Brain and Behavior Mechanisms of Irritability and Cognitive Flexibility in Children

项目总结/摘要： 背景：易怒是儿童和青少年接受精神科治疗的最常见原因。 护理，与儿童期和随后的成年期的重大损害有关， 许多DSM-分类障碍-但我们没有临床上有用的，有效的生物行为标志物或措施 以指导临床医生对儿童易激惹的诊断或治疗。为了解决这个问题， 2014年NIMH儿科易激惹研讨会和2015年第一届儿科易激惹大会预示着需要 更多地研究儿科易怒的大脑/行为机制，包括跨诊断研究 在损伤范围内抽取样本，而不是单一的DSM障碍和测试多个 维度刺激性评估。以前，我们已经研究了大脑/行为的改变， 认知灵活性-定义为对不断变化的奖励和惩罚的行为适应-作为 符合双相情感障碍分类定义的儿童易激惹的一种潜在机制 （欣快症和易怒发作）或严重情绪失调（慢性易怒）与对照。现在我们 寻求在这方面的研究中迈出下一步。本申请的目的是定义 大脑/行为机制为基础的子类型的易怒和认知灵活性的跨诊断样本 8-12岁的儿童被划分为不同的损伤范围。我们的核心方法是测试电路和 认知灵活性的行为改变识别不同的易怒亚型，使用单一时间点 易怒问卷/访谈和一种新的多时间点易怒生态瞬时评估 (EMA)Android应用程序，并利用新颖的计算精神病学分析技术来确定 模型最好地解释了基于大脑/行为的易怒集群。我们的核心假设是所有的易怒 不是由单一机制引起的，而是由特定的PFC引起的独特的易怒症状群， 颞-纹状体回路改变介导认知灵活性。提出这一建议的理由是， 更深入地了解认知灵活性和易怒症状背后的生物学机制， 从而为患有易怒的儿童带来新的基于大脑的分类和治疗。我们的研究是 创新，因为我们将是第一个确定易怒的大脑/行为机制， 认知灵活性使用（1）跨诊断样本的儿童绘制的照顾和损害水平， 而不是DSM分类障碍，（2）新型EMA-易怒应用程序，（3）计算精神病学分析 技术，以及（4）从BD/SMD研究中提取的fMRI/行为任务加上RDoC矩阵。我们的研究是 因为对大脑/行为机制的更多理解， 易怒和认知灵活性的关键是实现精准医学方法的最终目标， 易激惹--生物行为标记（扫描和测试）用于更具体/更早的分类 以及诊断加上生物学引导的治疗（例如，药物、认知补救和TMS/TDCS）。

PROJECT SUMMARY/ABSTRACT: Background: Irritability is: the most common reason children and adolescents are brought for psychiatric care, associated with significant impairment in childhood and subsequently in adulthood, a symptom found in many DSM-categorical disorders—yet we have no clinically useful, validated bio-behavioral marker or measure to guide clinician's diagnosis or treatment of children presenting with irritability. To address this problem, the 2014 NIMH Pediatric Irritability Workshop and the 2015 1st Congress on Pediatric Irritability heralded the need for greater research on brain/behavior mechanisms of pediatric irritability, including studies in trans-diagnostic samples drawn across the range of impairment, rather than a single DSM disorder and testing multiple dimensional irritability assessments. Previously, we have investigated the brain/behavior alterations underlying cognitive flexibility—defined as behavioral adaptation in response to changing rewards and punishments—as one potential mechanism underlying irritability in children meeting categorical definitions of bipolar disorder (episodes of euphoria and irritability) or severe mood dysregulation (chronic irritability) vs. controls. Now, we seek to take the next step in this line of research. The objective of this application is to define the brain/behavior mechanism-based sub-types of irritability and cognitive flexibility in a trans-diagnostic sample of children ages 8-12 drawn across the range of impairment. Our central methodology is to test how circuit and behavior alterations in cognitive flexibility identify different sub-types of irritability, using single time point irritability questionnaires/interviews and a novel multi-time point irritability ecological momentary assessment (EMA) Android app, and harnessing novel computational psychiatry analytic techniques to determine which model best explains brain/behavior-based clusters of irritability. Our central hypothesis is that all irritability does not result from a single mechanism; rather unique symptom clusters of irritability result from specific PFC- temporo-striatal circuit alterations mediating cognitive flexibility. The rationale for this proposal is that greater understanding of the biological mechanisms underlying cognitive flexibility and irritability symptoms will lead to novel brain-based classification and treatments for children suffering from irritability. Our study is innovative because we will be the first to identify the brain/behavior mechanisms underlying irritability and cognitive flexibility using (1) a trans-diagnostic sample of children drawn across levels of care and impairment, rather than DSM categorical disorder(s), (2) novel EMA-irritability app, (3) computational psychiatry analytic techniques, and (4) fMRI/behavioral tasks drawn from BD/SMD research plus the RDoC matrix. Our study is both significant and clinically meaningful because greater understanding of the brain/behavior mechanisms of irritability and cognitive flexibility is critical to achieving the ultimate goal of a precision medicine approach for irritability—whereby bio-behavioral markers (scans and tests) are used for more specific/earlier classification and diagnosis plus biologically-guided treatment (e.g., medications, cognitive remediation, and TMS/TDCS).