Mechanisms of Frustration and the Pathophysiology of Severe Irritability in Youth

青少年严重烦躁的沮丧机制和病理生理学

• 批准号: 10703913
• 负责人: Ellen Leibenluft
• 金额: $ 250.98万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703913
• 关键词: Affective; Anger; Animals; Anterior; Anxiety; Anxiety Disorders; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral Paradigm; Bipolar Disorder; Brain; Brain region; Child; Childhood; Chronic; Clinic; Clinical; Clinical Trials; Cognitive; Complex; Corpus striatum structure; DSM-V; Data; Data Analyses; Data Set; Development; Diagnosis; Dimensions; Disease; Enrollment; Evidence based treatment; Exhibits; Feedback; Formulation; Frustration; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Graph; Hospitalization; Human; Hyperactivity; Impairment; Intervention; Knowledge; Lead; Learning; Mediating; Modeling; Moods; National Institute of Mental Health; Operant Conditioning; Parents; Parietal; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Phase; Play; Population; Process; Prognosis; Protocols documentation; Psychological reinforcement; Public Health; Publications; Publishing; Recovery; Research; Research Domain Criteria; Rest; Rewards; Role; Sampling; Scanning; Signal Transduction; Standardization; Symptoms; Testing; Time; Toxic effect; Unipolar Depression; Update; Work; Youth; behavioral study; brain based; brain dysfunction; cognitive control; cognitive task; comparison group; design; dysphoria; emotion regulation; environmental change; flexibility; heuristics; indexing; informant; maladaptive behavior; neuroadaptation; neuroimaging; novel; pandemic disease; peer; personalized medicine; prevent; psychiatric symptom; recruit; response; reward processing; severe mood dysregulation; standardize measure; translational approach; translational model

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.

考虑到对患有慢性，严重烦躁的儿童的适当诊断，我们表征了这样的年轻人。这项工作构成了DSM-5中对情绪失调障碍（DMDD）的新诊断的基础。自该项目成立以来（Zia MH002786-17），大约有650名高度易怒的年轻人以及200多个患有多动症的青年。 （许多DMDD患者患有多动症，患有多动症的年轻人往往比患有DMDD但健康的年轻人更易烦躁；因此，他们是一个合适的比较组。）今年约有75名新患者被招募。 DMDD的年轻人在接受的药物，住院和标准化功能指标方面遭受严重损害。烦恼是儿童中最常见的精神病症状之一，但基于大脑的研究很少，几乎没有循证治疗。在2017 - 18年度，我们阐明了一种可测试的，启发式的易怒模型，继续指导我们的研究。该模型认为，小儿烦躁的核心缺陷包括对挫败感的异常反应和对威胁的异常方法的反应。对挫败感的异常反应暗示奖励学习电路功能障碍，例如，工具性学习缺陷可以防止适应不断变化的环境意外情况，或夸张的预测错误响应对预期奖励的省略。由于该模型的原始表述，我们对其进行了更新，以包括证据表明认知控制缺陷（特别是缺陷抑制性控制）可能会导致适应不良行为，以应对挫败感或威胁。 烦恼非常适合研究领域标准（RDOC）的转换，翻译方法。在DMDD和其他组中，即焦虑症，ADHD中，我们将烦躁的变量表征为连续变量。在神经影像学期间，我们使用令人沮丧的任务，因为烦躁的标志是难以容忍挫败感。在我们的工作中，我们使用了三个不同的神经影像学任务来引起青年人的挫败感。我们最常用的挫败感任务是情感上的Posner任务，该任务使用注意力任务和预扣奖励来引起挫败感。在195名DMDD，ADHD和/或焦虑症和健康青年的195名青年中使用这项任务的发表工作中，我们发现当年轻人在收到令人沮丧的反馈后尝试这项任务时，烦恼与增加的前额叶和纹状体参与有关。 在新的66名DMDD，ADHD或无疾病的新样本中，我们使用了此任务，同时还可以在任务前后立即获取静止状态的功能连接数据。这种设计使我们能够在沮丧期间和之后研究行为和神经适应，并测试这些适应性和易怒之间的关联。因此，我们将挫败感视为一个动态，不断发展的全脑网络过程。 我们使用图理论方法来分析数据。这种方法假设大脑被组织成大脑区域（节点）的复杂子网（模块）。当节点群集成模块变化时，会发生网络重新配置。 两个模块在基线（即预交静止状态）处识别出，一个前默认模式 - 固定式limbic和一个额叶 - 长方体模块在沮丧期间和之后都为重新配置做出了最大的贡献。全球效率索引了网络所有地区之间交换信息的能力。在任务后静止状态中存在的模块的全球效率都预测了以前看不见的数据中的自我和观察者评分的烦恼。这一发现表明，从挫败感中不良适应性恢复可能在易怒的病理生理学中起核心作用，并可以指导未来干预措施的发展。具体而言，我们发现存在的额叶limbic模块的全球效率可以预测自我报告的烦恼，而父母评分的烦躁不良是通过腹侧前额叶 - 皮质和体面运动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，这些预测是特定于烦躁的。焦虑，注意力或多动症等级不会预测全球效率。 值得注意的是，我们还分析了在50名青年中获得的数据，该数据在第二次挫败感任务中扫描了更改任务，并使用前和任务后的静止状态数据进行了更改任务。变化任务与情感上的挫败感（挫败感短的障碍，散布在非填充块中，与不折磨的长期障碍，然后是长期的挫败感）和认知任务（认知灵活性与注意力方向的长期挫败感）不同。我们处理变更任务的工作产生了情感上的工作结果的部分复制。在这两项任务中，网络重新配置在额叶延迟的沿线和额开始模块中最为突出。 同样在这两个任务中，只有在任务后静止状态期间存在的模块中的全球效率预测了易怒，预测模块包括额颞中边缘模块。但是，尽管在情感上的Posner任务中，但在任务后的静止状态中，额颞中边缘模块的全球效率预测了其烦恼的儿童等级，但在变更任务中，同一指标预测了孩子的父母评分。 这凸显了研究信息对烦躁的影响的重要性。 我们最近在我们的诊所以及公开可获得的数据集中完成了对700名青年的分析，并将为发布做准备。 除了情感上的posner和更改范式外，我们还使用第三项挫败感。这项任务，嘉年华旨在测试烦恼是否与基线和挫败感后的增强学习缺陷有关。强化学习是人们学习将得到奖励的过程。这种学习的缺陷可能导致易怒的青年挫败感。增强学习的一个组成部分是预测错误处理，即大脑信号传导表明预期和接收的奖励之间的不匹配。流行前，我们在扫描仪中的34名青年中试行了这项任务，并获得了与预测误差处理相关的预期挫败感和预期的大脑激活。如果烦躁与工具性学习缺陷有关，则将具有直接的治疗意义。