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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.

IntroductionIrritability, characterized by a tendency to exhibit increased anger, is a common clinical problem in youth. Irritability is a significant clinical issue in youth with various psychiatric diagnoses, especially disruptive behavior, and mood disorders (Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, and Disruptive Mood Dysregulation Disorder). Although there have been previous studies focusing on functional alteration in the amygdala related to irritability, there is no comprehensive model between emotional, neuronal, and behavioral characteristics.MethodsUsing an functional magnetic resonance imaging (fMRI) procedure, we investigated the relationships between behavioral irritability, selective impairments in processing facial emotions and the amygdala neural response in youth with increased irritability. Fifty-nine youth with disruptive mood and behavior disorder completed a facial expression processing task with an event-related fMRI paradigm. The severity of irritability was evaluated using the Affective Reactivity Index.ResultsIn the result of behavioral data, irritability, and reaction time (RT) differences between interpreting negative (fear) and positive (happiness) facial expressions were positively correlated. In the fMRI result, youth showed higher activation in the right cingulate gyrus, bilateral cerebellum, right amygdala, right precuneus, right superior frontal gyrus, right middle occipital gyrus, and middle temporal gyrus, during the happiness condition vs. fear condition. No brain region exhibited greater activation in the fear than in the happiness conditions. In the result of the mediator analysis, increased irritability was associated with a longer RT toward positive vs. negative facial expressions. Irritability was also positively associated with the difference in amygdala blood oxygen level-dependent responses between the two emotional conditions (happiness > fear). This difference in amygdala activity mediated the interaction between irritability and the RT difference between negative and positive facial expressions.DiscussionWe suggest that impairment in the implicit processing of facial emotional expressions with different valences causes distinct patterns of amygdala response, which correlate with the level of irritability. These results broaden our understanding of the biological mechanism of irritability at the neural level and provide information for the future direction of the study.

Typical fMRI analyses often assume a canonical hemodynamic response function (HRF) that primarily focuses on the peak height of the overshoot, neglecting other morphological aspects. Consequently, reported analyses often reduce the overall response curve to a single scalar value. In this study, we take a data-driven approach to HRF estimation at the whole-brain voxel level, without assuming a response profile at the individual level. We then employ a roughness penalty at the population level to estimate the response curve, aiming to enhance predictive accuracy, inferential efficiency, and cross-study reproducibility. By examining a fast event-related FMRI dataset, we demonstrate the shortcomings and information loss associated with adopting the canonical approach. Furthermore, we address the following key questions: 1) To what extent does the HRF shape vary across different regions, conditions, and participant groups? 2) Does the data-driven approach improve detection sensitivity compared to the canonical approach? 3) Can analyzing the HRF shape help validate the presence of an effect in conjunction with statistical evidence? 4) Does analyzing the HRF shape offer evidence for whole-brain response during a simple task?

Abstract Previous studies examining structural brain correlates of irritability have taken a region-specific approach and have been relatively inconsistent. In a sample of adolescents with and without clinically impairing irritability, the current study examines: (i) cortical volume (CV) in canonical functional networks; (ii) the association between the CV of functional networks and severity of irritability; and (iii) the extent to which IQ mediates the association between structural abnormalities and severity of irritability. Structural MRI and IQ data were collected from 130 adolescents with high irritability (mean age = 15.54±1.83 years, 58 females, self-reported Affective Reactivity Index [ARI] ≥ 4) and 119 adolescents with low irritability (mean age = 15.10±1.93 years, 39 females, self-reported ARI < 4). Subject-specific network-wise CV was estimated after parcellating the whole brain into 17 previously reported functional networks. Our Multivariate Analysis of Covariance (MANCOVA) revealed that adolescents with high irritability had significantly reduced CV of the bilateral control and default-mode networks (p

Abstract 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.

Abstract Objective Anxiety symptoms often increase in late childhood/early adolescence, particularly among girls. However, few studies examine anxiety‐relevant gender differences during anticipation and avoidance of naturalistic experiences during adolescence. The current study uses ecological momentary assessment (EMA) to examine associations among clinical anxiety, gender, anticipation, and attempted avoidance of person‐specific anxiety‐provoking experiences in youth ages 8–18. Method 124 youth (73 girls) completed 7 consecutive days of EMA. Seventy participants (42 girls) met criteria for one or more anxiety disorders, while the remaining 54 were healthy controls (31 girls). Participants reported the experience that they were “most worried about happening that day” and completed ratings about that event including whether they attempted to avoid that experience. Multilevel models examined whether diagnostic group (anxious, healthy), gender (boys, girls), or their interaction predicted anticipatory ratings or avoidance of these experiences. Results Analyses revealed significant diagnostic group by gender interactions for anticipatory ratings. Specifically, anxious girls reported greater worry and predicted more negative outcomes related to future experiences. However, only a main effect of diagnostic group emerged for attempted avoidance. Finally, anticipatory worry predicted higher rates of attempted avoidance, but this association did not vary by diagnostic group, gender, or their interaction. Conclusion These findings extend the literature on the interplay of anticipation and avoidance to person‐specific naturalistic experiences in pediatric anxiety. They reveal that anxious girls report more anticipatory anxiety and worry, while avoidance of real‐world anxiety‐provoking scenarios is a key concern for anxious youth independent of gender. By using EMA to examine person‐specific anxiety‐inducing experiences we can begin to understand how these processes and experiences unfold in the real world.

Influential theories implicate variations in the mechanisms supporting threat learning in the severity of anxiety symptoms. We use computational models of associative learning in conjunction with structural imaging to explicate links among the mechanisms underlying threat learning, their neuroanatomical substrates, and anxiety severity in humans. We recorded skin-conductance data during a threat-learning task from individuals with and without anxiety disorders (N=251; 8-50 years; 116 females). Reinforcement-learning model variants quantified processes hypothesized to relate to anxiety: threat conditioning, threat generalization, safety learning, and threat extinction. We identified the best-fitting models for these processes and tested associations among latent learning parameters, whole-brain anatomy, and anxiety severity. Results indicate that greater anxiety severity related specifically to slower safety learning and slower extinction of response to safe stimuli. Nucleus accumbens gray-matter volume moderated learning-anxiety associations. Using a modeling approach, we identify computational mechanisms linking threat learning and anxiety severity and their neuroanatomical substrates.

Attention-deficit/hyperactivity disorder (ADHD), characterized by symptoms of inattention and/or hyperactivity and impulsivity, is a neurodevelopmental disorder associated with executive dysfunctions, including response inhibition and error processing. Research has documented a common co-occurrence between ADHD and pediatric irritability. The latter is more characterized by affective symptoms, specifically frequent temper outbursts and low frustration tolerance relative to typically developing peers. Shared and non-shared neural correlates of youths with varied profiles of ADHD and irritability symptoms during childhood remain largely unknown. This study first classified a large sample of youths in the Adolescent Brain Cognitive Development (ABCD) study at baseline into distinct phenotypic groups based on ADHD and irritability symptoms (N = 11,748), and then examined shared and non-shared neural correlates of response inhibition and error processing during the Stop Signal Task in a subset of sample with quality neuroimaging data (N = 5,948). Latent class analysis (LCA) revealed four phenotypic groups, i.e., high ADHD with co-occurring irritability symptoms (n = 787, 6.7%), moderate ADHD with low irritability symptoms (n = 901, 7.7%), high irritability with no ADHD symptoms (n = 279, 2.4%), and typically developing peers with low ADHD and low irritability symptoms (n = 9,781, 83.3%). Latent variable modeling revealed group differences in the neural coactivation network supporting response inhibition in the fronto-parietal regions, but limited differences in error processing across frontal and posterior regions. These neural differences were marked by decreased coactivation in the irritability only group relative to youths with ADHD and co-occurring irritability symptoms and typically developing peers during response inhibition. Together, this study provided initial evidence for differential neural mechanisms of response inhibition associated with ADHD, irritability, and their co-occurrence. Precision medicine attending to individual differences in ADHD and irritability symptoms and the underlying mechanisms are warranted when treating affected children and families.

Abstract Introduction Irritability has both mood and behavioral manifestations. These frequently co-occur, and it is unclear to what extent they are dissociable domains. We used confirmatory factor analysis and external validators to investigate the independence of mood and behavioral components of irritability. Methods The sample comprised 246 patients (mean age 45 years; 63% female) from four outpatient programs (depression, anxiety, bipolar, and schizophrenia) at a tertiary hospital. A clinical instrument rated by trained clinicians was specifically designed to capture irritable mood and disruptive behavior dimensionally, as well as current categorical diagnoses i.e., intermittent explosive disorder (IED); oppositional defiant disorder (ODD); and an adaptation to diagnose disruptive mood dysregulation disorder (DMDD) in adults. Confirmatory factor analysis (CFA) was used to test the best fitting irritability models and regression analyses were used to investigate associations with external validators. Results Irritable mood and disruptive behavior were both frequent, but diagnoses of disruptive syndromes were rare (IED, 8%; ODD, 2%; DMDD, 2%). A correlated model with two dimensions, and a bifactor model with one general dimension and two specific dimensions (mood and behavior) both had good fit indices. The correlated model had root mean square error of approximation (RMSEA) = 0.077, with 90% confidence interval (90%CI) = 0.071-0.083; comparative fit index (CFI) = 0.99; and Tucker-Lewis index (TLI) = 0.99, while the bifactor model had RMSEA = 0.041; CFI = 0.99; and TLI = 0.99 respectively). In the bifactor model, external validity for differentiation of the mood and behavioral components of irritability was also supported by associations between irritable mood and impairment and clinical measures of depression and mania, which were not associated with disruptive behavior. Conclusions Psychometric and external validity data suggest both overlapping and specific features of the mood vs. disruptive behavior dimensions of irritability.

Background: Irritability and callous-unemotional (CU; reduced guilt/empathy) traits vary dimensionally in the typically developing population but may be particularly marked in youth with conduct disorder (CD). While these dimensional traits are positively correlated, they have been associated with divergent forms of dysfunction, particularly with respect to threat processing (i.e., irritability with increased, and CU traits with decreased, threat responsiveness). This suggests that interactions between these two dimensions may be complex at the neurobiological level. However, this issue has received minimal empirical attention.Methods: The study included 105 adolescents (typically developing and cases with CD; N = 59). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding.Results: Significant irritability-by-CU traits-by-Direction-by-Emotion interactions were seen within right thalamus/PAG, left lingual gyrus and right fusiform gyrus; irritability was positively associated with the BOLD response for Looming Threatening vs. Receding Threatening trials, particularly for youth with low CU traits. In contrast, CU traits were negatively associated with the same differential BOLD response but particularly for youth showing higher levels of irritability. Similar findings were seen within left ventral anterior and posterior cingulate cortices, though the addition of the interaction with CU traits was only seen at slightly more lenient thresholds.Conclusions: The results support previous work linking irritability to increased, and CU traits to reduced, threat responsiveness. However, for adolescents with high irritability, if CU traits are also high, the underlying neuropathology appears to relate to reduced, rather than increased, threat responsiveness.

The current study examined the link between temperamental reactivity in infancy and amygdala development in middle childhood. A sample (n = 291) of four-month-old infants was assessed for infant temperament, and two groups were identified: those exhibiting negative reactivity (n = 116) and those exhibiting positive reactivity (n = 106). At 10 and 12 years of age structural imaging was completed on a subset of these participants (n = 75). Results indicate that, between 10 and 12 years of age, left amygdala volume increased more slowly in those with negative compared to positive reactive temperament. These results provide novel evidence linking early temperament to distinct patterns of brain development over middle childhood.

Neuroimaging studies typically focus on either resting state or task-based fMRI data. Prior research has shown that similarity in functional connectivity between rest and cognitive tasks, interpreted as reconfiguration efficiency, is related to task performance and IQ. Here, we extend this approach from adults to children, and from cognitive tasks to a threat-based attention task. The goal of the current study was to examine whether similarity in functional connectivity during rest and an attention bias task relates to threat bias, IQ, anxiety symptoms, and social reticence. fMRI was measured during resting state and during the dot-probe task in 41 children (M = 13.44, SD = 0.70). Functional connectivity during rest and dot-probe was positively correlated, suggesting that functional hierarchies in the brain are stable. Similarity in functional connectivity between rest and the dot-probe task only related to threat bias (puncorr

Face emotion imaging paradigms are widely used in both healthy and psychiatric populations. Here, in children and adolescents, we evaluate the test-retest reliability of blood oxygenation-level dependent (BOLD) activation and task-based functional connectivity on a widely used implicit face emotion processing task (i.e., gender labeling). Twenty-five healthy youth (M age = 13.97 year s; 60% female) completed two functional magnetic resonance imaging (fMRI) scan sessions approximately two months apart. Participants identified the gender of faces displaying angry, fearful, happy, and neutral emotions. A Bayesian adaptation of the intraclass correlation (ICC) assessed reliability of evoked BOLD activation and amygdala seed-based functional connectivity on task events vs. baseline as well as contrasts between face emotions. For each face emotion vs. baseline, good reliability of activation was demonstrated across key emotion processing regions including middle, medial, and inferior frontal gyri. However, contrasts between face emotions yielded variable results. Contrasts of angry to neutral or happy faces exhibited good reliability of amygdala connectivity to prefrontal regions. Contrasts of fearful to happy faces exhibited good reliability of activation in the anterior cingulate. Findings inform the reproducibility literature and emphasize the need for continued evaluation of task reliability.

Intra-subject variation in reaction time (ISVRT) is a developmentally-important phenomenon that decreases from childhood through young adulthood in parallel with the development of executive functions and networks. Prior work has shown a significant association between trial-by-trial variations in reaction time (RT) and trial-by-trial variations in brain activity as measured by the blood-oxygenated level-dependent (BOLD) response in functional magnetic resonance imaging (fMRI) studies. It remains unclear, however, whether such “RT-BOLD” relationships vary with age. Here, we determined whether such trial-by-trial relationships vary with age in a cross-sectional design. We observed an association between age and RT-BOLD relationships in 11 clusters located in visual/occipital regions, frontal and parietal association cortex, precentral/postcentral gyrus, and thalamus. Some of these relationships were negative, reflecting increased BOLD associated with decreased RT, manifesting around the time of stimulus presentation and positive several seconds later. Critically for present purposes, all RT-BOLD relationships increased with age. Thus, RT-BOLD relationships may reflect robust, measurable changes in the brain-behavior relationship across development.

Social anxiety disorder typically begins in adolescence, a sensitive period for brain development, when increased complexity and salience of peer relationships requires novel forms of social learning. Disordered social learning in adolescence may explain how brain dysfunction promotes social anxiety. Socially anxious adolescents (n = 15) and adults (n = 19) and non-anxious adolescents (n = 24) and adults (n = 32) predicted, then received, social feedback from high and low-value peers while undergoing functional magnetic resonance imaging (fMRI). A surprise recall task assessed memory biases for feedback. Neural correlates of social evaluation prediction errors (PEs) were assessed by comparing engagement to expected and unexpected positive and negative feedback. For socially anxious adolescents, but not adults or healthy participants of either age group, PEs elicited heightened striatal activity and negative fronto-striatal functional connectivity. This occurred selectively to unexpected positive feedback from high-value peers and corresponded with impaired memory for social feedback. While impaired memory also occurred in socially-anxious adults, this impairment was unrelated to brain-based PE activity. Thus, social anxiety in adolescence may relate to altered neural correlates of PEs that contribute to impaired learning about social feedback. Small samples necessitate replication. Nevertheless, results suggest that the relationship between learning and fronto-striatal function may attenuate as development progresses.

The striatum codes motivated behavior. Delineating age-related differences within striatal circuitry can provide insights into neural mechanisms underlying ontogenic behavioral changes and vulnerabilities to mental disorders. To this end, a dual ventral/dorsal model of striatal function was examined using resting state intrinsic functional connectivity (iFC) imaging in 106 healthy individuals, ages 9–44. Broadly, the dorsal striatum (DS) is connected to prefrontal and parietal cortices and contributes to cognitive processes; the ventral striatum (VS) is connected to medial orbitofrontal and anterior cingulate cortices, and contributes to affective valuation and motivation. Findings revealed patterns of age-related changes that differed between VS and DS iFCs. We found an age-related increase in DS iFC with posterior cingulate cortex (pCC) that stabilized after the mid-twenties, but a decrease in VS iFC with anterior insula (aIns) and dorsal anterior cingulate cortex (dACC) that persisted into mid-adulthood. These distinct developmental trajectories of VS vs. DS iFC might underlie adolescents’ unique behavioral patterns and vulnerabilities to psychopathology, and also speaks to changes in motivational networks that extend well past 25 years old.

Youth with bipolar disorder (BD) and those with severe, non-episodic irritability (severe mood dysregulation, SMD) show face-emotion labeling deficits. These groups differ from healthy volunteers (HV) in neural responses to emotional faces. It is unknown whether awareness is required to elicit these differences. We compared activation in BD (N = 20), SMD (N = 18), and HV (N = 22) during “Aware” and “Non-aware” priming of shapes by emotional faces. Subjects rated how much they liked the shape. In aware, a face (angry, fearful, happy, neutral, blank oval) appeared (187 ms) before the shape. In non-aware, a face appeared (17 ms), followed by a mask (170 ms), and shape. A Diagnosis-by-Awareness-by-Emotion ANOVA was not significant. There were significant Diagnosis-by-Awareness interactions in occipital regions. BD and SMD showed increased activity for non-aware vs. aware; HV showed the reverse pattern. When subjects viewed angry or neutral faces, there were Emotion-by-Diagnosis interactions in face-emotion processing regions, including the L precentral gyrus, R posterior cingulate, R superior temporal gyrus, R middle occipital gyrus, and L medial frontal gyrus. Regardless of awareness, BD and SMD differ in activation patterns from HV and each other in multiple brain regions, suggesting that BD and SMD are distinct developmental mood disorders.

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.

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.