Search

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.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, hammering version after version into shape. Acknowledging these biases, here are the 2022 articles that we think deserve your attention or at least a second read.

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.

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.

Typical FMRI analyses assume a canonical hemodynamic response function (HRF) with a focus on the overshoot peak height, while other morphological aspects are largely ignored. Thus, in most reported analyses, the overall effect is reduced from a curve to a single scalar. Here, we adopt a data-driven approach to HRF estimation at the whole-brain voxel level, without assuming a response profile at the individual level. Then, we estimate the response in its entirety with a roughness penalty at the population level to improve predictive accuracy, inferential efficiency, and cross-study reproducibility. Using a fast event-related FMRI dataset, we demonstrate the extent of under-fitting and information loss that occurs when adopting the canonical approach. We also address the following questions:How much does the HRF shape vary across regions, conditions, and groups?Does an agnostic approach improve sensitivity to detect an effect compared to an assumed HRF?Can examining HRF shape help validate the presence of an effect complementing statistical evidence?Could the HRF shape provide evidence for whole-brain BOLD response during a simple task?

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.

Emotion dysregulation, understood as a critical transdiagnostic factor in the etiology and maintenance of psychopathology, is among the most common reasons youth are referred for psychiatric care. The present systematic review examines two decades of questionnaires used to assess emotion (dys)regulation in youth.Using "emotion (dys)regulation," we searched PsycINFO, PubMed, and Web of Science for empirical, peer-reviewed journal studies published prior to May 2021 in clinical and/or non-clinical youth. A total of 510 studies met selection criteria and were included.Across the literature, 115 distinct self-, parent-, or other -informant-reported measures of emotion (dys)regulation were used in cross-sectional (67.1%), longitudinal (22.4%), intervention (9.0%), and mixed design (1.6%) studies. Out of 115 different questionnaires, a subset of just five measures of emotion (dys)regulation were used in most of the literature (i.e., 59.6% of studies). Moreover, reviewed studies examined emotion (dys)regulation in over 20 distinct clinical groups, further supporting emotion dysregulation as a transdiagnostic construct.Numerous themes emerged. Broadly, we found that measures differ in their ability to capture: internal versus external components of emotion dysregulation; the use of adaptive versus maladaptive responses; and subjective experiences more broadly versus particular affective states. These findings serve to guide researchers and clinicians in selecting appropriate measurement tools for assessing specific domains of child and adolescent emotion dysregulation.

Research on the assessment, diagnosis, and treatment of clinically impairing irritability in children and adolescents has increased dramatically over the past several decades.

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

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.

Objective Computational models provide information about cognitive components underlying behavior. When applied to psychopathology-relevant processes, they offer additional insight to observed differences in behavioral performance. Drift diffusion models have been successfully applied to investigate processing efficiency during binary choice tasks. Using these models, we examine the association between psychopathology (irritability and inattention/hyperactivity) and processing efficiency under different attentional demands. Method A total of 187 youths with attention-deficit/hyperactivity disorder (ADHD), disruptive mood dysregulation disorder (DMDD), both disorders, or no major psychopathology (age, mean ± SD, 13.09 ± 2.55 y, 34% female) completed an Eriksen Flanker task. Of these, 87 youths provided complete data on dimensional measures of the core symptom of DMDD (irritability) and those of ADHD (inattention and hyperactivity). Results In a categorical diagnosis-based analysis (n = 187), we found significant interactive effects among ADHD, DMDD, and task condition on processing efficiency, whereby changes in processing efficiency between conflict and nonconflict conditions were larger in youths without psychopathology compared with patients. Analysis of symptom severity (n = 87) across diagnoses similarly revealed an interaction between symptom dimensions and task condition on processing efficiency. Irritability moderated the magnitude of association between inattention symptoms and difference in processing efficiency between conflict and nonconflict conditions. Conclusion Adapting processing efficiency to cognitive demands may represent a shared cognitive endophenotype for both ADHD and DMDD. Highly irritable and/or inattentive youth may have difficulty adjusting processing efficiency to changing task demands, possibly reflecting impairments in cognitive flexibility.

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.

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.

The COVID-19 pandemic is a chronically stressful event, particularly for youth. Here, we examine (i) changes in mood and anxiety symtpoms, (ii) pandemic-related stress as a mediator of change in symptoms, and (ii) threat processing biases as a predictor of increased anxiety during the pandemic. A clinically well-characterized sample of 81 youth ages 8–18 years (M = 13.8 years, SD = 2.65; 40.7% female) including youth with affective and/or behavioral psychiatric diagnoses and youth without psychopathology completed pre- and during pandemic assessments of anxiety and depression and COVID-related stress. Forty-six youth also completed a threat processing fMRI task pre-pandemic. Anxiety and depression significantly increased during the pandemic (all ps Fs(1.95,81.86) > 14.44, ps

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.

Objectives Bipolar disorder (BD) and familial risk for BD have been associated with aberrant white matter (WM) microstructure in the corpus callosum and fronto-limbic pathways. These abnormalities might constitute trait or state marker and have been suggested to result from aberrant maturation and to relate to difficulties in emotion regulation. Methods To determine whether WM alterations represent a trait, disease or resilience marker, we compared youth at risk for BD (n = 36 first-degree relatives, REL) to youth with BD (n = 36) and healthy volunteers (n = 36, HV) using diffusion tensor imaging. Results Individuals with BD and REL did not differ from each other in WM microstructure and, compared to HV, showed similar aberrations in the superior corona radiata (SCR)/corticospinal tract (CST) and the body of the corpus callosum. WM microstructure of the anterior CC showed reduced age-related in-creases in BD compared to REL and HV. Further, individuals with BD and REL showed in-creased difficulties in emotion regulation, which were associated with the microstructure of the anterior thalamic radiation. Discussion Alterations in the SCR/CST and the body of the corpus callosum appear to represent a trait marker of BD, whereas changes in other WM tracts seem to be a disease state marker. Our findings also support the role of aberrant developmental trajectories of WM microstructure in the risk architecture of BD, although longitudinal studies are needed to confirm this association. Finally, our findings show the relevance of WM microstructure for difficulties in emotion regulation-a core characteristic of BD.

Objective Despite the clinical importance of chronic and severe irritability, there is a paucity of controlled trials for its pharmacological treatment. Here, we examine the effects of adding citalopram (CTP) to methylphenidate (MPH) in the treatment of chronic severe irritability in youth using a double-blind randomized placebo-controlled design. Method After a lead-in phase of open treatment with stimulant, 53 youth meeting criteria for severe mood dysregulation (SMD) were randomly assigned to receive CTP or placebo (PBO) for 8 weeks. A total of 49 participants, 48 of them (98%) meeting disruptive mood dysregulation disorder (DMDD) criteria, were included in the intent-to-treat analysis. The primary outcome measure was the proportion of response based on improvements of irritability at the week 8 of the trial. Results At the end of the trial, a significantly higher proportion of response was seen in those participants randomly assigned to CTP+MPH compared to PBO+MPH (35% CTP+MPH versus 6% PBO+MPH; odds ratio = 11.70, 95% CI = 2.00−68.16, p = 0.006). However, there were no differences in functional impairment between groups at the end of the trial. No differences were found in any adverse effect between treatment groups, and no trial participant exhibited hypomanic or manic symptoms. Conclusion Adjunctive CTP might be efficacious in the treatment of chronic severe irritability in youth resistant to stimulant treatment alone. Clinical trial registration information A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation; https://clinicaltrials.gov ; NCT00794040 .

BackgroundFrustration, the response to blocked goal attainment, is a universal affective experience, but how the brain embodies frustration is not known. Understanding brain network dynamics during frustration may provide insight into pediatric irritability, one of the most frequent reasons for psychiatric consultation in youth and a risk factor for affective disorders and suicidality.MethodsUsing fMRI, we investigated changes in neural network architecture from a baseline resting-state, through a task that included frustrative nonreward (FNR) and anticipation of new feedback following FNR (FNR+1), to a post-task resting-state in a transdiagnostic sample of 66 youth (33 female, mean age 14 years). Using a train/test/held-out procedure, we aimed to predict past-week irritability from the global efficiency (i.e., Eglob, capacity for parallel information processing) of brain networks before, during, and after frustration.ResultsCompared to pre-task resting state, FNR+1 and the post-state resting state were uniquely associated with a more segregated brain network organization. Nodes that were originally affiliated with the default-mode-temporal-limbic and fronto-parietal networks contributed most to this reconfiguration. Solely Eglob of brain networks that emerged after the frustrating task predicted self- and observer-rated irritability in previously unseen data. Self-reported irritability was predicted by Eglob of a fronto-temporal-limbic module, while observer-rated irritability was predicted by Eglob of motor-parietal and ventral-prefrontal-subcortical modules.DiscussionWe characterize frustration as an evolving brain network process and demonstrate the importance of the post-frustration recovery period for the pathophysiology of irritability; an insight that, if replicated, suggests specific intervention targets for irritability.

Assessing and improving test-retest reliability is critical to efforts to address concerns about replicability of task-based functional magnetic resonance imaging. The current study uses two statistical approaches to examine how scanner and task-related factors influence reliability of neural response to face-emotion viewing. Forty healthy adult participants completed two face-emotion paradigms at up to three scanning sessions across two scanners of the same build over approximately 2 months. We examined reliability across the main task contrasts using Bayesian linear mixed-effects models performed voxel-wise across the brain. We also used a novel Bayesian hierarchical model across a predefined whole-brain parcellation scheme and subcortical anatomical regions. Scanner differences accounted for minimal variance in temporal signal-to-noise ratio and task contrast maps. Regions activated during task at the group level showed higher reliability relative to regions not activated significantly at the group level. Greater reliability was found for contrasts involving conditions with clearly distinct visual stimuli and associated cognitive demands (e.g., face vs. nonface discrimination) compared to conditions with more similar demands (e.g., angry vs. happy face discrimination). Voxel-wise reliability estimates tended to be higher than those based on predefined anatomical regions. This work informs attempts to improve reliability in the context of task activation patterns and specific task contrasts. Our study provides a new method to estimate reliability across a large number of regions of interest and can inform researchers' selection of task conditions and analytic contrasts.

Irritability, defined as proneness to anger, is among the most common reasons youth are seen for psychiatric care. Youth with irritability demonstrate aberrant processing of anger-related stimuli; however, the neural mechanisms remain unknown. We applied a drift-diffusion model (DDM), a computational tool, to derive a latent behavioral metric of attentional bias to angry faces in youth with varying levels of irritability during functional magnetic resonance imaging (fMRI). We examined associations among irritability, task behavior using a DDM-based index for preferential allocation of attention to angry faces (i.e., extra-decisional time bias; Δt0), and amygdala context-dependent connectivity during the dot-probe task. Our transdiagnostic sample, enriched for irritability, included 351 youth (ages 8–18; M = 12.92 years, 51% male, with primary diagnoses of either attention deficit/hyperactivity disorder [ADHD], disruptive mood dysregulation disorder [DMDD], an anxiety disorder, or healthy controls). Models accounted for age, sex, in-scanner motion, and co-occurring symptoms of anxiety. Youth and parents rated youth’s irritability using the Affective Reactivity Index. An fMRI dot-probe task was used to assess attention orienting to angry faces. In the angry-incongruent vs. angry-congruent contrast, amygdala connectivity with the bilateral inferior frontal gyrus (IFG), insula, caudate, and thalamus/pulvinar was modulated by irritability level and attention bias to angry faces, Δt0, all ts350 > 4.46, ps t0 was associated with a weaker amygdala connectivity. In contrast, in youth with low irritability, elevated Δt0 was associated with stronger connectivity in those regions. No main effect emerged for irritability. As irritability is associated with reactive aggression, these results suggest a potential neural regulatory deficit in irritable youth who have elevated attention bias to angry cues.

Objectives Irritability is a transdiagnostic symptom in developmental psychopathology, conceptualized as a low threshold for frustration and increased proneness to anger. While central to emotion regulation, there is a vital need for empirical studies to explore the relationship between irritability and underlying physiological mechanisms of cardiovascular arousal. Methods We examined the relationship between irritability and cardiovascular arousal (i.e., heart rate [HR] and heart rate variability [HRV]) in a transdiagnostic sample of 51 youth (M = 12.63 years, SD = 2.25; 62.7% male). Data was collected using the Empatica E4 during a laboratory stop‐signal task. In addition, the impact of motion activity, age, medication, and sleep on cardiovascular responses was explored. Results Main findings showed that irritability was associated with increased HR and decreased HRV during task performance. Conclusions Findings support the role of peripheral physiological dysregulation in youth with emotion regulation problems and suggest the potential use of available wearable consumer electronics as an objective measure of irritability and physiological arousal in a transdiagnostic sample of youth.

Although emotion dysregulation has been defined as a maladaptive process of emotional experiences, there is no specific reference to the emotional valence of the dysregulation. To date, child psychiatry has focused primarily on dysregulation of negative affect. Here, we suggest that positive emotion dysregulation requires additional clinical and research attention.First, we present a developmental approach to the study of positive emotion regulation within a temperament framework. Second, we describe emerging research findings regarding dysregulation of positive emotion in early childhood. Third, we integrate neuroscientific approaches to positive emotion regulation and introduce a framework for future investigations and clinical applications.Dysregulation in positive affect can be examined from temperamental, developmental, clinical, and neuroscientific perspectives. Both temperamental surgency, which includes positive affect, and the proposed clinical extension, excitability, are associated with increased risk of externalizing symptoms and clinical impairment in youth.Studying the role of both temperamental surgency and clinically impairing positive affect, or excitability, in developmental psychopathology will help to elucidate the full spectrum of emotion dysregulation and to clarify the neural basis of dysregulation. A more comprehensive conceptualization of positively valanced emotion dysregulation will provide a more nuanced understanding of developmental risk and potential targets for intervention.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.

The parent-report Affective Reactivity Index (ARI-P) is the most studied brief scale specifically developed to assess irritability, but relatively little is known about its performance in early childhood (i.e., ≤8 years). Support in such populations is particularly important given developmental shifts in what constitutes normative irritability across childhood. We examined the performance of the ARI-P in a diverse, treatment-seeking sample of children ages 3 to 8 years ( N = 115; mean age = 5.56 years; 58.4% from ethnic/racial minority backgrounds). In this sample, confirmatory factor analysis supported the single-factor structure of the ARI-P previously identified with older youth. ARI-P scores showed large associations with another irritability index, as well as small-to-large associations with aggression, anxiety, depression, and attention problems, supporting the convergent and concurrent validity of the ARI-P when used with children in this younger age range. Findings support the ARI-P as a promising parent-report tool for assessing irritability in early childhood, particularly in clinical samples.

Attention bias modification training (ABMT) and cognitive behavioral therapy (CBT) likely target different aspects of aberrant threat responses in anxiety disorders and may be combined to maximize therapeutic benefit. However, studies investigating the effect of ABMT in the context of CBT have yielded mixed results. Here, we propose an enhanced ABMT to target the attentional bias towards threat, in addition to classic CBT for anxiety disorders in youth. This enhanced ABMT integrates the modified dot-probe task used in previous studies, where a target is always presented at the previous location of the neutral and not the simultaneously presented threatening stimulus, with a visual search, where the targets are always presented distally of threatening distractors. These two training elements (modified dot-probe and visual search) are embedded in an engaging game to foster motivation and adherence. Our goal is to determine the efficacy of the enhanced ABMT in the context of CBT. Further, we aim to replicate two previous findings: (a) aberrant amygdala connectivity being the neurobiological correlate of the attentional bias towards threat at baseline; and (b) amygdala connectivity being a mediator of the ABMT effect. We will also explore moderators of treatment response (age, sex, depressive symptoms and irritability) on a behavioral and neuronal level. One hundred and twenty youth (8–17 years old) with a primary anxiety disorder diagnosis all receive CBT and are randomized to nine weeks of either active or control ABMT and symptom improvement will be compared between the two study arms. We will also recruit 60 healthy comparison youth, who along with eligible anxious youth, will be assessed with the dot-probe task during fMRI (anxious youth: before and after training; healthy volunteers: second measurement twelve weeks after initial assessment). The present study will contribute to the literature by (1) potentially replicating that aberrant amygdala connectivity mediates the attentional bias towards threat in anxious youth; (2) determining the efficacy of enhanced ABMT; and (3) advancing our understanding of the mechanisms underlying ABMT. Clinicaltrials.gov: NCT03283930 Trial registration date: September 14th 2017. The trial registration took place retrospectively. Data acquisition started February 1st 2017.

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

OBJECTIVES Little is known about potential differences in the pathophysiology of bipolar disorder (BD) across development. The present study aimed to characterize age-related neural mechanisms of BD. METHODS Youths and adults with and without BD (N = 108, age range = 9.8-55.9 years) completed an emotional face labeling task during fMRI acquisition. We leveraged three different fMRI analytic tools to identify age-related neural mechanisms of BD, investigating (a) change in neural responses over the course of the task, (b) neural activation averaged across the entire task, and (c) amygdala functional connectivity. RESULTS We found converging Age Group × Diagnosis patterns across all three analytic methods. Compared to healthy youths vs adults, youths vs adults with BD show an altered pattern in response to repeated presentation of emotional faces in medial prefrontal, amygdala, and temporoparietal regions, as well as amygdala-temporoparietal connectivity. Specifically, medial prefrontal and lingual activation decreases over the course of repeated emotional face presentations in healthy youths vs adults but increases in youths with BD compared to adults with BD. Moreover, youths vs adults with BD show less medial prefrontal activation and amygdala-temporoparietal junction connectivity averaged over the task, but this difference is not found for healthy youths vs adults. CONCLUSION Although longitudinal confirmation and replication will be necessary, these findings suggest that neural development may be aberrant in BD and that some neural mechanisms mediating BD may differ in adults vs children with the illness.

Background Callous-Unemotional (CU) and psychopathic traits are consistently associated with impaired recognition of others' emotions, specifically fear and sadness. However, no studies have examined whether the association between CU traits and emotion recognition deficits is due primarily to genetic or environmental factors. Methods The current study used data from 607 Caucasian twin pairs (N = 1,214 twins) to examine the phenotypic and genetic relationship between the Inventory of Callous-Unemotional Traits (ICU) and facial emotion recognition assessed via the laboratory-based Facial Expression Labeling Task (FELT). Results The uncaring/callous dimension of the ICU was significantly associated with impaired recognition of happiness, sadness, fear, surprise, and disgust. The unemotional ICU dimension was significantly associated with improved recognition of surprise and disgust. Total ICU score was significantly associated with impaired recognition of sadness. Significant genetic correlations were found for uncaring/callous traits and distress cue recognition (i.e. fear and sadness). The observed relationship between uncaring/callous traits and deficits in distress cue recognition was accounted for entirely by shared genetic influences. Conclusions The results of the current study replicate previous findings demonstrating impaired emotion recognition among youth with elevated CU traits. We extend these findings by replicating them in an epidemiological sample not selected or enriched for pathological levels of CU traits. Furthermore, the current study is the first to investigate the genetic and environmental etiology of CU traits and emotion recognition, and results suggest genetic influences underlie the specific relationship between uncaring/callous traits and distress cue (fear/sadness) recognition in others.

This study uses novel approaches to examine genetic and environmental influences shared between childhood behavioral inhibition (BI) and symptoms of preadolescent anxiety disorders. Three hundred and fifty-two twin pairs aged 9–13 and their mothers completed questionnaires about BI and anxiety symptoms. Biometrical twin modeling, including a direction-of-causation design, investigated genetic and environmental risk factors shared between BI and social, generalized, panic and separation anxiety. Social anxiety shared the greatest proportion of genetic (20%) and environmental (16%) variance with BI with tentative evidence for causality. Etiological factors underlying BI explained little of the risk associated with the other anxiety domains. Findings further clarify etiologic pathways between BI and anxiety disorder domains in children.

Objective: This study outlines the construction and initial psychometric properties of the Coronavirus Impact Scale in multiple large and diverse samples of families with children and adolescents. The scale was established to capture the impact of the coronavirus pandemic. Differences in impact between samples and internal structure within samples were assessed.Method: Five hundred, seventy-two caregivers of children and adolescents or expecting mothers in diverse clinical and research settings completed the Coronavirus Impact Scale. Samples differed in developmental stage, background, inpatient/outpatient status, and primary research or clinical setting. Model free methods were used to measure the scale’s internal structure and determine a scoring method. Differences between samples in specific item responses were measured by multivariate ordinal regression.Results: The Coronavirus Impact Scale demonstrated good internal consistency in a variety of clinical and research populations. Single, immigrant, predominantly Latinx mothers of young children reported the greatest impact across groups, with elevated impact on food access and finances. Individuals receiving outpatient or inpatient care reported greater impacts on health care access. Impact was positively associated with measures of caregiver anxiety and both caregiver- and child-reported stress at a moderate effect size.Conclusion: The Coronavirus Impact Scale is a publicly available scale with adequate psychometric properties for use in measuring the impact of the coronavirus pandemic in diverse populations.

Mapping individual differences in behavior is fundamental to personalized neuroscience, but quantifying complex behavior in real world settings remains a challenge. While mobility patterns captured by smartphones have increasingly been linked to a range of psychiatric symptoms, existing research has not specifically examined whether individuals have person-specific mobility patterns. We collected over 3000 days of mobility data from a sample of 41 adolescents and young adults (age 17-30 years, 28 female) with affective instability. We extracted summary mobility metrics from GPS and accelerometer data and used their covariance structures to identify individuals and calculated the individual identification accuracy-i.e., their "footprint distinctiveness". We found that statistical patterns of smartphone-based mobility features represented unique "footprints" that allow individual identification (p 0.001). Critically, mobility footprints exhibited varying levels of person-specific distinctiveness (4-99%), which was associated with age and sex. Furthermore, reduced individual footprint distinctiveness was associated with instability in affect (p 0.05) and circadian patterns (p 0.05) as measured by environmental momentary assessment. Finally, brain functional connectivity, especially those in the somatomotor network, was linked to individual differences in mobility patterns (p 0.05). Together, these results suggest that real-world mobility patterns may provide individual-specific signatures relevant for studies of development, sleep, and psychopathology.

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.

Background Anxiety and irritability frequently co-occur in youth and are mediated by aberrant threat responses. However, empirical evidence on neural mechanisms underlying this co-occurrence is limited. To address this, we apply data-driven latent phenotyping to data from a prior report of a well-validated threat extinction recall fMRI paradigm. Methods Participants included 59 youth (28 anxiety disorder, 31 healthy volunteers; Mage=13.15 yrs) drawn from a transdiagnostic sample of 331 youth, in which bifactor analysis was conducted to derive latent factors representing shared vs. unique variance of dimensionally-assessed anxiety and irritability. Participants underwent threat conditioning and extinction. Approximately three weeks later, during extinction recall fMRI, participants made threat-safety discriminations under two task conditions: current threat appraisal and explicit recall of threat contingencies. Linear mixed-effects analyses examined associations of a “negative affectivity” factor reflecting shared anxiety and irritability variance with whole-brain activation and task-dependent amygdala connectivity. Results During recall of threat-safety contingencies, higher negative affectivity was associated with greater prefrontal (ventrolateral/ventromedial, dorsolateral, orbitofrontal), motor, temporal, parietal, and occipital activation. During threat appraisal, higher negative affectivity was associated with greater amygdala-inferior parietal lobule connectivity to threat/safety ambiguity. Limitations Sample included only healthy youth and youth with anxiety disorders. Results may not generalize to other diagnoses for which anxiety and irritability are also common, and our negative affectivity factor should be interpreted as anxiety disorders with elevated irritability. Reliability of some subfactors was poor. Conclusions Aberrant amygdala-prefrontal-parietal circuitry during extinction recall of threat-safety stimuli may be a mechanism underlying the co-occurrence of pediatric anxiety and irritability.

IntroductionIrritability is defined as a tendency towards anger in response to frustration. Clinically, impairing irritability is a significant public health problem. There is a need for mechanism-based psychotherapies targeting severe irritability as it manifests in the context of disruptive mood dysregulation disorder (DMDD). This study protocol describes a randomised multiple baseline design testing the preliminary efficacy of a new treatment, exposure-based cognitive-behavioral therapy for severe irritability in youth, which also integrates components of parent management training. We will investigate associations of this intervention with primary clinical measures, as well as ecological momentary assessment measures.Methods and analysisForty youth will be enrolled. Participants, aged 8–17 years, must present at least one of two core symptoms of DMDD: abnormal mood or increased reactivity to negative emotional stimuli, with severe impairment in one domain (home, school, peers) and moderate in another, or moderate impairment in at least two domains. Each participant is randomised to a 2-week, 4-week or 6-week baseline observation period, followed by 12 active treatment sessions. Clinical ratings are conducted at baseline, biweekly (clinician), weekly (parent/child) throughout treatment, post-treatment, and 3-month and 6-month follow-up (clinician). Clinician ratings on the Affective Reactivity Index and Clinical Global Impressions-Improvement scale for DMDD are our primary outcome measures. Secondary outcome measures include parent and child reports of irritability. Post hoc additional symptom measures include clinician, parent and self-ratings of depression, anxiety and overall functional impairment. Prospective, digitally based event sampling of symptoms is acquired for a week pre-treatment, mid-treatment and post-treatment. Based on our pathophysiological model of irritability implicating frustrative non-reward, aberrant threat processing and instrumental learning, we probe these three brain-based targets using functional MRI paradigms to assess target engagement.Ethics and disseminationThe research project and all related materials were submitted and approved by the appropriate Institutional Review Board (IRB) of the National Institute of Mental Health (NIMH).Trial registration numbersNCT02531893 and NCT00025935.

The concept of test-retest reliability indexes the consistency of a measurement across time. High reliability is critical for any scientific study, but specifically for the study of individual differences. Evidence of poor reliability of commonly used behavioral and functional neuroimaging tasks is mounting. Reports on low reliability of task-based fMRI have called into question the adequacy of using even the most common, well-characterized cognitive tasks with robust population-level effects, to measure individual differences. Here, we lay out a hierarchical framework that estimates reliability as a correlation divorced from trial-level variability, and show that reliability estimates tend to be higher compared to the conventional framework that adopts condition-level modeling and ignores across-trial variability. We examine how estimates from the two frameworks diverge and assess how different factors (e.g., trial and subject sample sizes, relative magnitude of cross-trial variability) impact reliability estimates. We also show that, under specific circumstances, the two statistical frameworks converge. Results from the two approaches are approximately equivalent if (a) the trial sample size is sufficiently large, or (b) cross-trial variability is in the same order of magnitude as, or less than, cross-subject variability. As empirical data indicate that cross-trial variability is large in most tasks, this work highlights that a large number of trials (e.g., greater than 100) may be required to achieve precise reliability estimates. We reference the tools TRR and 3dLMEr for the community to apply trial-level models to behavior and neuroimaging data and discuss how to make these new measurements most useful for current studies.

The concept of test-retest reliability indexes the consistency of a measurement across time. High reliability is critical for any scientific study, but specifically for the study of individual differences. Evidence of poor reliability of commonly used behavioral and functional neuroimaging tasks is mounting. Reports on low reliability of task-based fMRI have called into question the adequacy of using even the most common, well-characterized cognitive tasks with robust population-level effects, to measure individual differences. Here, we lay out a hierarchical framework that estimates reliability as a correlation divorced from trial-level variability, and show that reliability tends to be underestimated under the conventional intraclass correlation framework through summary statistics based on condition-level modeling. In addition, we examine how reliability estimation between the two statistical frameworks diverges and assess how different factors (e.g., trial and subject sample sizes, relative magnitude of cross-trial variability) impact reliability estimates. As empirical data indicate that cross-trial variability is large in most tasks, this work highlights that a large number of trials (e.g., greater than 100) may be required to achieve precise reliability estimates. We reference the tools TRR and 3dLMEr for the community to apply trial-level models to behavior and neuroimaging data and discuss how to make these new measurements most useful for future studies.

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.

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.