Neural mechanisms of risk for irritability across the transition to adolescence

项目摘要/摘要 易怒是最常见的精神疾病之一，它是对非奖励的反应的夸大愤怒。 因为儿童后期和青春期的易怒预示着一生中的精神障碍， 涉及青春期易怒的神经机制对干预至关重要。 在青少年易怒问题在青春期后期形成根深蒂固的精神障碍之前 成人期。易怒与奖励过程中的异常联系在一起，这可能导致更大的挫折感 当没有收到奖励的时候。这种奖赏加工的脆弱性可以通过更好的抑制来改善 对照，正常情况下随着成熟而增加。然而，奖励处理和奖励处理之间的相互作用 易怒的抑制性控制尚不清楚。研究神经回路的纵向变化很重要 因为奖赏和抑制相关的神经网络经历了从童年到 青春期。我们的总体目标是识别与奖赏和抑制相关的神经通路， 在过渡到青春期期间易怒的变化。为此，该提案利用了来自 青春期大脑认知发展(ABCD)研究，一项大型的、全国性的青春期前纵向样本 每年评估(N=~8,312个可用数据集；基线年龄=9-10岁；1年随访[1-YRFU]年龄=10-11岁； 2-YRFU年龄=11-12岁)。在Baseline和2-YRFU中，年轻人完成金钱激励延迟和停止信号任务 在fMRI获取期间，分别评估对奖赏和抑制控制的神经反应。横跨所有 Waves，青少年易怒和共生的精神病理通过临床访谈和父母- 和青年报告措施，以及青年奖励的多重行为和父母和青年报告措施 收集了加工和抑制控制。我们的中心假设是青春期前有奖赏- 与抑制相关的神经缺陷更有可能表现出持续的高水平或不断增加的易怒情绪。 过渡到青春期，而青春期前有奖赏相关的大脑缺陷，但更好的抑制，将 表现出易怒情绪的减少。具体目标是确定(1)单独的和(2)互动的贡献 奖赏和抑制相关的神经功能与同时易怒的关系；识别(3a)青春期前奖赏- 和抑制相关的神经预测因子以及(3b)奖赏和抑制神经的发育变化 在过渡到青春期的过程中，易怒轨迹和未来精神病理学的机制； 探索(4)发展-生物-背景因素(性别、青春期、种族/民族、社会经济地位、 家族特征)对这些大脑-行为关系的影响。这项提议将通过揭示 易怒的神经回路。创新方面包括专注于关键年龄范围(过渡到 青春期)预防成年障碍，多时间点成像，配方新颖全面 基于奖励的易怒模型、机器学习方法和复制分析。我们的项目是 意义重大，因为它将成为一项研究计划的催化剂，为治疗过敏性疾病的精密医学提供信息。

PROJECT SUMMARY/ABSTRACT Irritability—exaggerated anger in response to non-reward—is among the most common psychiatric complaints. Because irritability in late childhood and adolescence predicts mental disorders across the lifespan, identifying the neural mechanisms involved in irritability across the transition to adolescence is paramount to intervene before youth irritability problems harden into entrenched psychiatric disorders in later adolescence and adulthood. Irritability is linked with abnormalities in reward processing, which may lead to greater frustration when rewards are not received. Such reward processing vulnerabilities may be ameliorated by better inhibitory control, which normatively increases with maturation. However, the interplay between reward processing and inhibitory control in irritability is unknown. Investigating longitudinal changes in neural circuitry is important because reward- and inhibition-related neural networks undergo substantial change from childhood through adolescence. Our overall goal is to identify reward- and inhibition-related neural pathways that characterize changes in irritability over the transition to adolescence. To this end, the proposal leverages data from the Adolescent Brain Cognitive Development (ABCD) Study, a large, national longitudinal sample of preadolescents assessed annually (N=~8,312 with usable datasets; baseline age=9-10; 1-Year Follow-Up [1-YRFU] age=10-11; 2-YRFU age=11-12). At baseline and 2-YRFU, youth complete monetary incentive delay and stop-signal tasks during fMRI acquisition that assess neural responses to reward and inhibitory control, respectively. Across all waves, youth irritability and co-occurring psychopathology are assessed using clinical interviews and parent- and youth-report measures, and multiple behavioral and parent- and youth-reported measures of youth reward processing and inhibitory control are collected. Our central hypothesis is that preadolescents with both reward- and inhibition-related neural deficits are more likely to show persistently high or increasing irritability across the transition to adolescence, whereas preadolescents with reward-related brain deficits, but better inhibition, will demonstrate decreases in irritability. Specific aims are to identify (1) separate and (2) interactive contributions of reward- and inhibition-related neural function to concurrent irritability; to identify (3a) preadolescent reward- and inhibition-related neural predictors and (3b) developmental changes in reward and inhibition neural mechanisms, of irritability trajectories and future psychopathology across the transition to adolescence; and to explore (4) the moderating role of developmental-biological-contextual factors (sex, puberty, race/ethnicity, SES, familial characteristics) on these brain-behavior relationships. This proposal will advance the field by revealing the neural circuitry of irritability. Innovative aspects include focusing on a key age range (transition to adolescence) to prevent adult disorders, multiple time point imaging, formulation of a novel and comprehensive reward-based model of irritability, machine learning methodology, and replication analyses. Our project is significant because it will be a catalyst for a research program to inform precision medicine for irritability.