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ObjectiveIrritability 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.MethodWe 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).ResultsIn 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.ConclusionThe 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.

Few studies have examined threat generalization across development and no developmental studies have compared the generalization of social versus nonsocial threat, making it difficult to identify contextual factors that contribute to threat learning across development. The present study assessed youth and adults multivoxel neural representations of social versus nonsocial threat stimuli. Twenty adults (Mage  = 25.7 ± 4.9) and 16 youth (Mage  = 14.1 ± 1.7) completed two conditioning and extinction recall paradigms: one social and one nonsocial paradigm. Three weeks after conditioning, participants underwent a functional magnetic resonance imaging extinction recall task that presented the extinguished threat cue (CS+), a safety cue (CS-), and generalization stimuli (GS) consisting of CS-/CS+ blends. Across age groups, neural activity patterns and self-reported fear and memory ratings followed a linear generalization gradient for social threat stimuli and a quadratic generalization gradient for nonsocial threat stimuli, indicating enhanced threat/safety discrimination for social relative to nonsocial threat stimuli. The amygdala and ventromedial prefrontal cortex displayed the greatest neural pattern differentiation between the CS+ and GS/CS-, reinforcing their role in threat learning and extinction recall. Contrary to predictions, age did not influence threat representations. These findings highlight the importance of the social relevance of threat on generalization across development.

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.

Irritability is common in Attention-Deficit Hyperactivity Disorder (ADHD), but little is known about whether irritability predicts the course of ADHD symptoms over time. Adolescence is a dynamic period of emotional development as well as shifts in ADHD symptoms; an important goal is to identify youth at risk of increasing or persisting symptoms. We examined irritability as a longitudinal predictor of change in adolescents' ADHD symptoms, as well as how this link may differ in females versus males. The sample included 108 youth (72 males) age 12-16 years (M = 14.21 years, SD = 1.44 years), 62 of whom met criteria for ADHD. Approximately 18 months later, 80 participants (48 males) were followed up at Time 2. A dimensional approach was used to examine changes over time in parent-reported inattentive and hyperactive/impulsive symptoms. Longitudinal path analysis revealed that irritability at Time 1 predicted higher relative hyperactive/impulsive symptoms at Time 2 after controlling for age and longitudinal stability in all variables. A multiple-group analysis examining moderation by sex/gender revealed that this association was significant only for females. These results suggest that irritability may play a key role in the persistence and worsening of hyperactive/impulsive symptoms across adolescence for females, with potential implications for the diagnosis and treatment of females with ADHD.

Background: Sleep, or a lack thereof, is strongly related to mood dysregulation. Although considerable research uses symptom scales to examine this relation, few studies use longitudinal, real‐time methods focused on pediatric irritability. This study leveraged an ecological momentary assessment (EMA) protocol, assessing bidirectional associations between momentary irritability symptoms and daily sleep duration in a transdiagnostic pediatric sample enriched for irritability. Methods: A total of N = 125 youth (Mage = 12.58 years, SD = 2.56 years; 74% male; 68.8% White) completed digital, in vivo surveys three times a day for 7 days. For a subset of youth, their parents also completed the EMA protocol. Trait irritability was measured using youth‐, parent‐, and clinician‐report to test its potential moderating effect on the association between sleep duration and momentary irritability. Results: Results from multilevel modeling dynamically linked sleep to irritability. Specifically, according to youth‐ and parent‐report, decreased sleep duration was associated with increased morning irritability (bs ≤ −.09, ps <.049). A bidirectional association between parent‐reported nightly sleep duration and anger was found—increased evening anger related to decreased nightly sleep duration, and decreased sleep duration related to increased morning anger (bs ≤ −.17, ps <.019). Trait irritability moderated this association, which was stronger for more irritable youth (b = −.03, p <.027). Conclusions: This study adds to the literature and suggests sleep‐irritability dynamics as a potential treatment target. [ABSTRACT FROM AUTHOR]

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth. Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat- anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure. Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05). Limitations: Limitations included the modest sample size and the cross-sectional design. Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry., Introduction Anticipation of threat engages conserved neural circuitry that has evolved to facilitate defensive behaviours; (1-3) perturbations in this circuitry could generate excessive anticipatory response, a core element of pathological [...]

BackgroundBipolar disorder (BD) is highly familial, but studies have yet to examine preschoolers at risk for BD using standardized, developmentally appropriate clinical assessment tools. We used such methods to test whether preschoolers at familial risk for BD have more observed difficulty modulating emotions and behaviors than do low-risk preschoolers. Identification of emotional and behavioral difficulties in at-risk preschoolers is crucial for developing new approaches for early intervention and prevention of BD.MethodsUsing the standardized disruptive behavior diagnostic observation schedule (DB-DOS) protocol for preschoolers, we compared 23 preschoolers (M(age): 4.53 ± 0.73 years; 18 males) with a first-degree relative with BD to 21 preschoolers (M(age): 4.65 ± 0.84 years; 11 males) without a family history of BD. We characterized psychopathology in this sample using the Preschool Aged Psychiatric Assessment and behavioral and emotional problems using the Child Behavior Checklist.ResultsHigh-risk preschoolers demonstrated significantly more intense, pervasive, and clinically concerning problems in anger modulation and behavior dysregulation on the DB-DOS than the low-risk group. High-risk relative to low-risk preschoolers, were also more likely to have maternal-reported anxiety and oppositional defiant disorders and internalizing and externalizing problems.ConclusionsClinically concerning problems in anger modulation and behavior regulation, measured during standardized laboratory observation, differentiate preschoolers at high familial risk for BD from those at low risk. Investigation in a large longitudinal sample is critical for replication and for determining whether these observed behavioral differences can be reliably used as prodromal indicators of mood disorders.

Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype.