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Aberrant microstructure of the uncinate fasciculus (UNC), a white matter (WM) tract implicated in emotion regulation, has been hypothesized as a neurobiological mechanism of depression. However, studies testing this hypothesis have yielded inconsistent results. The present meta-analysis consolidates evidence from 44 studies comparing fractional anisotropy (FA) and radial diffusivity (RD), two metrics characterizing WM microstructure, of the UNC in individuals with depression (n = 5016) to healthy individuals (n = 18 425). We conduct meta-regressions to identify demographic and clinical characteristics that contribute to cross-study heterogeneity in UNC findings. UNC FA was reduced in individuals with depression compared to healthy individuals. UNC RD was comparable between individuals with depression and healthy individuals. Comorbid anxiety explained inter-study heterogeneity in UNC findings. Depression is associated with perturbations in UNC microstructure, specifically with respect to UNC FA and not UNC RD. The association between depression and UNC microstructure appears to be moderated by anxiety. Future work should unravel the cellular mechanisms contributing to aberrant UNC microstructure in depression; clarify the relationship between UNC microstructure, depression, and anxiety; and link UNC microstructure to psychological processes, such as emotion regulation.

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.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 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.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.

Objective Childhood irritability, operationalized as disproportionate and frequent temper tantrums and low frustration tolerance relative to peers, is a transdiagnostic symptom across many pediatric disorders. Studies using task-dependent functional magnetic resonance imaging (fMRI) to probe neural dysfunction in irritability have increased. However, an integrated review summarizing the published methods and synthesized fMRI results remains lacking. Method We conducted a systematic search using irritability terms and task functional neuroimaging in key databases in March 2021, and identified 30 studies for our systematic review. Sample characteristics and fMRI methods were summarized. A subset of 28 studies met the criteria for extracting coordinate-based data for quantitative meta-analysis. Ten activation-likelihood estimations were performed to examine neural convergence across irritability measures and fMRI task domains. Results Systematic review revealed small sample sizes (median = 58, mean age range = 8-16 years) with heterogeneous sample characteristics, irritability measures, tasks, and analytical procedures. Meta-analyses found no evidence for neural activation convergence of irritability across neurocognitive functions related to emotional reactivity, cognitive control, and reward processing, or within each domain. Sensitivity analyses partialing out variances driven by heterogeneous tasks, irritability measures, stimulus types, and developmental ages all yielded null findings. Results were compared with a review on irritability-related structural anomalies from 11 studies. Conclusion The lack of neural convergence suggests a need for common, standardized irritability assessments and more homogeneous fMRI tasks. Thoughtfully designed fMRI studies probing commonly defined neurocognitive functions may be more fruitful to elucidate the neural mechanisms of irritability. Open science practices, data mining in large neuroscience databases, and standardized analytical methods promote meaningful collaboration in irritability research.

BackgroundIrritability, which can be defined as proneness to anger that can reach a pathological extent, is one of the most common reasons youth present for psychiatric evaluation and care. Aberrant responses to frustrative non-reward (FNR, the response to omission of an expected reward) are central to the pathophysiology of irritability. FNR is a cross-species RDoC construct. The development of preclinical FNR models could advance mechanistic studies of the important, and relatively understudied, clinical phenomenon of irritability.MethodsWe used FNR, a translational construct across species, as a conceptual framework for a novel behavioral paradigm (Alternate Poking Reward Omission, APRO) in mice. After APRO, mice were examined with a battery of behavioral tests to determine the effects of frustration. Also, whole brain imaging of c-Fos expression was used to identify brain regions activated by FNR.ResultsMice, regardless of sex, increased locomotion, and aggression towards conspecifics after APRO. There was no change in anxiety-like, depression-like, or non-aggressive social behaviors. APRO causes activation of 13 regions in the prelimbic, ACC, hippocampus, dorsal thalamus, cuneiform nucleus, pons, and pallidum areas, and shifts the brain network towards a more global processing mode.ConclusionOur novel FNR paradigm produces a frustration effect and alters brain processing in ways resembling the symptoms and brain network reconfiguration observed in youth with severe irritability. The novel behavioral paradigm and brain regions identified to be selectively activated by it lay the groundwork for further mechanistic studies of frustration and irritability in rodents.

Objective Irritability is a common characteristic in ADHD. We examined whether dysfunction in neural connections supporting threat and reward processing was related to irritability in adolescents and young adults with ADHD. Method We used resting-state fMRI to assess connectivity of amygdala and nucleus accumbens seeds in those with ADHD ( n = 34) and an age- and gender-matched typically-developing comparison group ( n = 34). Results In those with ADHD, irritability was associated with atypical functional connectivity of both seed regions. Amygdala seeds showed greater connectivity with right inferior frontal gyrus and caudate/putamen, and less connectivity with precuneus. Nucleus accumbens seeds showed altered connectivity with middle temporal gyrus and precuneus. Conclusion The irritability-ADHD presentation is associated with atypical functional connectivity of reward and threat processing regions with cognitive control and emotion processing regions. These patterns provide novel evidence for irritability-associated neural underpinnings in adolescents and young adults with ADHD. The findings suggest cognitive and behavioral treatments that address response to reward, including omission of an expected reward and irritability, may be beneficial for ADHD.

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.

BACKGROUND: Bipolar disorder (BD) is a severe mental disorder, characterized by prominent mood swings and emotion regulation (ER) deficits. The uncinate fasciculus (UF), a white matter tract connecting the amygdala and the ventral prefrontal cortex, has been implicated in ER. Aberrancies in UF microstructure may be an endophenotype associated with increased risk for BD. However, findings in individuals with BD and their first-degree relatives (REL) have yielded inconsistent findings. This meta-analysis takes a region-of-interest approach to consolidate the available evidence and elucidate the role of the UF in the risk-architecture of BD. METHODS: Using web-based search engines, we identified diffusion tensor imaging (DTI) studies focusing on the left and right UF and conducted meta-analyses comparing fractional anisotropy (FA) and radial diffusivity (RD) between BD or REL and healthy control participants (HC). RESULTS: We included 32 studies (n(BD)=1186, n(REL)=289, n(HC)=2315). Compared to HC, individuals with BD showed lower FA in the right (WMD=−0.31, p

Irritability, characterized by a tendency to exhibit increased anger, is a common clinical problem in youth. This study investigated relationships among irritability, selective impairment in process of facial emotion, and neural responses in amygdala in youth with irritability during implicit emotion processing task under functional MRI (fMRI). Fifty-nine youths with disruptive mood and behavior disorder completed a facial expression processing task with an event-related fMRI paradigm. We found a positive relationship between irritability and RT difference between negative (fear) and positive (happiness) facial expressions. Increased irritability was associated with a longer reaction time toward positive vs. negative facial expressions. Irritability was also positively associated with the difference of 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. We 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.

Background: Social reticence in early childhood is characterized by shy and anxiously avoidant behavior, and it confers risk for pediatric anxiety disorders later in development. Aberrant threat processing may play a critical role in this association between early reticent behavior and later psychopathology. The goal of this longitudinal study is to characterize developmental trajectories of neural mechanisms underlying threat processing and relate these trajectories to associations between early-childhood social reticence and adolescent anxiety. Methods: In this 16-year longitudinal study, social reticence was assessed from 2 to 7 years of age; anxiety symptoms and neural mechanisms during the dot-probe task were assessed at 10, 13, and 16 years of age. The sample included 144 participants: 71 children provided data at age 10 (43 girls, meanage = 10.62), 85 at age 13 (46 girls, meanage = 13.25), and 74 at age 16 (36 girls, meanage = 16.27). Results: A significant interaction manifested among social reticence, anxiety symptoms, and time, on functional connectivity between the left amygdala and the left dorsolateral prefrontal cortex, voxelwise p < .001, clusterwise familywise error p < .05. Children with high social reticence showed a negative association between amygdala–dorsolateral prefrontal cortex connectivity and anxiety symptoms with age, compared to children with low social reticence, suggesting distinct neurodevelopmental pathways to anxiety. Conclusions: These findings were present across all conditions, suggesting task-general effects in potential threat processing. Additionally, the timing of these neurodevelopmental pathways differed for children with high versus low social reticence, which could affect the timing of effective preventive interventions.

Irritability is a transdiagnostic symptom dimension in developmental psychopathology, closely related to the Research Domain Criteria (RDoC) construct of frustrative nonreward. Consistent with the RDoC framework and calls for transdiagnostic, developmentally-sensitive assessment methods, we report data from a smartphone-based, naturalistic ecological momentary assessment (EMA) study of irritability. We assessed 109 children and adolescents (Mage = 12.55 years; 75.20% male) encompassing several diagnostic groups – disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), anxiety disorders (ANX), healthy volunteers (HV). The participants rated symptoms three times per day for 1 week. Compliance with the EMA protocol was high. As tested using multilevel modeling, EMA ratings of irritability were strongly and consistently associated with in-clinic, gold-standard measures of irritability. Further, EMA ratings of irritability were significantly related to subjective frustration during a laboratory task eliciting frustrative nonreward. Irritability levels exhibited an expected graduated pattern across diagnostic groups, and the different EMA items measuring irritability were significantly associated with one another within all groups, supporting the transdiagnostic phenomenology of irritability. Additional analyses utilized EMA ratings of anxiety as a comparison with respect to convergent validity and transdiagnostic phenomenology. The results support new measurement tools that can be used in future studies of irritability and frustrative nonreward.

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

Objective: A preliminary investigation of the impact of a serotonergic agent (fluoxetine) on symptom profile and neural response in youths with disruptive behavior disorders (DBDs) and a history of trauma exposure. Methods: There were three participant groups: (i) Youths with DBDs and trauma exposure who received fluoxetine treatment for 8 weeks (n = 11); (ii) A matched group of youths with DBDs and trauma exposure who received routine regular follow-up in an outpatient clinic (n = 10); and (iii) Typically developing youths (n = 18). All participants conducted an expression processing functional magnetic resonance imaging task twice, 8 weeks apart: (pretreatment and post-treatment for youths with DBDs). Results: Youths with DBDs and trauma exposure who received fluoxetine treatment compared to the other two groups showed: (i) significant improvement in externalizing, oppositional defiant disorder, irritability, anxiety-depression, and trauma-related symptoms; (ii) as a function of fearful expression intensity, significantly decreased amygdala response and increased recruitment of regions implicated in top-down attention control (insula cortex, inferior parietal lobule, and postcentral gyrus) and emotional regulation (ventromedial prefrontal cortex [vmPFC]); and (iii) correlation between DBD/irritability symptom improvement and increased activation of top-down attention control areas (inferior parietal lobule, insula cortex, and postcentral gyrus) and an emotion regulation area (vmPFC). Conclusions: This study provides preliminary evidence that a serotonergic agent (fluoxetine) can reduce disruptive behavior and mood symptoms in youths with DBDs and trauma exposure and that this may be mediated by enhanced activation of top-down attention control and emotion regulation areas (inferior parietal lobule, insula cortex, and vmPFC).

Neuroimaging studies point to neurostructural abnormalities in youth with anxiety disorders. Yet, findings are based on small-scale studies, often with small effect sizes, and have limited generalizability and clinical relevance. These issues have prompted a paradigm shift in the field towards highly powered (i.e., big data) individual-level inferences, which are data-driven, transdiagnostic, and neurobiologically informed. Here, we built and validated neurostructural machine learning (ML) models for individual-level inferences based on the largest-ever multi-site neuroimaging sample of youth with anxiety disorders (age: 10-25 years, N=3,343 individuals from 32 global sites), as compiled by three ENIGMA Anxiety Working Groups: Panic Disorder (PD), Generalized Anxiety Disorder (GAD), and Social Anxiety Disorder (SAD). ML classifiers were trained on MRI-derived regional measures of cortical thickness, surface area, and subcortical volumes to classify patients and healthy controls (HC) for each anxiety disorder separately and across disorders (transdiagnostic classification). Modest, yet robust, classification performance was achieved for PD vs. HC (AUC=0.62), but other disorder-specific and transdiagnostic classifications were not significantly different from chance. However, above chance-level transdiagnostic classifications were obtained in exploratory subgroup analyses of male patients vs. male HC, unmedicated patients vs. HC, and patients with low anxiety severity vs. HC (AUC 0.59-0.63). The above chance-level classifications were based on plausible and specific neuroanatomical features in fronto-striato-limbic and temporo-parietal regions. This study provides a realistic estimate of classification performance in a large, ecologically valid, multi-site sample of youth with anxiety disorders, and may as such serve as a benchmark.

This commentary focuses on irritability, one subtype of emotion dysregulation. We review literature demonstrating that irritability is not a developmental phenotype of bipolar disorder, but is longitudinally associated with unipolar depression and anxiety and genetically associated with unipolar depression, anxiety, and attention-deficit hyperactivity disorder. We describe how irritability is amenable to translational research, in part because of the relevance of frustrative nonreward, a model developed in rodents, to human irritability. Last, we demonstrate how such research has suggested a novel exposure-based intervention for irritability.

Objective: The Affective Reactivity Index (ARI) is widely used to assess young people’s irritability symptoms, but youth and caregivers often diverge in their assessments. Such informant discrepancy might stem from poor reliability. However, evidence from genetic, imaging and treatment studies suggests that irritability may not be a unitary construct. Hence informants might be sensitive to different aspects of irritability. We use an out-of-sample replication approach and a longitudinal design to test these hypotheses. Method: Across two independent samples (N1=765, 8-21 years; N2=1910, 6-21 years), we investigate the reliability and measurement invariance of the ARI, examine sociodemographic and clinical predictors of discrepant reporting, and probe the utility of a bifactor model for cross-informant integration. Results: Despite good internal consistency and 6-week-retest-reliability of parent and youth forms, we confirm substantial informant discrepancy in ARI ratings, which is stable over six weeks (n1=177). Measurement invariance across informants was weak, indicating that parents and youth may interpret ARI items differently. Informant-discrepancy increased with irritability severity, but which informant reported higher child-irritability depended on the child’s diagnostic status. In both datasets, a bifactor model parsing informant-specific from shared irritability-related variance fit the data well. Conclusion: Parent and youth ARI reports and their discrepancy are reliable. However, parent and youth ratings may reflect different interpretations of the scale items; hence they should not be averaged. Our findings suggest that irritability is not a unitary construct. Future work should investigate and model different aspects of irritability, which might be more accessible to specific informants.

While it is normal to be scared of things, some children are so scared that it disrupts their lives. This is called an anxiety disorder. To help children with anxiety disorders, we need to know how anxiety disorders start. From other research we knew that toddlers who avoid new situations are more likely to become anxious later in life. They are more likely, which does not mean they all become more anxious, just some of them. We wanted to know if brain activity could predict which children would become anxious. We studied avoidance in toddlers and invited them back as preteens. We studied their brains while they were resting and while they were making mistakes in front of somebody else. We found that brain responses to mistakes predicted which avoidant toddlers became very anxious as preteens. This helps us understand who might develop anxiety, so that we can help!

Prior work on has demonstrated that irritability and anxiety are associated with bullying perpetration and victimization, respectively. Even though symptoms of irritability and anxiety often occur concurrently, few studies have tested their interactive effects on perpetration or victimization. The current study recruited 131 youths from a broader program of research that examines the pathophysiology and treatment of pediatric irritability and anxiety. Two moderation tests were performed to examine concurrent irritability and anxiety symptoms and their relation to perpetration and victimization of bullying. More severe anxiety was associated with greater victimization. However, more severe irritability was associated with, not just greater perpetration, but also greater victimization. An irritability-by-anxiety interaction demonstrated that youths with more severe irritability and lower levels of anxiety engaged in more perpetration. Our findings suggest a more nuanced approach to understanding how the commonly comorbid symptoms of irritability and anxiety interact in relation to peer-directed behavior in youths.

Aberrant decision-making characterizes various pediatric psychopathologies; however, deliberative choice strategies have not been investigated. A transdiagnostic sample of 95 youths completed a child-friendly sequential sampling paradigm. Participants searched for the best offer by sampling a finite list of offers. Participants’ willingness to explore was measured as the number of offers sampled, and ideal task performance was modeled using a Markov decision-process model. As in previous findings in adults, youths explored more offers when lists were long compared with short, yet participants generally sampled fewer offers relative to model-estimated ideal performance. Searching deeper into the list was associated with choosing better price options. Analyses examining the main and interactive effects of transdiagnostic anxiety and irritability symptoms indicated a negative correlation between anxiety and task performance ( p = .01, η p2 = .08). Findings suggest the need for more research on exploratory decision impairments in youths with anxiety symptoms.

Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We test whether the 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. BI was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, electroencephalogram (EEG) was recorded while children performed a flanker task to measure the 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 a 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.

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.

Irritability cuts across many pediatric disorders and is a common presenting complaint in child psychiatry; however, its neural mechanisms remain unclear. One core pathophysiological deficit of irritability is aberrant responses to frustrative nonreward. Here, we conducted a preliminary fMRI study to examine the ability of functional connectivity during frustrative nonreward to predict irritability in a transdiagnostic sample. This study included 69 youths (mean age = 14.55 years) with varying levels of irritability across diagnostic groups: disruptive mood dysregulation disorder (n = 20), attention-deficit/hyperactivity disorder (n = 14), anxiety disorder (n = 12), and controls (n = 23). During fMRI, participants completed a frustrating cognitive flexibility task. Frustration was evoked by manipulating task difficulty such that, on trials requiring cognitive flexibility, “frustration” blocks had a 50% error rate and some rigged feedback, while “nonfrustration” blocks had a 10% error rate. Frustration and nonfrustration blocks were randomly interspersed. Child and parent reports of the affective reactivity index were used as dimensional measures of irritability. Connectome-based predictive modeling, a machine learning approach, with tenfold cross-validation was conducted to identify networks predicting irritability. Connectivity during frustration (but not nonfrustration) blocks predicted child-reported irritability (ρ = 0.24, root mean square error = 2.02, p = 0.03, permutation testing, 1000 iterations, one-tailed). Results were adjusted for age, sex, medications, motion, ADHD, and anxiety symptoms. The predictive networks of irritability were primarily within motor-sensory networks; among motor-sensory, subcortical, and salience networks; and between these networks and frontoparietal and medial frontal networks. This study provides preliminary evidence that individual differences in irritability may be associated with functional connectivity during frustration, a phenotype-relevant state.

Objectives: Temporal reward discounting impulsivity (TDI) reflects a propensity to choose smaller immediate rather than larger delayed rewards relative to age/IQ-matched peers. Previous work with adults has linked TDI to an increased risk for antisocial behavior but also psychopathology in general. However, little work has examined TDI in adolescents with conduct disorder (CD), or considered whether TDI might be associated dimensionally with traits associated with antisocial behavior, that is, impulsivity, irritability, and/or callous–unemotional traits. In this study TDI was investigated in a large adolescent group with varying levels of antisocial behavior. Methods: Participants consisted of 195 adolescents (67 with CD, 77 in a psychiatric comparison group and 51 typically developing adolescents). Participants performed a temporal discounting task and individual differences were measured through the Connors rating scale for attention-deficit/hyperactivity disorder (impulsivity), Affective Reactivity Index (irritability), and Inventory of Callous–Unemotional traits. Results: The adolescents with CD and those in the psychiatric comparison group showed significantly greater TDI than typically developing adolescents. However, these group differences were abolished when dimensional covariates were included. Irritability was significantly associated with TDI. Conclusions: We conclude that TDI reflects a transdiagnostic form of dysfunction that particularly manifests in adolescents with increased irritability.

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.

Objectives Frustration is associated with impaired attention, heightened arousal, and greater unhappiness in youths with bipolar disorder (BD) vs. healthy volunteers (HV). Little is known about functional activation and connectivity in the brain of BD youths in response to frustration. This exploratory study compared BD youths and HV on attentional abilities, self-reported affect, and functional activation and connectivity during a frustrating attention task. Methods 20 BD (Mage =15.86) and 20 HV (Mage =15.55) youths completed an fMRI paradigm that differentiated neural responses during processing of frustrating feedback from neural responses during attention orienting following frustrating feedback. We examined group differences in (1) functional connectivity using amygdala, inferior frontal gyrus (IFG), and striatum as seeds and (2) whole-brain and regions of interest (amygdala, IFG, striatum) activation. We explored task performance (accuracy, reaction time), self-reported frustration and unhappiness, and correlations between these variables and irritability, depressive, and manic symptoms. Results BD youths, relative to HV, exhibited positive IFG-ventromedial prefrontal cortex (vmPFC) connectivity yet failed to show negative striatum-insula connectivity during feedback processing. Irritability symptoms were positively associated with striatum-insula connectivity during feedback processing. Moreover, BD vs. HV youths showed positive IFG-parahippocampal gyrus (PHG)/periaqueductal gray (PAG) connectivity and negative amygdala-cerebellum connectivity during attention orienting following frustration. BD was not associated with atypical activation patterns. Conclusions Positive IFG-vmPFC connectivity and striatum-insula decoupling in BD during feedback processing may mediate heightened sensitivity to reward-relevant stimuli. Elevated IFG-PAG/PHG connectivity in BD following frustration may suggest greater recruitment of attention network to regulate arousal and maintain goal-directed behavior.

Although both pediatric and adult patients with anxiety disorders exhibit similar neural responding to threats, age-related differences have been found in some functional MRI (fMRI) studies. To reconcile disparate findings, the authors compared brain function in youths and adults with and without anxiety disorders while rating fear and memory of ambiguous threats.Two hundred medication-free individuals ages 8-50 were assessed, including 93 participants with an anxiety disorder. Participants underwent discriminative threat conditioning and extinction in the clinic. Approximately 3 weeks later, they completed an fMRI paradigm involving extinction recall, in which they rated their levels of fear evoked by, and their explicit memory for, morph stimuli with varying degrees of similarity to the extinguished threat cues.Age moderated two sets of anxiety disorder findings. First, as age increased, healthy subjects compared with participants with anxiety disorders exhibited greater amygdala-ventromedial prefrontal cortex (vmPFC) connectivity when processing threat-related cues. Second, age moderated diagnostic differences in activation in ways that varied with attention and brain regions. When rating fear, activation in the vmPFC differed between the anxiety and healthy groups at relatively older ages. In contrast, when rating memory for task stimuli, activation in the inferior temporal cortex differed between the anxiety and healthy groups at relatively younger ages.In contrast to previous studies that demonstrated age-related similarities in the biological correlates of anxiety disorders, this study identified age differences. These findings may reflect this study's focus on relatively late-maturing psychological processes, particularly the appraisal and explicit memory of ambiguous threat, and inform neurodevelopmental perspectives on anxiety.