Mechanisms of Frustration and the Pathophysiology of Severe Irritability in Youth

National Institute Of Mental Health

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Abstract

Given concerns about the appropriate diagnosis for children with chronic, severe irritability, we characterized such youth; this work formed the basis for the new diagnosis of mood dysregulation disorder with dysphoria (DMDD) in DSM-5. Since the inception of this project (ZIA MH002786-17), approximately 600 highly irritable youth have enrolled, along with more than 200 youth with ADHD. (Many DMDD patients have ADHD, and youth with ADHD tend to have less irritability than those with DMDD but more than healthy youth; hence they are an appropriate comparison group.) Approximately 50 new patients were recruited this year. Youth with DMDD suffer severe impairment, in terms of medications received, hospitalizations, and standardized measures of function. Irritability is one of the most common psychiatric symptoms in children, but there has been little brain-based research on it, and there are few evidence-based treatments. In 2017-18, we articulated a testable, heuristic, translational model of irritability that continues to guide our research. The model posits that core deficits in pediatric irritability include aberrant responses to frustration and aberrant approach responses to threat. Aberrant responses to frustration implicate reward learning circuitry dysfunction e.g., instrumental learning deficits that prevent adaptation to changing environmental contingencies, or exaggerated prediction error responses to the omission of an expected reward. Since the original formulation of the model, we have updated it to include evidence suggesting that cognitive control deficits (specifically, deficient inhibitory control) may contribute to maladaptive behavior in response to either frustration or threat. Irritability is well-suited for the transdiagnostic, translational approach of the Research Domain Criteria (RDoC). We characterize irritability as a continuous variable, in DMDD and other groups i.e., anxiety disorders, ADHD. We use frustrating tasks during neuroimaging, since a hallmark of irritability is difficulty tolerating frustration. In a manuscript published in 2019, we used an fMRI frustration paradigm (the affective Posner task) to study 195 youth with DMDD, ADHD, and/or anxiety disorders, as well as healthy youth. We found that irritability is associated with increased prefrontal and striatal engagement when youth attempt an attention orienting task after receiving frustrating feedback. Our plan was to replicate and extend this finding by scanning a new sample of youth with the affective Posner task while also acquiring resting state functional connectivity data immediately before and after the task. This design allows us to study behavioral and neural adaptations during and after frustration, and to test associations between these adaptations and irritability. Thus, we study frustration as a dynamic, evolving, whole-brain network process. While we were not able to scan subjects this year because of the pandemic, we were able to analyze data acquired pre-pandemic in 66 youth. Of note, we also analyzed data acquired pre-pandemic in 50 youth scanned on a second frustration task, the Change task, again with pre- and post-task resting state data. The Change task differs from the affective Posner in the timing of frustration (short blocks of frustration, interspersed randomly with non-frustrating blocks, vs. a long block of non-frustration followed by a long bout of frustration) and in the cognitive task (cognitive flexibility vs. attention orienting). In addition to analyzing the new Change data, this year we published an older study using the Change task that included data from 69 youth with DMDD, anxiety, ADHD or healthy volunteers. In the published study, we used connectome-based predictive modeling, a machine learning approach, to identify networks predicting irritability. Connectivity during frustration (but not non-frustration) blocks predicted child-reported irritability. To analyze data from the two studies using a frustration task (either affective Posner or change) flanked by pre- and post-resting state data, we used a graph theoretical approach. The latter assumes that the brain is organized into complex subnetworks (modules) of brain regions (nodes). When the clustering of nodes into modules changes, network reconfiguration occurs. Two findings emerge from both studies, despite the use of different tasks. First, network reconfiguration occurs during and after frustration, with reconfiguration of frontal-temporal-limbic and fronto-parietal networks being most prominent. Second, the global efficiency (Eglob) of modules formed during and after the paradigm may predict irritability. Eglob indexes the capacity to exchange information among all regions of a network. Both find that Eglob in modules present during resting-state after frustration predicts irritability, highlighting the potential clinical relevance of the post-frustration period. In addition to the affective Posner and change paradigms, we use a third frustration task. This task, Carnival, was designed to test whether irritability is associated with reinforcement learning deficits at baseline and after frustration. Reinforcement learning is the process by which people learn what behaviors will be rewarded. Deficits in such learning could lead to increased frustration in irritable youth. One component of reinforcement learning is prediction error processing i.e., brain signaling indicating a mismatch between an expected and a received reward. Pre-pandemic, we piloted this task in 34 youth in the scanner and obtained both the expected frustration and expected brain activation associated with prediction error processing. If irritability is associated with instrumental learning deficits, this would have direct treatment implications. Our translational model posits that aberrant responses to both threat and frustration are important core mechanisms in irritability. Therefore, we were interested in investigating associations among brain networks mediating these two psychological processes. This year we analyzed data in 307 youth (DMDD, anxiety, ADHD, healthy) who completed a threat-attention task and/or the affective Posner frustration task. We used canonical correlation analysis to integrate brain activity during these two separate fMRI tasks. We found that activity in networks mediating frustration and threat were significantly correlated but largely anatomically distinct. We also found associations between parent-rated irritability and activity on the AP task in default mode and motor networks. This work is being prepared for publication. Our increased recruitment of youth with ADHD over the past two years has also allowed us to begin to examine in more depth the phenomenology and pathophysiology of irritability occurring in the context of ADHD. In a study we published this year, 489 youth with DMDD, subclinical irritability, anxiety, ADHD, or no diagnosis, high levels of ADHD symptoms were associated with increased rates of phasic irritability (temper outbursts and aggression) but not tonic irritability (irritable mood between outbursts). Further evidence of external validity for the distinction between phasic and tonic irritability could have important treatment implications.