Mechanisms of Frustration and the Pathophysiology of Severe Irritability in Youth

考虑到对慢性严重易怒儿童的适当诊断，我们描述了这样的青少年；本工作为DSM-5中心境失调伴烦躁症（DMDD）的新诊断奠定了基础。自该项目开始以来（ZIA MH002786-17），大约650名高度易怒的青年和200多名患有多动症的青年参加了研究。（许多DMDD患者同时患有ADHD，而患有ADHD的青少年往往比DMDD患者易怒程度低，但比健康青少年易怒程度高，因此他们是一个合适的对照组。）该实验室PI将于2023年7月31日退休，实验室将关闭。因此，今年没有新的患者入组，该项目将在本报告结束后终止。今年的工作重点是发布已经收集到的数据。

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 650 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.) The PI of this lab will be retiring on July 31, 2023, and the lab will be closing. Therefore, new patients were not enrolled this year and this project will be terminated after this report. Work this year focused on publishing already collected data. 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. 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 used frustrating tasks during neuroimaging, since a hallmark of irritability is difficulty tolerating frustration. In our work, we have used three different neuroimaging tasks to induce frustration in youth while they undergo fMRI. Our most commonly used frustration task is the affective Posner task, which uses an attentional task and the withholding of expected reward to induce frustration. Frustration can be experienced as unfairness, and responses to frustration and unfairness could be moderated by youths experiences living in underserved neighborhoods. Therefore, we undertook a post-hoc analysis of Affective Posner imaging data (216 youth, mean age 12.9 years; 48% female; 67% White, 75% with a psychiatric disorder diagnosis) to test whether neighborhood resources (operationalized by the Childhood Opportunity Index (COI)) moderate affective and neurobiological responses to experimentally induced unfairness. Youth growing up in neighborhoods with lower COI scores responded to unfairness with an attenuated increase in frustration and a steeper increase in sadness. During the frustrating unfair condition only, low COI scores were associated with a more integrated processing mode; specifically, the emergence of highly connected (hub) regions in the motor and prefrontal cortices, increased efficiency of information processing within the control network, and heightened connectivity between the control and motor-salience networks. This study adds to a growing literature documenting how inequity may affect the brain, behavior, and youth mental health. This work is being prepared for publication. Similarly, we are also analyzing 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). Finally, our third frustration task, Carnival, has been incorporated into the work of other investigators and data collection is still ongoing. Carnival was designed to test whether irritability is associated with deficits in reinforcement learning (i.e., the process by which people learn what behaviors will be rewarded) deficits at baseline and after frustration. Our other imaging analysis this year will be submitted for publication soon. We tested associations between clinical symptoms (i.e., irritability, inattention, and hyperactivity) and white matter structural connectivity (i.e., fractional anisotropy, FA, assessed with diffusion tensor imaging). We found shared associations between the three symptoms and whole-brain FA, as well as with FA of the corticospinal tract. This shared association also related to an independent measure of impulsivity. These data suggest that perturbed white matter microstructure may represent a shared neurobiological mechanism of irritability, inattention, and hyperactivity related to heightened impulsivity. In addition to this neuroimaging work, we also submitted a paper using data from the Adolescent Brain and Cognitive Development (ABCD) Study (discovery and replication subsamples, each n = 3,722) to test cross-sectional and longitudinal associations among parent-reported irritability, ADHD symptoms, and behaviorally-assessed inhibitory control. These three variables frequently coexist clinically, but their associations are unclear. Irritability and ADHD symptoms exhibited strong cross-sectional and reciprocal cross-lagged associations. Higher ADHD symptoms at age 10 were associated concurrently with poorer inhibitory control and predicted poorer inhibitory control at age 12. However, inhibitory control was not associated with irritability cross-sectionally nor predictive of later irritability or ADHD symptoms. These findings highlight strong links between irritability and ADHD. While inhibitory control deficits were linked to ADHD and predictive of its symptom course, it had no significant associations with irritability. Finally, all of these studies depend on valid and reliable reports of a childs irritability, typically provided by both the parent and the child. Across two independent samples (NCohort-1 = 765, 8-21 years; NCohort-2 = 1910, 6-21 years), we found substantial discrepancy between informants (i.e., parent and child) but good consistency within informant. These findings suggest that parent and child may consistently report different aspects of the irritability phenomenon. Future work should investigate which aspects of irritability are particularly salient to each informant.