Neural mechanisms of risk and resilience in early childhood irritability

项目摘要/摘要 易怒，定义为当经历RDoC构建令人沮丧的非奖励时愤怒的阈值降低， 即得不到预期的回报，是儿科精神病学评估最常见的原因之一。 我们的工作表明，及早发现是至关重要的：如果学龄前(3-6岁，一年级之前)持续易怒 进入学龄期(一年级以后)，大约50%的学龄前易怒儿童，如 持续的易怒会让孩子在一生中走上精神障碍的道路。因此，识别神经 儿童在易怒中坚持与缓解的机制对早期干预至关重要 临床级联反应。易怒与奖励过程中的异常联系在一起，这可能导致更大的 得不到奖励时的挫败感。这样的奖励处理漏洞可能会通过更好的 抑制性控制，随着成熟度的增加而正常增加。然而，奖励之间的相互作用 易怒轨迹中的加工和抑制是未知的。研究神经的纵向变化 由于奖赏和抑制相关的神经网络在这一发育阶段中的回路很重要 经历实质性的变化，并可能最容易受到早期干预。我们的总体目标是确定 儿童早期坚持与缓解的奖赏和抑制相关神经通路 易怒。为此，拟议的项目将纵向描述神经和症状轨迹 学龄前儿童进入学龄期。我们将收集与奖励和抑制控制相关的措施 215名5-6岁儿童在一年级前的基线脑功能和24个月随访，以及 在每次6个月的随访中评估儿童的易怒和抑制。对儿童的全面评估 (认知、气质、精神病理学)、父母(精神病理学)和背景因素(例如，父母教养、 应激源)也将在基线和24个月评估中进行评估。我们的中心假设是年轻的 有奖赏和抑制相关神经缺陷的儿童更有可能持续易怒 那些汇款的人。具体目标是确定(1)奖赏和抑制相关神经的同时作用 对每个年龄段(学龄前、学龄期)易怒的作用；(2)奖赏的发展变化--和 儿童早期到中期易怒轨迹的抑制相关神经机制 奖赏和抑制相关神经预测易怒轨迹和未来的精神病理学；以及(4) 儿童性别、父母心理疾病、父母教养方式和生活压力对这些大脑行为的调节作用 联想。这一提议将通过揭示易怒、风险和弹性的神经回路来推动该领域的发展。 创新方面包括重点关注关键的年龄范围(5-6岁)，以预防后来的疾病，多次 点成像和机器学习方法。我们的项目意义重大，因为它将为 治疗易怒的精准药物：为正确的人提供正确的治疗(基于神经机制) (将坚持易怒的儿童)，在适当的时间(学龄前，在易怒问题恶化之前)。

PROJECT SUMMARY/ABSTRACT Irritability, defined as lowered threshold for anger when experiencing the RDoC construct frustrative non-reward, i.e., failing to receive expected rewards, is one of the most common reasons for pediatric psychiatric evaluation. Our work shows that early detection is critical: If irritability in preschool-age (3-6 years, before 1st grade) continues into school-age (after 1st grade), as it does for approximately 50% of preschool-age irritable children, such persistent irritability puts children on the path to mental disorder across the lifespan. Thus, identifying the neural mechanisms by which children persist vs. remit in irritability is paramount to intervene in the earliest phase of the clinical cascade. 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 inhibition in irritability trajectories is unknown. Investigating longitudinal changes in neural circuitry during this developmental period is important because the reward- and inhibition-related neural networks undergo substantial change and may be most malleable to early intervention. Our overall goal is to identify reward- and inhibition-related neural pathways that characterize persistence vs. remission of early childhood irritability. To this end, the proposed project will longitudinally characterize the neural and symptom trajectories of preschool-age children into school-age. We will collect measures of reward- and inhibitory control-related brain function at baseline and 24-month follow-up from 215 5-6-year-old children prior to 1st grade, alongside assessments of child irritability and inhibition at each 6-month follow-up. A comprehensive assessment of child (cognition, temperament, psychopathology), parent (psychopathology) and contextual factors (e.g., parenting, stressors) will also be assessed at baseline and 24-month assessments. Our central hypothesis is that young children with reward- and inhibition-related neural deficits are more likely to persist in irritability compared to those who remit. Specific aims are to identify (1) concurrent contributions of reward- and inhibition-related neural function to irritability at each age (preschool-age, school-age); (2) developmental changes in reward- and inhibition-related neural mechanisms of irritability trajectories from early to middle childhood; (3) early childhood reward- and inhibition-related neural predictors of irritability trajectories and future psychopathology; and (4) the moderating role of child sex, parent psychopathology, parenting, and life stress on these brain-behavior associations. This proposal will advance the field by revealing the neural circuitry of irritability risk and resilience. Innovative aspects include focusing on a key age range (5-6 years) to prevent later disorders, multiple time point imaging, and machine learning methodology. Our project is significant because it will pave the way for precision medicine for irritability: providing the right treatment (based on neural mechanisms) to the right people (children who will persist in irritability), at the right time (preschool age, before irritability problems worsen).