The Pathophysiology and Treatment of Children with Severe Irritability

儿童严重烦躁的病理生理学和治疗

• 批准号: 10012696
• 负责人: Ellen Leibenluft
• 金额: $ 314.89万
• 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/10012696
• 关键词: Adolescent; Adverse event; Animals; Antidepressive Agents; Anxiety; Anxiety Disorders; Attention; Attention deficit hyperactivity disorder; Base of the Brain; Behavior; Behavioral; Brain; Child; Childhood; Chronic; Citalopram; Clinical; Clinical Trials; Cognitive; Corpus striatum structure; DSM-V; Data; Development; Diagnosis; Dimensions; Disease; Double-blind trial; Enrollment; Evidence based treatment; Exhibits; Feedback; Fostering; Frustration; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Hospitalization; Human; Image; Impairment; Individual; Knowledge; Lead; Learning; Literature; Machine Learning; Manuscripts; Mediating; Methodology; Modeling; Moods; National Institute of Mental Health; Operant Conditioning; Participant; Patients; Pharmaceutical Preparations; Phase; Placebos; Play; Population; Process; Protocols documentation; Public Health; Publishing; Research; Research Domain Criteria; Rest; Rewards; Sampling; Symptoms; Techniques; Testing; Time; Unipolar Depression; Variant; Work; Youth; analytical method; anxious; atypical antipsychotic; brain dysfunction; childhood anxiety; childhood bipolar disorder; cognitive control; cognitive task; comparison group; design; dysphoria; emotion regulation; environmental change; flexibility; heuristics; improved; inhibitor/antagonist; neuroimaging; novel; precision medicine; prevent; psychiatric symptom; recruit; relating to nervous system; response; reuptake; reward circuitry; severe mood dysregulation; side effect; standardize measure; translational approach; translational model; trial design

Given concerns about the appropriate diagnosis for children with chronic, severe irritability, we defined severe mood dysregulation (SMD) to capture youth with severe irritability, as well as hyperarousal. SMD 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 450 highly irritable (i.e., those with SMD, DMDD, or sub-threshold DMDD) have enrolled into the project, along with more than 125 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. Recently, we published several major reviews and theoretical articles articulating a testable, heuristic, translational model of irritability to guide future 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., deficits instrumental learning deficits that prevent adaptation to changing environmental contingencies, or exaggerated prediction error responses to the omission of an expected reward. In addition, evidence suggests 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, including youth with anxiety disorders or ADHD. We use frustrating tasks during neuroimaging, since a hallmark of irritability is difficulty tolerating frustration. Previously, we demonstrated behavioral and neural differences between irritable and non-irritable youth during a frustrating attentional task. We improved that paradigm and obtained fMRI data from approximately 200 youth with DMDD, ADHD, and/or anxiety disorders, as well as healthy youth. In a manuscript published this year, we found that irritability is associated with increased prefrontal and striatal engagement when youth attempt an attention orienting task after receiving frustrating feedback. This finding is more prominent in children than adolescents. Since prefrontal engagement is important in emotion regulation, this may indicate that prefrontal emotion regulation mechanisms are less efficient in irritable vs. non-irritable youth. Alternatively, in irritable youth, increased prefrontal engagement may be required after frustration to down-regulate exaggerated subcortical limbic responses e.g., in the striatum. These effects of irritability are present even when ADHD and anxiety are taken into account. In work published in 2018, we demonstrated associations between irritability and brain function when youth with DMDD, anxiety, or healthy subjects completed a threat-attention task. Because our translational model posits that both threat and reward (i.e., frustration) circuitry are implicated in irritability, we will next directly compare function in two brain circuits and the associations each have with irritability. Since youth with irritability have heterogeneous clinical presentations, precision medicine approaches would be fostered by testing whether irritable youth can be sub-grouped by dysfunction in threat vs. reward circuitry. We use previously acquired fMRI data from subjects who completed both the threat- and frustration-processing paradigms to develop and pilot new analytic methods and test these questions. We are also gathering data from a new, large sample of DMDD, anxious and ADHD subjects using the same two paradigms, to test these questions. In addition to the attention shifting frustration task described above, we have piloted two additional frustration tasks. The second frustration task differs from the first 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 (attention orienting vs. cognitive flexibility). This second task allows us to test whether, across different task timing and cognitive tasks, increased irritability is associated with increased prefrontal engagement after frustration. We are now using new machine learning techniques to analyze data from 80 healthy youth or those with DMDD, anxiety, or ADHD. We have adapted the second task so that, while it maintains its unique methodological features, its design is sufficiently comparable to the frustrating attentional task to allow direct statistical comparisons. This will allow us to identify frustration-related findings that are robust to methodological variation, while also isolating the impact of different approaches on the findings. Such data will thus be informative not only about the brain mechanisms associated with irritability, but also future directions of research. In addition, both frustration tasks are accompanied by resting state data acquired pre- and post- the frustration task, so we can identify how frustration, elicited by two different techniques, impacts on intrinsic brain connectivity. Our third frustration task allows us to determine if irritability is associated with instrumental learning deficits at baseline and after frustration. Instrumental learning is the process by which people learn which of their behaviors will be rewarded. Deficits in such learning could lead to increased frustration in irritable youth. We successfully piloted this task outside the scanner and are now acquiring imaging data. A long-standing and important question in the literature is the extent to which deficits in cognitive control, particularly inhibitory control, play in the pathophysiology of temper outbursts. Given the significant overlap between ADHD symptoms and irritability, an important goal of this study is to differentiate the associations of each of these with deficient inhibitory ability. We are testing youth with DMDD, ADHD, and anxiety on an extensive battery of inhibitory control tasks. The use of this extensive battery allows us to derive latent variables which are more stable than those derived from an individual study and are thus more likely to yield replicable results. As noted above, a major focus of our work is treatment. We completed our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability. In a sample of 49 youth, we demonstrated that indeed, stimulant plus citalopram is more effective in reducing irritability than is stimulant plus placebo. These data have recently been published. Stimulant and SRI treatment tend to have fewer side-effects than atypical antipsychotic treatment, which is used frequently in youth with severe irritability. Therefore, this work has considerable public health importance. New treatment approaches are now being developed and tested under 15-M-0182 (NCT02531893); PI: Brotman.

考虑到对患有慢性、严重烦躁的儿童进行适当诊断的担忧，我们定义了严重情绪失调 (SMD)，以捕捉患有严重烦躁和过度警觉的青少年。 SMD 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 450 名高度易怒的人（即患有 SMD、DMDD 或亚阈值 DMDD 的人）以及超过 125 名患有 ADHD 的青少年加入了该项目。 （许多 DMDD 患者患有 ADHD，而患有 ADHD 的青少年往往比 DMDD 患者更少烦躁，但比健康青少年更多；因此他们是一个合适的对照组。）今年招募了大约 50 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。最近，我们发表了几篇重要评论和理论文章，阐明了可测试的、启发式的、可转化的易怒模型，以指导未来的研究。 该模型假设，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。此外，有证据表明，认知控制缺陷（特别是抑制控制不足）可能会导致应对挫折或威胁时的适应不良行为。 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（包括患有焦虑症或多动症的青少年）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。之前，我们证明了易怒和不易烦躁的年轻人在一项令人沮丧的注意力任务中的行为和神经差异。我们改进了这一范式，并从大约 200 名患有 DMDD、ADHD 和/或焦虑症的青少年以及健康青少年中获得了功能磁共振成像数据。在今年发表的一份手稿中，我们发现，当年轻人在收到令人沮丧的反馈后尝试进行注意力集中任务时，烦躁与前额叶和纹状体参与度的增加有关。这一发现在儿童中比青少年更为突出。由于前额叶参与在情绪调节中很重要，这可能表明前额叶情绪调节机制在易怒的年轻人中比非易怒的年轻人效率较低。或者，在易怒的年轻人中，在受挫后可能需要增加前额叶的参与，以下调过度的皮层下边缘反应，例如纹状体中的反应。即使考虑到注意力缺陷多动症和焦虑症，这些烦躁的影响仍然存在。 在 2018 年发表的研究中，我们证明了当患有 DMDD、焦虑症或健康受试者完成威胁注意任务的青少年时，烦躁与大脑功能之间存在关联。因为我们的翻译模型假设威胁和奖励（即挫败）回路都与烦躁有关，所以接下来我们将直接比较两个大脑回路的功能以及每个回路与烦躁的关联。由于易激惹的青少年具有异质性的临床表现，因此可以通过测试是否可以根据威胁与奖励回路的功能障碍对易激惹的青少年进行分组，从而促进精准医学方法的发展。我们使用之前从完成威胁和挫折处理范例的受试者那里获得的功能磁共振成像数据来开发和试验新的分析方法并测试这些问题。我们还使用相同的两个范例从 DMDD、焦虑和 ADHD 受试者的新大样本中收集数据，以测试这些问题。 除了上述转移注意力的挫败任务之外，我们还试点了两项额外的挫败任务。第二个挫败任务与第一个挫败任务的不同之处在于挫败的时间（短的挫败块，随机散布着非挫败块，与长的非挫败块，然后是长时间的挫败感）和认知任务（注意力导向与认知灵活性）。第二个任务使我们能够测试在不同的任务时间和认知任务中，烦躁性的增加是否与挫折后前额叶参与度的增加有关。我们现在正在使用新的机器学习技术来分析来自 80 名健康青少年或患有 DMDD、焦虑或多动症的患者的数据。我们对第二个任务进行了调整，以便在保持其独特的方法论特征的同时，其设计与令人沮丧的注意力任务具有足够的可比性，从而可以进行直接的统计比较。 这将使我们能够识别与挫折相关的发现，这些发现对方法论变化是稳健的，同时也隔离了不同方法对发现的影响。因此，这些数据不仅可以提供有关与烦躁相关的大脑机制的信息，还可以提供未来研究的方向。 此外，这两项挫折任务都伴随着在挫折任务之前和之后获得的静息状态数据，因此我们可以确定由两种不同技术引起的挫折如何影响内在的大脑连接。 我们的第三个挫折任务使我们能够确定烦躁是否与基线和挫折后的工具性学习缺陷有关。工具性学习是人们了解自己的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。我们在扫描仪之外成功地试验了这项任务，现在正在采集成像数据。 文献中一个长期存在的重要问题是认知控制，特别是抑制控制的缺陷在脾气爆发的病理生理学中发挥的作用程度。 鉴于多动症症状和烦躁之间的显着重叠，这项研究的一个重要目标是区分这些症状与抑制能力缺陷之间的关联。我们正在对患有 DMDD、ADHD 和焦虑症的青少年进行一系列广泛的抑制控制任务测试。使用这种广泛的电池使我们能够得出比单个研究得出的潜在变量更稳定的潜在变量，因此更有可能产生可复制的结果。 如上所述，我们工作的一个主要重点是治疗。我们完成了双盲试验，旨在确定西酞普兰（一种血清素再摄取抑制剂（SRI）抗抑郁药，可有效治疗儿童焦虑症）加兴奋剂在治疗严重烦躁方面是否比安慰剂加兴奋剂更有效。在 49 名青少年的样本中，我们证明，兴奋剂加西酞普兰确实比兴奋剂加安慰剂更能有效地减少烦躁。这些数据最近已公布。兴奋剂和 SRI 治疗往往比非典型抗精神病药物治疗副作用更少，非典型抗精神病药物常用于患有严重烦躁的青少年。因此，这项工作具有相当大的公共卫生重要性。目前正在根据 15-M-0182 (NCT02531893) 开发和测试新的治疗方法； PI：布罗特曼。