI, anxiety symptoms became, with age, more negatively associated with right amygdala-left dorsolateral-PFC connectivity when attention was to be maintained on threat. In contrast, with age, low-BI children showed an increasingly positive anxiety-connectivity association during the same task condition. Behaviorally, at age 10, anxiety symptoms did not relate to fluctuations in attention bias (attention bias variability, ABV) in either group; by age 13, low-BI children showed a negative anxiety-ABV association, whereas high-BI children showed a positive anxiety-ABV association. CONCLUSIONS: Early-childhood BI levels predict distinct neurodevelopmental pathways to pediatric anxiety symptoms. These pathways involve distinct relations among brain function, behavior, and anxiety symptoms, which may inform diagnosis and treatment.

Sympathetic nervous system dominance during stress recovery mediates associations between stress sensitivity and social anxiety symptoms in female adolescents.

Social anxiety disorder (SAD) is commonly diagnosed during adolescence and is associated with psychological stress reactivity and heightened physiological arousal. No study, however, has systematically examined which aspects of autonomic nervous system function mediate likely links between stress sensitivity and social anxiety symptoms in adolescents. Here, we assessed 163 adolescents (90 females; 12.29 ± 1.39 years) with respect to life stress and social anxiety symptoms, and measured respiratory sinus arrhythmia (RSA) and skin conductance levels (SCL) during a psychosocial stress paradigm. We operationalized stress sensitivity as the residual variance in subjective stress severity after accounting for objective severity and changes in autonomic regulation using standardized change scores in RSA and SCL. In females only, stress sensitivity and social anxiety symptoms were significantly correlated with each other (p < .001) and with autonomic regulation during both reactivity and recovery (all ps < 0.04). Further, sympathetic nervous system dominance during recovery specifically mediated associations between stress sensitivity and social anxiety symptoms (B = 1.06, 95% CI: 0.02-2.64). In contrast, in males, stress sensitivity, autonomic regulation during reactivity or recovery, and social anxiety symptoms were not significantly associated (all ps > 0.1). We interpret these results in the context of psychobiological models of SAD and discuss implications for interventions targeting autonomic processes.

Developmental pathways to social anxiety and irritability: The role of the ERN.

Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We tested whether error-related negativity (ERN) moderates the link between early behavior and later psychopathology in two early childhood phenotypes: behavioral inhibition and irritability. From ages 2 to 7 years, children (n = 291) were assessed longitudinally for behavioral inhibition (BI) and irritability. Behavioral inhibition was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, an electroencephalogram (EEG) was recorded while children performed a flanker task to measure ERN, a neural indicator of error monitoring. Clinical assessments of anxiety and irritability were conducted using questionnaires (i.e., Screen for Child Anxiety Related Disorders and Affective Reactivity Index) and clinical interviews. Error monitoring interacted with early BI and early irritability to predict later psychopathology. Among children with high BI, an enhanced ERN predicted greater social anxiety at age 12. In contrast, children with high childhood irritability and blunted ERN predicted greater irritability at age 12. This converges with previous work and provides novel insight into the specificity of pathways associated with psychopathology.

Fine Particle Air Pollution and Physiological Reactivity to Social Stress in Adolescence: The Moderating Role of Anxiety and Depression.

OBJECTIVE: Exposure to high levels of fine particle air pollution (PM2.5) is associated with adolescent pathophysiology. It is unclear, however, if PM2.5 is associated with physiology within psychosocial contexts, such as social stress, and whether some adolescents are particularly vulnerable to PM2.5-related adverse effects. This study examined the association between PM2.5 and autonomic reactivity to social stress in adolescents and tested whether symptoms of anxiety and depression moderated this association. METHODS: Adolescents from Northern California (N = 144) participated in a modified Trier Social Stress Test while providing high-frequency heart rate variability and skin conductance level data. PM2.5 data were recorded from CalEnviroScreen. Adolescents reported on their own symptoms of anxiety and depression using the Youth Self-Report, which has been used in prior studies and has good psychometric properties (Cronbach's α in this sample was .86). RESULTS: Adolescents residing in neighborhoods characterized by higher concentrations of PM2.5 demonstrated greater autonomic reactivity (i.e., indexed by lower heart rate variability and higher skin conductance level) (ß = .27; b = .44, p = .001, 95% CI = 0.19 to 0.68) in response to social stress; this association was not accounted for by socioeconomic factors. In addition, adolescents who reported more severe anxiety and depression symptoms showed the strongest association between PM2.5 and autonomic reactivity to social stress (ß = .53; b = .86, p < .001, 95% CI = 0.48 to 1.23). CONCLUSIONS: Exposure to PM2.5 may heighten adolescent physiological reactivity to social stressors. Moreover, adolescents who experience anxiety and depression may be particularly vulnerable to the adverse effects of PM2.5 on stress reactivity.

Heart rate variability as a biomarker of anxious depression response to antidepressant medication.

BACKGROUND: There is a need to identify biomarkers of treatment outcomes for major depressive disorder (MDD) that can be disseminated. We investigated the predictive utility of pretreatment heart rate variability (HRV) for outcomes of antidepressant medication in MDD, with pretreatment anxious depression as a hypothesized moderator of HRV effects. METHODS: A large, randomized, multicenter practical trial (International Study to Predict Optimized Treatment in Depression) in patients with current nonpsychotic MDD (N = 1,008; 722 completers) had three arms: escitalopram, sertraline, and venlafaxine-extended release. At pretreatment, patients were defined as having anxious (N = 309) versus nonanxious (N = 413) depression and their resting high-frequency HRV (root mean square of successive differences) was assessed. Patients' usual treating clinicians managed medication. At 8 weeks, primary outcomes were clinician-rated depressive symptom response and remission; secondary outcomes were self-reported response and remission. RESULTS: Pretreatment HRV predicted antidepressant outcomes as a function of anxious versus nonanxious depression. In anxious depression, patients with higher HRV had better outcomes, whereas patients with lower HRV had poorer outcomes. In nonanxious depression, patients with lower HRV had better outcomes, whereas patients with higher HRV had poorer outcomes. Some simple effects were not significant. Results did not differ by treatment arm and remained significant when controlling for important covariates. CONCLUSIONS: These findings inform a precision medicine approach in which clinical and biological assessments may be integrated to facilitate treatment outcome prediction. Knowing about HRV may help determine which patients with anxious depression could benefit from antidepressants and which patients may require a different treatment approach.

Advancing clinical neuroscience through enhanced tools: Pediatric social anxiety as an example.

BACKGROUND: Clinical researchers face challenges when trying to quantify diverse processes engaged during social interactions. We report results from two studies, each demonstrating the potential utility of tools for examining processes engaged during social interactions. METHOD: In the first study, youth (n = 57) used a smartphone-based tool to rate mood and responses to social events. A subset (n = 20) completed the second, functional magnetic resonance imaging study. This second study related anxiety to error-evoked brain responses in two social conditions-while being observed and when alone. We also combined these tools to bridge clinical, social-contextual, and neural levels of measurement. RESULTS: Results from the first study showed an association between negatively-perceived social experiences and a range of negative emotions. In the second study there was a positive correlation during error monitoring between social-anxiety severity and context-specific activation of the pregenual anterior cingulate cortex. Finally, during imaging, the perceived quality of peer interactions as assessed using the smartphone-based tool, interacted with social context to predict levels of activation in the hippocampus and superior frontal gyrus. CONCLUSIONS: By improving measurement, enhanced tools may provide new means for studying relationships among anxiety, brain function, and social interactions.

A latent profile analysis of age of onset in trichotillomania.

BACKGROUND: Trichotillomania (TTM) onset may occur across the lifespan; however, adolescent onset is most frequently reported. Several studies have explored clinical differences between TTM age-of-onset groups with mixed results. We investigated empirically defined age-of-onset groups in adults with TTM, and clinical differences between groups. METHODS: Participants included 1,604 adult respondents to an internet survey who endorsed DSM-IV-TR TTM criteria. Latent profile analysis was performed to identify TTM age-of-onset subgroups, which were then compared on demographic and clinical features. RESULTS: The most optimal model was a 2-class solution comprised of a large group with average TTM onset during adolescence (n = 1,539; 95.9% of the sample; mean age of onset = 12.4) and a small group with average onset in middle adulthood (n = 65; 4.1% of the sample; mean age of onset = 35.6). The late-onset group differed from the early-onset group on several clinical variables (eg, less likely to report co-occurring bodyfocused repetitive behaviors). CONCLUSIONS: Findings suggest the presence of at least 2 distinct TTM age-of-onset subgroups: an early-onset group with onset during adolescence, and a late-onset group with onset in middle adulthood. Future research is needed to further validate these subgroups and explore their clinical utility.

Inhibitory control and emotion dysregulation: A framework for research on anxiety.

While emotional dysregulation is a broad construct, the current paper adopts a narrow approach to facilitate translational neuroscience research on pediatric anxiety. The paper first presents data on an adapted version of the antisaccade task and then integrates these data into a research framework. Data on an adapted version of the antisaccade task were collected in 57 youth, including 35 seeking treatment for an anxiety disorder. Associations were examined between performance on the antisaccade task and (a) age, (b) performance on other cognitive-control tasks (i.e., the stop-signal delay and flanker tasks), and (c) level of anxiety symptoms. Better performance on the antisaccade task occurred in older relative to younger subjects and correlated with better performance on the flanker task. Across the 57 youth, higher levels of anxiety correlated with shorter latency for correct antisaccades. These data can be placed within a three-step framework for translational neuroscience research. In the first step, a narrow index of emotion dysregulation is targeted. In the second step, this narrow index is linked to other correlated indicators of the same underlying narrow latent construct. In the third and final step, associations are examined with clinical outcomes and response to treatment.

Parsing neurodevelopmental features of irritability and anxiety: Replication and validation of a latent variable approach.

Irritability and anxiety are two common clinical phenotypes that involve high-arousal negative affect states (anger and fear), and that frequently co-occur. Elucidating how these two forms of emotion dysregulation relate to perturbed neurodevelopment may benefit from alternate phenotyping strategies. One such strategy applies a bifactor latent variable approach that can parse shared versus unique mechanisms of these two phenotypes. Here, we aim to replicate and extend this approach and examine associations with neural structure in a large transdiagnostic sample of youth (N = 331; M = 13.57, SD = 2.69 years old; 45.92% male). FreeSurfer was used to extract cortical thickness, cortical surface area, and subcortical volume. The current findings replicated the bifactor model and demonstrate measurement invariance as a function of youth age and sex. There were no associations of youth's factor scores with cortical thickness, surface area, or subcortical volume. However, we found strong convergent and divergent validity between parent-reported irritability and anxiety factors with clinician-rated symptoms and impairment. A general negative affectivity factor was robustly associated with overall functional impairment across symptom domains. Together, these results support the utility of the bifactor model as an alternative phenotyping strategy for irritability and anxiety, which may aid in the development of targeted treatments.

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

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

Irritability, Externalizing, and Internalizing Psychopathology in Adolescence: Cross-Sectional and Longitudinal Associations and Moderation by Sex.

Irritability is a common feature of many psychiatric disorders, including both externalizing and internalizing disorders. There is little research, however, examining associations between irritability and these symptom domains, particularly during the important developmental period of adolescence, characterized by sex differences in the prevalence of disorders. We examined the cross-sectional associations between irritability, measured with the Affective Reactivity Index, and symptoms of externalizing and internalizing domains of psychopathology, measured with the Youth Self Report, in a volunteer community sample (N = 183) of 9- to 13-year-old (M = 11.39, SD = 1.07) boys and girls (37% White/Caucasian, 8% Asian, 11% Hispanic, 8% African American, 2% Native American, 2% Pacific Islander, 28% Other, and 3% not reported). A subset of the sample (n = 112) provided data at a 2-year follow-up, used to extend these associations. There were no sex differences in levels of irritability; however, the associations between irritability and symptom domains were moderated by sex. Specifically, in girls, irritability was associated equally with externalizing and internalizing symptoms. In contrast, in boys, irritability was associated more strongly with externalizing symptoms than with internalizing symptoms. Thus, across both sexes, irritability was moderately associated with externalizing symptoms, but the association between irritability and internalizing symptoms was stronger in girls than in boys. At follow-up, sex moderated the association between baseline irritability and later externalizing and internalizing symptoms. These findings indicate that irritability is associated with both externalizing and internalizing symptoms in early adolescence and that irritability is associated with internalizing symptoms more strongly in girls than in boys.