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

Abstract

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‐related neural responses to frustrative nonreward in adolescents with trauma histories: A preliminary investigation

“…In addition, across task conditions, youths with greater irritability exhibited hypoactivation and amygdala hypoconnectivity. Overall, our results (both the regions identified as well as the pattern of opposite responses in youths with higher versus lower levels of irritability) are in line with prior work (Deveney et al, 2013;Dougherty et al, 2018;Kryza-Lacombe et al, 2021;Scheinost et al, 2021;Stoddard et al, 2017;Tseng et al, 2019Tseng et al, , 2020Wiggins et al, 2016). As an interesting side note, right and left amygdala networks both evidenced significant associations with irritability, but not in the same regions/task conditions; although our results do not clearly support a particular lateralized view of amygdala function, these asymmetric patterns suggest differing emotional functions for left and right amygdala networks.…”

“…(both the regions identified as well as the pattern of opposite responses in youths with higher versus lower levels of irritability) are in line with prior work (Deveney et al, 2013;Dougherty et al, 2018;Kryza-Lacombe et al, 2021;Scheinost et al, 2021;Stoddard et al, 2017;Tseng et al, 2019Tseng et al, , 2020Wiggins et al, 2016). As an interesting side note, right and left amygdala networks both evidenced significant associations with irritability, but not in the same regions/task conditions;…”

“…However, during our scan of interest, the task was rigged, such that after hitting the target, the reward was now denied 60% of the time (Figure 1; Dougherty et al, 2018). Although previous studies altered attentionorienting/inhibition tasks to provide rigged, monetary feedback (Deveney et al, 2013;Scheinost et al, 2021;Tseng et al, 2019), we F I G U R E 1 fMRI frustration task. In this novel frustration task, a modified version of a child-friendly monetary incentive delay task (Dougherty et al, 2018), participants first saw a cue (piñata dropping for 2000 ms) alerting them that a target (piñata) with possible reward was about to drop.…”

“…First, to our knowledge, only two studies have examined brain connectivity during frustration in youth with irritability. Scheinost et al (2021) demonstrated network connectivity alterations globally, and Tseng et al (2019) found functional connectivity distinctions within inferior frontal gyrus and amygdala networks, yet much remains unknown about specific brain networks, for example, rewardand threat-related, to target for treatment. Second, whereas functional connectivity and activation have been explored in separate studies, there are few depictions of these neural patterns side-by-side to provide complementary information of the underpinnings of frustrative nonreward in irritability.…”

Investigating Neural Substrates of Individual Independence and Interdependence Orientations via Efficiency-Based Dynamic Functional Connectivity: A Machine Learning Approach

“…Shown in Table 2, the XGBoost regression model reached a comparative Furthermore, to demonstrate the superiority of efficiencybased dynamic FC in the presented method over static FC as well as nodal efficiency itself, we performed an experiment by using static rsFC or nodal efficiency on time course to predict individual self-construals under same experiment protocol. Steiger test is performed to compare the significance of dependent correlation coefficients [51,52]. As a result, the zscores of Steiger test between the proposed FC and static FC are 1.036 for IndSC and 2.240 for InterSC.…”