Mechanisms of Frustration and the Pathophysiology of Severe Irritability in Youth

考虑到对患有慢性、严重烦躁的儿童进行适当诊断的担忧，我们对此类青少年进行了描述；这项工作为 DSM-5 中心境失调障碍伴烦躁症 (DMDD) 的新诊断奠定了基础。自该项目 (ZIA MH002786-17) 启动以来，已有约 650 名高度易怒的青少年以及 200 多名患有多动症的青少年加入。 （许多 DMDD 患者患有 ADHD，而患有 ADHD 的青少年往往比 DMDD 患者的烦躁性要少，但比健康青少年的烦躁性要高；因此，他们是一个合适的对照组。）今年大约招募了 75 名新患者。 患有 DMDD 的青少年在接受药物治疗、住院治疗和标准化功能测量方面遭受严重损害。烦躁是儿童最常见的精神症状之一，但对此进行的基于大脑的研究很少，也很少有基于证据的治疗方法。 2017-18 年，我们阐述了一个可测试的、启发式的、可转化的易怒模型，该模型继续指导我们的研究。该模型认为，儿科烦躁的核心缺陷包括对挫折的异常反应和对威胁的异常反应。对挫折的异常反应意味着奖励学习回路功能障碍，例如，工具性学习缺陷阻碍了对不断变化的环境突发事件的适应，或者对预期奖励的遗漏做出了夸大的预测错误反应。自模型的最初制定以来，我们对其进行了更新，以包含表明认知控制缺陷（特别是抑制控制不足）可能导致应对挫折或威胁的适应不良行为的证据。 烦躁非常适合研究领域标准 (RDoC) 的跨诊断、转化方法。我们将 DMDD 和其他群体（即焦虑症、ADHD）中的烦躁描述为连续变量。我们在神经影像学检查中使用令人沮丧的任务，因为烦躁的标志是难以忍受沮丧。在我们的工作中，我们使用了三种不同的神经影像任务来诱导年轻人在接受功能磁共振成像时感到沮丧。我们最常用的挫败任务是情感波斯纳任务，它使用注意力任务和抑制预期奖励来引发挫败感。在已发表的研究中，我们对 195 名患有 DMDD、ADHD 和/或焦虑症的青少年以及健康青少年进行了这项任务，我们发现，当青少年在收到令人沮丧的反馈后尝试执行该任务时，易怒与前额叶和纹状体参与度增加有关。 在 66 名患有 DMDD、ADHD 或没有疾病的青少年的新样本中，我们使用了这项任务，同时还在任务前后立即获取静息状态功能连接数据。这种设计使我们能够研究挫折期间和之后的行为和神经适应，并测试这些适应和烦躁之间的关联。因此，我们将挫折感视为一个动态的、不断发展的、全脑网络过程来研究。 我们使用图论方法来分析数据。这种方法假设大脑被组织成大脑区域（节点）的复杂子网络（模块）。当模块中的节点集群发生变化时，就会发生网络重新配置。 在基线（即任务前静息状态）确定的两个模块，前默认模式颞边缘和额顶叶模块，对挫折期间和之后的重新配置贡献最大。全局效率衡量网络所有区域之间交换信息的能力。只有任务后静息状态下存在的模块的全局效率才能预测以前未见过的数据中的自我评价和观察者评价的烦躁程度。这一发现表明，从挫折中适应不良的恢复可能在烦躁的病理生理学中发挥核心作用，并可以指导未来干预措施的发展。具体来说，我们发现自我报告的烦躁是通过额颞叶边缘模块的整体效率来预测的，而父母额定的烦躁是通过腹侧前额叶皮质下和躯体运动顶叶模块的效率来预测的。这些模块包括集中参与情绪调节和奖励处理的节点。 重要的是，这些预测是针对烦躁的。总体效率不是通过焦虑、注意力或多动评级来预测的。 值得注意的是，我们还分析了大流行前 50 名青少年在第二项挫折任务（即“改变”任务）中扫描的数据，同样使用了任务前和任务后的静息状态数据。改变任务与情感波斯纳的不同之处在于挫折的时间安排（短的挫折块，随机散布着非挫折块，与长的非挫折块，然后是长时间的挫折）和认知任务（认知灵活性与注意力导向）。我们对“改变”任务的工作部分复制了波斯纳情感工作的结果。在这两项任务中，网络重新配置在额叶-颞叶-边缘和额顶叶模块中最为突出。 同样，在这两项任务中，只有任务后静息状态下存在的模块的全局效率可以预测烦躁性，并且预测模块包括额颞叶边缘模块。然而，在情感波斯纳任务中，任务后静息状态下额颞叶边缘模块的整体效率预测了孩子对其烦躁性的评分，而改变任务中的相同指标则预测了父母对孩子烦躁性的评分。 这凸显了研究知情者对烦躁的影响的重要性。 我们最近完成了对我们诊所的 700 名青少年以及公开数据集的分析，并将准备发布。 除了情感波斯纳和变革范式之外，我们还使用第三个挫折任务。这项名为“嘉年华”的任务旨在测试基线时和挫折后的烦躁是否与强化学习缺陷相关。强化学习是人们了解哪些行为会得到奖励的过程。这种学习的缺陷可能会导致易怒的年轻人更加沮丧。强化学习的一个组成部分是预测误差处理，即指示预期奖励和收到奖励之间不匹配的大脑信号。在大流行之前，我们在扫描仪中对 34 名青少年进行了这项任务试点，并获得了与预测错误处理相关的预期挫败感和预期大脑激活。如果烦躁与工具性学习缺陷有关，这将对治疗产生直接影响。

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.) Approximately 75 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 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. In published work using this task in 195 youth with DMDD, ADHD, and/or anxiety disorders, and healthy youth, we found that irritability is associated with increased prefrontal and striatal engagement when youth attempt the task after receiving frustrating feedback. In a new sample of 66 youth with DMDD, ADHD, or no illness, we used this 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. We used a graph theoretical approach to analyze the data. This approach 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 modules identified at baseline (i.e., pre-task resting-state), an anterior default-mode-temporal-limbic and a fronto-parietal module, contributed most to reconfiguration during and after frustration. Global efficiency indexes the capacity to exchange information among all regions of a network. Only global efficiency of modules present in the post-task resting state predicted self- and observer-rated irritability in previously unseen data. This finding suggests that maladaptive recovery from frustration may play a central role in the pathophysiology of irritability and could guide the development of future interventions. Specifically, we found that self-reported irritability was predicted by global efficiency of a fronto-temporal-limbic module present, while parent-rated irritability was predicted by efficiency of ventral-prefrontal-subcortical and somatomotor-parietal modules. These modules include nodes centrally involved in emotion regulation and reward processing. Importantly, the predictions were specific to irritability; global efficiency was not predicted by anxiety, attention, or hyperactivity ratings. 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). Our work with the Change task yielded a partial replication of the results of the affective Posner work. In both tasks, network reconfiguration was most prominent in the frontal-temporal-limbic and fronto-parietal modules. Also in both tasks, only global efficiency in modules present during the post-task resting state predicted irritability, and the predictive modules included a fronto-temporal-limbic module. However, whereas in the affective Posner task, global efficiency of the fronto-temporal-limbic module in the post-task resting state predicted child ratings of their irritability, this same metric in the Change task predicted parent ratings of the childs irritability. This highlights the importance of research on informant effects in irritability. We have recently completed an analysis of this in 700 youth from our clinic as well as in a publicly available data set and will be preparing this for publication. 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.