Associations Between Neighborhood Resources and Youths' Response to Reward Omission in a Task Modeling Negatively Biased Environments.

OBJECTIVE: Neighborhoods provide essential resources (eg, education, safe housing, green space) that influence neurodevelopment and mental health. However, we need a clearer understanding of the mechanisms mediating these relationships. Limited access to neighborhood resources may hinder youths from achieving their goals and, over time, shape their behavioral and neurobiological response to negatively biased environments blocking goals and rewards. METHOD: To test this hypothesis, 211 youths (aged ∼13.0 years, 48% boys, 62% identifying as White, 75% with a psychiatric disorder diagnosis) performed a task during functional magnetic resonance imaging. Initially, rewards depended on performance (unbiased condition); but later, rewards were randomly withheld under the pretense that youths did not perform adequately (negatively biased condition), a manipulation that elicits frustration, sadness, and a broad response in neural networks. We investigated associations between the Childhood Opportunity Index (COI), which quantifies access to youth-relevant neighborhood features in 1 metric, and the multimodal response to the negatively biased condition, controlling for age, sex, medication, and psychopathology. RESULTS: Youths from less-resourced neighborhoods responded with less anger (p < .001, marginal R2 = 0.42) and more sadness (p < .001, marginal R2 = 0.46) to the negatively biased condition than youths from well-resourced neighborhoods. On the neurobiological level, lower COI scores were associated with a more localized processing mode (p = .039, marginal R2 = 0.076), reduced connectivity between the somatic-motor-salience and the control network (p = .041, marginal R2 = 0.040), and fewer provincial hubs in the somatic-motor-salience, control, and default mode networks (all pFWE < .05). CONCLUSION: The present study adds to a growing literature documenting how inequity may affect the brain and emotions in youths. Future work should test whether findings generalize to more diverse samples and should explore effects on neurodevelopmental trajectories and emerging mood disorders during adolescence. DIVERSITY & INCLUSION STATEMENT: 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. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.

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.

Phasic Versus Tonic Irritability and Associations with Family Accommodation Among Youth with Selective Mutism: A Latent Profile Analysis.

Clinical presentations of selective mutism (SM) vary widely across affected youth. Although studies have explored general externalizing problems in youth with SM, research has not specifically examined patterns of irritability. Relatedly, research has not considered how affected families differentially accommodate the anxiety of youth with SM as a function of the child's temper outbursts (i.e., phasic irritability) and general angry mood (i.e., tonic irritability). Data were drawn from a sample of treatment-seeking children and adolescents with a primary diagnosis of selective mutism (N = 152; Mean age = 6.12 years; 67.11% female), and their caregivers. Latent profile analysis (LPA) was used to identify distinct profiles in SM youth that were characterized by varying levels of phasic and/or tonic irritability. Analyses further examined whether these different profiles were associated with different levels of family accommodation and global impairment. LPA identified 5 profiles: SM with No irritability, SM with Low Phasic Irritability, SM with High Phasic Irritability, SM with High Phasic and Moderate Tonic Irritability, and SM with High Phasic and High Tonic Irritability. Patterns of family accommodation and global impairment were highest among youth belonging to profiles characterized by high phasic irritability. Findings highlight separable patterns of irritability across youth with SM, with phasic irritability (i.e., temper outbursts) appearing particularly linked with increased family accommodation and overall global impairment. Assessing phasic irritability is critical for optimizing treatment in youth with SM and can be useful for flagging possible patterns of family accommodation contributing to overall impairment.

Multimodal study of the neural sources of error monitoring in adolescents and adults.

The ability to monitor performance during a goal-directed behavior differs among children and adults in ways that can be measured with several tasks and techniques. As well, recent work has shown that individual differences in error monitoring moderate temperamental risk for anxiety and that this moderation changes with age. We investigated age differences in neural responses linked to performance monitoring using a multimodal approach. The approach combined functional MRI and source localization of event-related potentials (ERPs) in 12-year-old, 15-year-old, and adult participants. Neural generators of two components related to performance and error monitoring, the N2 and ERN, lay within specific areas of fMRI clusters. Whereas correlates of the N2 component appeared similar across age groups, age-related differences manifested in the location of the generators of the ERN component. The dorsal anterior cingulate cortex (dACC) was the predominant source location for the 12-year-old group; this area manifested posteriorly for the 15-year-old and adult groups. A fMRI-based ROI analysis confirmed this pattern of activity. These results suggest that changes in the underlying neural mechanisms are related to developmental changes in performance monitoring.

Cross-sectional and Longitudinal Associations of Anxiety and Irritability With Adolescents' Neural Responses to Cognitive Conflict.

BACKGROUND: Psychiatric symptoms are commonly comorbid in childhood. The ability to disentangle unique and shared correlates of comorbid symptoms facilitates personalized medicine. Cognitive control is implicated broadly in psychopathology, including in pediatric disorders characterized by anxiety and irritability. To disentangle cognitive control correlates of anxiety versus irritability, the current study leveraged both cross-sectional and longitudinal data from early childhood into adolescence. METHODS: For this study, 89 participants were recruited from a large longitudinal research study on early-life temperament to investigate associations of developmental trajectories of anxiety and irritability symptoms (from ages 2 to 15) as well as associations of anxiety and irritability symptoms measured cross-sectionally at age 15 with neural substrates of conflict and error processing assessed at age 15 using the flanker task. RESULTS: Results of whole-brain multivariate linear models revealed that anxiety at age 15 was uniquely associated with decreased neural response to conflict across multiple regions implicated in attentional control and conflict adaptation. Conversely, irritability at age 15 was uniquely associated with increased neural response to conflict in regions implicated in response inhibition. Developmental trajectories of anxiety and irritability interacted in relation to neural responses to both error and conflict. CONCLUSIONS: Our findings suggest that neural correlates of conflict processing may relate uniquely to anxiety and irritability. Continued cross-symptom research on the neural correlates of cognitive control could stimulate advances in individualized treatment for anxiety and irritability during child and adolescent development.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Understanding Irritability in Relation to Anger, Aggression, and Informant in a Pediatric Clinical Population.

OBJECTIVE: Despite its clinical relevance to pediatric mental health, the relationship of irritability with anger and aggression remains unclear. We aimed to quantify the relationships between well-validated, commonly used measurements of these constructs and informant effects in a clinically relevant population. METHOD: A total of 195 children with primary diagnoses of attention-deficit/hyperactivity disorder, disruptive mood dysregulation disorder, or no major disorder and their parents rate irritability, anger, and aggression on measures of each construct. Construct and informant relationships were mapped via multi-trait, multi-method factor analysis. RESULTS: Parent- and child-reported irritability and child-reported anger are highly associated (r = 0.89) but have some significant differences. Irritability overlaps with outward expression of anger but diverges from anger in anger suppression and control. Aggression has weaker associations with both irritability (r = 0.56) and anger (r = 0.49). Across measures, informant source explains a substantial portion of response variance. CONCLUSION: Irritability, albeit distinct from aggression, is highly associated with anger, with notable overlap in child-reported outward expression of anger, providing empirical support for formulations of clinical irritability as a proneness to express anger outwardly. Diagnostic and clinical intervention work on this facet of anger can likely translate to irritability. Further research on external validation of divergence of these constructs in anger suppression and control may guide future scale revisions. The proportion of response variance attributable to informant may be an under-recognized confound in clinical research and construct measurement.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Rationale and validation of a novel mobile application probing motor inhibition: Proof of concept of CALM-IT.

Identification of behavioral mechanisms underlying psychopathology is essential for the development of novel targeted therapeutics. However, this work relies on rigorous, time-intensive, clinic-based laboratory research, making it difficult to translate research paradigms into tools that can be used by clinicians in the community. The broad adoption of smartphone technology provides a promising opportunity to bridge the gap between the mechanisms identified in the laboratory and the clinical interventions targeting them in the community. The goal of the current study is to develop a developmentally appropriate, engaging, novel mobile application called CALM-IT that probes a narrow biologically informed process, inhibitory control. We aim to leverage the rigorous and robust methods traditionally used in laboratory settings to validate this novel mechanism-driven but easily disseminatable tool that can be used by clinicians to probe inhibitory control in the community. The development of CALM-IT has significant implications for the ability to screen for inhibitory control deficits in the community by both clinicians and researchers. By facilitating assessment of inhibitory control outside of the laboratory setting, researchers could have access to larger and more diverse samples. Additionally, in the clinical setting, CALM-IT represents a novel clinical screening measure that could be used to determine personalized courses of treatment based on the presence of inhibitory control deficits.

Attention bias to negative versus non-negative faces is related to negative affectivity in a transdiagnostic youth sample.

This study identified a shared pathophysiological mechanism of pediatric anxiety and irritability. Clinically, anxiety and irritability are common, co-occurring problems, both characterized by high-arousal negative affective states. Behaviorally, anxiety and irritability are associated with aberrant threat processing. To build on these findings, we examined eye-tracking measures of attention bias in relation to the unique and shared features of anxiety and irritability in a transdiagnostic sample of youth (n = 97, 58% female, Mage = 13.03, SDage = 2.82). We measured attention bias to negative versus non-negative emotional faces during a passive viewing task. We employed bifactor analysis to parse the unique and shared variance of anxiety and irritability symptoms from self- and parent-report questionnaires. Negative affectivity is the derived latent factor reflecting shared variance of anxiety and irritability. We found that higher negative affectivity was associated with looking longer at negative versus non-negative faces, reflecting a shared mechanism of anxiety and irritability. This finding suggests that modification of elevated attention to negative emotional faces may represent a common potential treatment target of anxiety and irritability.

Phasic Versus Tonic Irritability: Differential Associations With Attention-Deficit/Hyperactivity Disorder Symptoms.

OBJECTIVE: Irritability is a multifaceted construct in pediatric psychopathology. It has been conceptualized as having a phasic dimension and a tonic dimension. Disruptive mood dysregulation disorder is defined by the presence of both dimensions. Severe irritability, or disruptive mood dysregulation disorder, is highly comorbid with attention-deficit/hyperactivity disorder (ADHD). However, it is unknown whether the presence of ADHD modulates the expression of phasic and tonic irritability. METHOD: A data-driven, latent variable approach was used to examine irritability and ADHD symptoms in a transdiagnostic pediatric sample (N = 489) with primary disruptive mood dysregulation disorder, ADHD, subclinical irritability symptoms, or no diagnosis. Using latent profile analyses, we identified 4 classes: high levels of both irritability and ADHD symptoms, high levels of irritability and moderate levels of ADHD symptoms, moderate levels of irritability and high levels of ADHD symptoms, and low levels of both irritability and ADHD symptoms. Confirmatory factor analysis operationalized phasic irritability and tonic irritability. RESULTS: As expected, the 2 latent classes characterized by high overall irritability exhibited the highest levels of both phasic and tonic irritability. However, between these 2 high irritability classes, highly comorbid ADHD symptoms were associated with significantly greater phasic irritability than were moderately comorbid ADHD symptoms. In contrast, the 2 high irritability groups did not differ on levels of tonic irritability. CONCLUSION: These findings suggest that phasic, but not tonic, irritability has a significant association with ADHD symptoms and that phasic and tonic might be distinct, though highly related, irritability dimensions. Future research should investigate potential mechanisms underlying this differential association.

Bilateral amygdala damage linked to impaired ability to predict others' fear but preserved moral judgements about causing others fear.

The amygdala is a subcortical structure implicated in both the expression of conditioned fear and social fear recognition. Social fear recognition deficits following amygdala lesions are often interpreted as reflecting perceptual deficits, or the amygdala's role in coordinating responses to threats. But these explanations fail to capture why amygdala lesions impair both physiological and behavioural responses to multimodal fear cues and the ability to identify them. We hypothesized that social fear recognition deficits following amygdala damage reflect impaired conceptual understanding of fear. Supporting this prediction, we found specific impairments in the ability to predict others' fear (but not other emotions) from written scenarios following bilateral amygdala lesions. This finding is consistent with the suggestion that social fear recognition, much like social recognition of states like pain, relies on shared internal representations. Preserved judgements about the permissibility of causing others fear confirms suggestions that social emotion recognition and morality are dissociable.

Maladaptive Fearlessness: An Examination of the Association Between Subjective Fear Experience and Antisocial Behaviors Linked With Callous Unemotional Traits.

The centrality of a fearless temperament as it relates to the construct of psychopathy remains an area of controversy, with some researchers arguing that the relationship between fearless temperament and psychopathy (and associated antisocial behavior) can be explained by shared associations with other core affective and interpersonal traits of psychopathy such as callous-unemotional (CU) traits. The authors investigated real-world subjectively experienced fear in 306 individuals with varying levels of CU traits and antisocial behavior and found that at low levels of subjective fear experience, decreases in subjective fear were associated with greater antisociality. Even after controlling for the positive relationship between CU traits and antisocial behavior, reduced subjectively experienced fear remained a significant predictor of antisocial behavior. These results provide evidence that experienced fear is related to antisocial behavior at lower than average levels of subjectively experienced fear and that this relationship persists after controlling for CU traits.

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.

Converging Multi-modal Evidence for Implicit Threat-Related Bias in Pediatric Anxiety Disorders.

This report examines the relationship between pediatric anxiety disorders and implicit bias evoked by threats. To do so, the report uses two tasks that assess implicit bias to negative-valence faces, the first by eye-gaze and the second by measuring body-movement parameters. The report contrasts task performance in 51 treatment-seeking, medication-free pediatric patients with anxiety disorders and 36 healthy peers. Among these youth, 53 completed an eye-gaze task, 74 completed a body-movement task, and 40 completed both tasks. On the eye-gaze task, patients displayed longer gaze duration on negative relative to non-negative valence faces than healthy peers, F(1, 174) = 8.27, p = .005. In contrast, on the body-movement task, patients displayed a greater tendency to behaviorally avoid negative-valence faces than healthy peers, F(1, 72) = 4.68, p = .033. Finally, implicit bias measures on the two tasks were correlated, r(38) = .31, p = .049. In sum, we found an association between pediatric anxiety disorders and implicit threat bias on two tasks, one measuring eye-gaze and the other measuring whole-body movements. Converging evidence for implicit threat bias encourages future research using multiple tasks in anxiety.

Mapping neural activity patterns to contextualized fearful facial expressions onto callous-unemotional (CU) traits: intersubject representational similarity analysis reveals less variation among high-CU adolescents.

Callous-unemotional (CU) traits are early-emerging personality features characterized by deficits in empathy, concern for others, and remorse following social transgressions. One of the interpersonal deficits most consistently associated with CU traits is impaired behavioral and neurophysiological responsiveness to fearful facial expressions. However, the facial expression paradigms traditionally employed in neuroimaging are often ambiguous with respect to the nature of threat (i.e., is the perceiver the threat, or is something else in the environment?). In the present study, 30 adolescents with varying CU traits viewed fearful facial expressions cued to three different contexts ("afraid for you," "afraid of you," "afraid for self") while undergoing functional magnetic resonance imaging (fMRI). Univariate analyses found that mean right amygdala activity during the "afraid for self" context was negatively associated with CU traits. With the goal of disentangling idiosyncratic stimulus-driven neural responses, we employed intersubject representational similarity analysis to link intersubject similarities in multivoxel neural response patterns to contextualized fearful expressions with differential intersubject models of CU traits. Among low-CU adolescents, neural response patterns while viewing fearful faces were most consistently similar early in the visual processing stream and among regions implicated in affective responding, but were more idiosyncratic as emotional face information moved up the cortical processing hierarchy. By contrast, high-CU adolescents' neural response patterns consistently aligned along the entire cortical hierarchy (but diverged among low-CU youths). Observed patterns varied across contexts, suggesting that interpretations of fearful expressions depend to an extent on neural response patterns and are further shaped by levels of CU traits.

Reduced Multivoxel Pattern Similarity of Vicarious Neural Pain Responses in Psychopathy.

Psychopathy is a personality construct characterized by interpersonal callousness, boldness, and disinhibition, traits that vary continuously across the population and are linked to impaired empathic responding to others' distress and suffering. Following suggestions that empathy reflects neural self-other mapping-for example, the similarity of neural responses to experienced and observed pain, measurable at the voxel level-we used a multivoxel approach to assess associations between psychopathy and empathic neural responses to pain. During fMRI scanning, 21 community-recruited participants varying in psychopathy experienced painful pressure stimulation and watched a live video of a stranger undergoing the same stimulation. As total psychopathy, coldheartedness, and self-centered impulsivity increased, multivoxel similarity of vicarious and experienced pain in the left anterior insula decreased, effects that were not observed following an empathy prompt. Our data provide preliminary evidence that psychopathy is characterized by disrupted spontaneous empathic representations of others' pain that may be reduced by instructions to empathize.

Activation in bed nucleus of the stria terminalis (BNST) corresponds to everyday helping.

Everyday prosociality includes helping behaviors such as holding doors or giving directions that are spontaneous and low-cost and are performed frequently by the average person. Such behaviors promote a wide array of positive outcomes that include increased well-being, trust, and social capital, but the cognitive and neural mechanisms that support these behaviors are not yet well understood. Whereas costly altruistic responding to others' distress is associated with elevated reactivity in the amygdala, we hypothesized that everyday prosociality would be more closely associated with activation in the bed nucleus of the stria terminalis (BNST), a region of the extended amygdala known for its roles in maintaining vigilance for relevant socio-affective environmental cues and in supporting parental care. One previous study of the neural correlates of everyday prosociality highlighted a functional cluster identified as the septal area but which overlapped with established coordinates of BNST. We used an anatomical mask of BNST (Torrisi et al., 2015) to evaluate the association of BNST activation and daily helping in a sample of 25 adults recruited from the community as well as 23 adults who had engaged in acts of extraordinary altruism. Results found that activation in left BNST during an empathy task predicted everyday helping over a subsequent 14-day period in both samples. BNST activation most strongly predicted helping strangers and proactive helping. We conclude that beyond facilitating care for offspring, activation in BNST may provide a basis for the motivation to engage in a broad array of everyday helping behaviors.