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.

A New Behavioral Paradigm for Frustrative Nonreward in Juvenile Mice.

Background: Irritability, defined as proneness to anger, can reach a pathological extent. It is a defining symptom of disruptive mood dysregulation disorder and one of the most common reasons youths present for psychiatric evaluation and care. Aberrant responses to frustrative nonreward (FNR), the response to omission of expected reward, are central to the pathophysiology of irritability. FNR is a translational construct to study irritability across species. The development of preclinical FNR models would advance mechanistic studies of the important and relatively understudied clinical phenomenon of irritability. Methods: We used FNR as a conceptual framework to develop a novel mouse behavioral paradigm named alternate poking reward omission. Juvenile mice were exposed to alternate poking reward omission and then examined with a battery of behavioral tests to determine the behavioral effect of FNR. Results: FNR increased locomotion and aggression regardless of sex. These behavioral changes elicited by FNR resemble the symptoms observed in youth with severe irritability. FNR had no effect on anxiety-like, depression-like, or nonaggressive social behaviors. Conclusions: Our alternate poking reward omission paradigm effectively elevated aggression and locomotion in juvenile mice. These frustration effects are directly related to behavioral symptoms of youth with severe irritability. Our novel behavioral paradigm lays the groundwork for further mechanistic studies of frustration and irritability in rodents.

Cross-Sectional and Longitudinal Relations Among Irritability, Attention-Deficit/Hyperactivity Disorder Symptoms, and Inhibitory Control.

OBJECTIVE: Irritability and attention-deficit/hyperactivity disorder (ADHD) symptoms frequently co-occur in youth. Although ADHD has been associated with inhibitory control deficits, the literature on irritability and inhibitory control is mixed. Examining how irritability, ADHD symptoms, and inhibitory control interrelate both cross-sectionally and longitudinally across development could shed light on common and distinct mechanisms of youth psychopathology. METHOD: We utilized a cross-lagged panel model with data from 2 time points (at ages 10 and 12 years) of the Adolescent Brain and Cognitive Development (ABCD) Study (N = 7,444, or ∼63% of the baseline sample with full data at each time point) to test cross-sectional and longitudinal associations among parent-reported irritability and ADHD symptoms and behaviorally assessed inhibitory control. This was performed separately across discovery and replication subsamples, each n = 3,722. RESULTS: As expected, irritability and ADHD symptoms exhibited strong cross-sectional and reciprocal cross-lagged associations. Higher ADHD symptoms at age 10 years were associated concurrently with poorer inhibitory control and predicted poorer inhibitory control at age 12. Contrary to predictions, inhibitory control was not significantly associated with irritability cross-sectionally, nor was it predictive of later irritability or ADHD symptoms. CONCLUSION: These findings highlight strong links between irritability and ADHD. Although inhibitory control deficits were linked to ADHD and predictive of its symptom course, inhibitory control had no significant associations with irritability. Future research should investigate other candidate mechanisms of the co-occurrence of irritability and ADHD symptoms and predictors of their developmental trajectories.

Modeling Shared and Specific Variances of Irritability, Inattention, and Hyperactivity Yields Novel Insights Into White Matter Perturbations.

OBJECTIVE: Irritability, inattention, and hyperactivity, which are common presentations of childhood psychopathology, have been associated with perturbed white matter microstructure. However, similar tracts have been implicated across these phenotypes; such non-specificity could be rooted in their high co-occurrence. To address this problem, we use a bifactor approach parsing unique and shared components of irritability, inattention, and hyperactivity, which we then relate to white matter microstructure. METHOD: We developed a bifactor model based on the Conners Comprehensive Behavioral Rating Scale in a sample of youth with no psychiatric diagnosis or a primary diagnosis of attention-deficit/hyperactivity disorder or disruptive mood dysregulation disorder (n = 521). We applied the model to an independent yet sociodemographically and clinically comparable sample (n = 152), in which we tested associations between latent variables and fractional anisotropy (FA). RESULTS: The bifactor model fit well (comparative fit index = 0.99; root mean square error of approximation = 0.07). The shared factor was positively associated with an independent measure of impulsivity (ρS = 0.88, pFDR < .001) and negatively related to whole-brain FA (r = -0.20), as well as FA of the corticospinal tract (all pFWE < .05). FA increased with age and deviation from this curve, indicating that altered white matter maturation was associated with the hyperactivity-specific factor (r = -0.16, pFWE < .05). Inattention-specific and irritability-specific factors were not linked to FA. CONCLUSION: Perturbed white matter microstructure may represent a shared neurobiological mechanism of irritability, inattention, and hyperactivity related to heightened impulsivity. Furthermore, hyperactivity might be uniquely associated with a delay in white matter maturation.

Irritability, Negative Life Events and the Course of Anxiety and Depressive Symptoms in a Clinical Sample of Youth: A Longitudinal Study.

Objective: Irritability, the tendency to react with anger, and the experience of negative life events (NLE) have independently been associated with the emergence of anxiety and depression. Here, we investigate how irritability and cumulative effects of NLE interactively predict the course of anxiety and depression in the context of common psychiatric disorders. Method: 432 youth with no psychiatric diagnosis, or a diagnosis of an anxiety disorder, Attention-Deficit/ Hyperactivity Disorder (ADHD), or Disruptive Mood Dysregulation Disorder (DMDD), participated in this study. At baseline, we assessed NLE, parent and youth reports of irritability and anxiety, and youth reports of depression. Symptoms were annually reassessed for up to four years. Results: In youth without psychiatric diagnoses but with elevated baseline irritability, the presence of NLE predicted decreasing anxiety, while the absence of NLE predicted increasing anxiety. In youth with an anxiety disorder, elevated baseline irritability predicted decreasing anxiety independent of NLE, while a large cumulative effect of NLE predicted increasing depression. NLE predicted persisting mild anxiety in ADHD and persisting mild depressive symptoms in DMDD. Conclusion: Our findings suggest that, particularly in non-referred samples, NLE might moderate the relationship between irritability and future anxiety such that irritability/ anger in the context of NLE can positively affect the course of anxiety. Future work replicating this finding while repeatedly measuring NLE and rigorously controlling for potentially confounding effects of treatment, is warranted.

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.

Neural Responses to Intranasal Oxytocin in Youths With Severe Irritability.

OBJECTIVE: The authors investigated the neural impact of intranasal oxytocin on emotion processing areas in youths with severe irritability in the context of disruptive mood and behavior disorders. METHODS: Fifty-two participants with severe irritability, as measured by a score ≥4 on the Affective Reactivity Index (ARI), with diagnoses of disruptive behavior disorders (DBDs) and/or disruptive mood dysregulation disorder (DMDD) were randomly assigned to treatment with intranasal oxytocin or placebo daily for 3 weeks. Assessments were conducted at baseline and at the end of the trial; the primary outcomes were measures of irritability on the ARI and ratings on the Clinical Global Impressions severity scale (CGI-S) focusing on DBD and DMDD symptoms, and secondary outcomes included the CGI improvement scale (CGI-I) and ratings of proactive and reactive aggressive behavior on the Reactive-Proactive Aggression Questionnaire. Forty-three participants (22 in the oxytocin group and 21 in the placebo group) completed pre- and posttreatment functional MRI (fMRI) scans with the affective Stroop task. RESULTS: Youths who received oxytocin showed significant improvement in CGI-S and CGI-I ratings compared with those who received placebo. In the fMRI data, blood-oxygen-level-dependent (BOLD) responses to emotional stimuli in the dorsomedial prefrontal cortex and posterior cingulate cortex were significantly reduced after oxytocin compared with placebo. These BOLD response changes were correlated with improvement in clinical severity. CONCLUSIONS: This study provides initial and preliminary evidence that intranasal oxytocin may induce neural-level changes in emotion processing in youths with irritability in the context of DBDs and DMDD. This may lead to symptom and severity changes in irritability.

Irritability in Youths: A Critical Integrative Review.

Irritability, defined as proneness to anger that may impair an individual's functioning, is common in youths. There has been a recent upsurge in relevant research. The authors combine systematic and narrative review approaches to integrate the latest clinical and translational findings and provide suggestions for addressing research gaps. Clinicians and researchers should assess irritability routinely, and specific assessment tools are now available. Informant effects are prominent, are stable, and vary by age and gender. The prevalence of irritability is particularly high among individuals with attention deficit hyperactivity disorder, autism spectrum disorder, and mood and anxiety disorders. Irritability is associated with impairment and suicidality risk independent of co-occurring diagnoses. Developmental trajectories of irritability (which may begin early in life) have been identified and are differentially associated with clinical outcomes. Youth irritability is associated with increased risk of anxiety, depression, behavioral problems, and suicidality later in life. Irritability is moderately heritable, and genetic associations differ based on age and comorbid illnesses. Parent management training is effective for treating psychological problems related to irritability, but its efficacy in treating irritability should be tested rigorously, as should novel mechanism-informed interventions (e.g., those targeting exposure to frustration). Associations between irritability and suicidality and the impact of cultural context are important, underresearched topics. Analyses of large, diverse longitudinal samples that extend into adulthood are needed. Data from both animal and human research indicate that aberrant responses to frustration and threat are central to the pathophysiology of irritability, revealing important translational opportunities.

Irritability in children and adolescents: past concepts, current debates, and future opportunities

Irritability is defined as a low threshold to experience anger in response to frustration. It is one of the most common symptoms in youth and is part of the clinical presentation of several disorders. Irritability can present early in life and is a predictor of long-term psychopathology; yet, the diagnostic status of irritability is a matter of intense debate. In the present article, we address two main components of the debate regarding irritability in youth: the misdiagnosis of chronic irritability as pediatric bipolar disorder, and the proposal of a new diagnosis in the DSM-5, disruptive mood dysregulation disorder, whose defining symptoms are chronic irritability and temper outbursts.

Cross-cultural adaptation and preliminary psychometric properties of the Affective Reactivity Index in Brazilian Youth: implications for DSM-5 measured irritability / Adaptação transcultural e propriedades psicométricas preliminares do Affective Reactivity Index em jovens brasileiros: implicações para a irritabilidade medida pelo DSM-5

Objective: To describe the cross-cultural adaptation of the Affective Reactivity Index (ARI) to Brazilian Portuguese and to investigate preliminary psychometric properties of the adapted version. Methods: Cross-cultural adaptation was based on the investigation of the theoretical and operational equivalences of the original ARI in the Brazilian context, followed by a process of translation, back-translation, and review by a committee of experts. Data analysis was carried out in a community sample of 133 schoolchildren aged 8 to 17 years to investigate the following characteristics of the ARI: 1) factor structure; 2) internal consistency; 3) construct validity comparing differential relationships between irritability and anxiety dimensions and impairment; and 4) item response theory (IRT) parameters. Results: A final Brazilian Portuguese version of the instrument was defined and is presented. Internal consistency was good, and our analysis supported the original single-factor structure of the ARI. Correlations of the ARI with distress-related anxiety dimensions were higher than with phobic-related anxiety dimensions, supporting its construct validity. In addition, higher ARI scores were associated with higher irritability-related impairment. IRT analysis underscored frequency of loss of temper as essential to inform about pathological states of irritability. Conclusion: The Brazilian Portuguese version of the ARI seems to be very similar to the original instrument in terms of conceptual, item, semantic, and operational equivalence. Our preliminary analysis replicates and extends previous evidence confirming promising psychometric properties for the ARI.

Objetivo: Descrever a adaptação transcultural do Affective Reactivity Index (ARI) para o português do Brasil e investigar propriedades psicométricas preliminares da versão adaptada. Método: A adaptação transcultural foi baseada na investigação das equivalências teórica e operacional da versão original do ARI no contexto brasileiro, seguida do processo de tradução, retrotradução e revisão por comitê de especialistas. A análise dos dados foi realizada em uma amostra comunitária de 133 escolares com idade entre 8 e 17 anos para investigar as seguintes características do ARI: 1) estrutura fatorial; 2) consistência interna; 3) validade do construto, comparando as relações diferenciais entre irritabilidade e as dimensões de ansiedade e prejuízo; e 4) parâmetros de teoria da resposta ao item (TRI). Resultados: Uma versão final em português do Brasil do instrumento foi definida e é apresentada. A consistência interna foi boa, e nossa análise confirmou a estrutura unifatorial original do ARI. As correlações do ARI com as dimensões de ansiedade relacionadas a sofrimento foram maiores do que com as dimensões de ansiedade relacionadas a fobias, reforçando a validade do construto. Além disso, escores mais altos no ARI foram associados a maior prejuízo relacionado à irritabilidade. A análise do TRI enfatizou a frequência de perda de controle como essencial para determinar estados patológicos de irritabilidade. Conclusão: A versão em português do Brasil do ARI parece ser muito semelhante ao instrumento original em termos de equivalência conceitual, de itens, semântica e operacional. Nossa análise preliminar reproduz e estende evidências anteriores que confirmam propriedades psicométricas promissoras para o ARI.