Neural mechanisms of risk for irritability across the transition to adolescence

项目总结/摘要 易怒--对没有奖励的反应而产生的夸张的愤怒--是最常见的精神疾病之一。 因为儿童晚期和青春期的易怒预示着一生中的精神障碍， 在向青春期过渡期间，涉及易怒的神经机制是最重要的干预措施。 在青少年易怒问题在青春期后期变成根深蒂固的精神障碍之前， 成年易怒与奖励处理的异常有关，这可能导致更大的挫折感 当没有奖励时。这种奖励处理漏洞可以通过更好的抑制来改善。 控制，其随成熟而正常增加。然而，奖励处理和 对易激惹性的抑制控制是未知的。研究神经回路的纵向变化很重要 因为与奖赏和抑制相关的神经网络从童年到成年经历了实质性的变化， 青春期我们的总体目标是确定奖励和抑制相关的神经通路， 在向青春期过渡期间易怒的变化。为此，该提案利用了 青少年大脑认知发展（ABCD）研究，一个大型的全国性青少年前纵向样本 每年评估一次（N=~ 8，312，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）。在基线和2-YRFU时，青少年完成了金钱激励延迟和停止信号任务 在功能磁共振成像采集，评估神经反应的奖励和抑制控制分别。跨所有 波，青年易怒和共同发生的精神病理学进行评估，使用临床访谈和家长， 以及青少年回报的多重行为、父母和青少年报告的措施 收集处理和抑制控制。我们的中心假设是，具有奖励- 与抑制相关的神经缺陷更有可能表现出持续的高或增加的易怒性， 过渡到青春期，而青春期前与奖励相关的大脑缺陷，但更好的抑制，将 表现出易怒的减少。具体目标是确定（1）单独和（2）互动的贡献 奖励和抑制相关的神经功能并发易怒;以确定（3a）青春期前的奖励- 和抑制相关的神经预测和（3b）发育变化的奖励和抑制神经 机制，易怒的轨迹和未来的精神病理学在整个过渡到青春期; 探索（4）发展生物背景因素（性别，青春期，种族/民族，SES， 家族特征）对这些大脑行为关系的影响。这项提案将通过揭示 易怒的神经回路创新方面包括侧重于一个关键的年龄范围（过渡到 青春期），以防止成人疾病，多个时间点成像，制定一个新的和全面的 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，为治疗烦躁症的精准医学提供信息。

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.