Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth.

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.

A preliminary study on functional activation and connectivity during frustration in youths with bipolar disorder.

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: Twenty 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 (a) functional connectivity using amygdala, inferior frontal gyrus (IFG), and striatum as seeds and (b) 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: Bipolar disorder 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.

A diffusion model analysis of sustained attention in children with attention deficit hyperactivity disorder.

OBJECTIVE: Whether children with attention deficit hyperactivity disorder (ADHD) have deficits in sustained attention remains unresolved due to the ongoing use of cognitive paradigms that are not optimized for studying vigilance and the fact that relatively few studies report performance over time. METHOD: In three independent samples of school-age children with (total N = 128) and without ADHD (total N = 59), we manipulated event rate, difficulty of discrimination, and use signal detection (SDT) and diffusion models (DM) to evaluate the cause of the vigilance decrement during a continuous performance task. RESULTS: For both groups of children, a bias toward "no-go" over time (as indexed by the SDT parameter B″ and the DM parameter z/a) was responsible for generating the vigilance decrement. However, among children with ADHD, the rate at which information accumulated to make a no-go decision (vNoGo) also increased with time on task, representing a possible secondary mechanism that biases children against engagement. At all time points, children with ADHD demonstrated reduced sensitivity to discriminate targets from nontargets. CONCLUSION: Children with ADHD are particularly sensitive to the cost of task engagement, but nonspecific slower drift rate may ultimately provide a better conceptualization of the cognitive atypicalities commonly observed in that group. Results are interpreted in the context of updated conceptualizations of sustained attention and vigilance. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A Double-Blind Randomized Placebo-Controlled Trial of Citalopram Adjunctive to Stimulant Medication in Youth With Chronic Severe Irritability.

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.

Brain Mechanisms of Attention Orienting Following Frustration: Associations With Irritability and Age in Youths.

OBJECTIVE: Childhood irritability is a common, impairing problem with changing age-related manifestations that predict long-term adverse outcomes. However, more investigation of overall and age-specific neural correlates is needed. Because youths with irritability exhibit exaggerated responses to frustrating stimuli, the authors used a frustration functional MRI (fMRI) paradigm to examine associations between irritability and neural activation and tested the moderating effect of age. METHOD: The authors studied a transdiagnostic sample of 195 youths with varying levels of irritability (disruptive mood dysregulation disorder, N=52; anxiety disorder, N=42; attention deficit hyperactivity disorder, N=40; and healthy volunteers, N=61). Irritability was measured by parent and child reports on the Affective Reactivity Index. The fMRI paradigm was a cued-attention task differentiating neural activity in response to frustration (rigged feedback) from activity during attention orienting in the trial following frustration. RESULTS: Whole-brain activation analyses revealed associations with irritability during attention orienting following frustration. Irritability was positively associated with frontal-striatal activation, specifically in the dorsolateral prefrontal cortex, inferior frontal gyrus, and caudate. Age moderated the association between irritability and activation in some frontal and posterior regions (the anterior cingulate cortex, medial frontal gyrus, cuneus, precuneus, and superior parietal lobule [F=19.04-28.51, df=1, 189, partial eta squared=0.09-0.13]). Specifically, higher irritability was more strongly related to increased activation in younger youths compared with older youths. CONCLUSIONS: Following frustration, levels of irritability correlated with activity in neural systems mediating attention orienting, top-down regulation of emotions, and motor execution. Although most associations were independent of age, dysfunction in the anterior cingulate cortex and posterior regions was more pronounced in young children with irritability.