Adverse life events, inflammation, and trajectories of emotional and behavioural problems in childhood

许多研究将不良生活事件与儿童情绪和行为问题的病因和维持联系起来。这些压力源可以启动生物过程，增加儿童这两种问题的风险，但尚未有研究证实炎症是压力源诱导的生物过程，可以增加这种风险。炎症通常被认为是身体对身体损伤或感染的主要反应。然而，现在有大量证据表明，压力源也可以引发炎症活动的显著增加，这可能解释了外部压力源是如何“深入皮肤”的。炎症的增加反过来又会引起行为的深刻变化，其中包括情绪悲伤、快感缺乏、疲劳以及社交和行为戒断等症状的开始。该项目将首次研究儿童期压力诱发炎症在儿童期至青少年期情绪和行为问题的病因学和维持中的作用。这是本项目的主要目的，我们将使用雅芳父母和孩子纵向研究（ALSPAC）的数据来满足这一目的。雅芳父母和孩子纵向研究（ALSPAC）是一项英国研究，在1991- 1992年对14000多名孕妇、怀孕后产生的孩子及其伴侣进行了研究。鉴于有证据表明，产前和童年逆境可以通过不同的机制影响儿童，将在产前和童年时期测量不良生活事件。我们还将探讨事件相互作用以预测儿童结局的复杂方式，调查按类型区分事件的重要性（例如，依赖型与独立型；慢性与偶发性），并检查其感知影响的作用。在4岁、7岁、8岁、9岁、12岁、13岁和16岁时，将使用优势和困难问卷（SDQ）来测量情绪和行为问题。在ALSPAC中，儿童炎症是在9岁左右用白细胞介素6和c反应蛋白水平测量的。我们的分析将考虑两个重要问题。首先，炎症可以由许多因素引起。因此，我们将控制各种健康风险行为（例如，不良饮食、缺乏锻炼、睡眠障碍）、环境挑战（例如，低社会经济地位）和围产期并发症，因为所有这些也可以激活炎症，我们将排除在测量炎症时感染的少数儿童。其次，炎症、压力源和情绪/行为问题之间的因果关系可能很复杂。例如，儿童的炎症既与压力源有关，也与情绪或行为问题有关。因此，我们还将探讨：i.不良生活事件在炎症中的作用。在项目的这一部分，我们将重点关注炎症测量之前的不良生活事件（即产前和0-9岁左右发生的事件），以及ii。情绪/行为问题在炎症中的作用。为此，我们将重点关注炎症测量之前的情绪/行为问题（即4-9岁左右）。还有另一个相关的目标：检查不良生活事件与情绪/行为问题之间相互影响的本质。不良的生活事件可能是这些问题的起因，也可能是结果。我们将能够使用不良生活事件的子集来检查这种关联的方向，即那些反复测量并同时评估情绪/行为问题的事件。这将使我们能够测试两种相互竞争的假设，即炎症在童年不良生活事件和情绪/行为问题之间的纵向联系中所起的作用。也就是说，a)问题引起炎症，导致生活事件，或者b)生活事件引起炎症，导致问题。

Much research has linked adverse life events to the aetiology and maintenance of emotional and behavioural problems in children. These stressors can initiate biological processes that increase risk for both types of problems in children but no study has yet examined inflammation as the stressor-induced biological process that can increase this risk. Inflammation is typically thought of as the body's primary response to physical injury or infection. However, there is now substantial evidence that stressors can also trigger significant increases in inflammatory activity which may account for how external stressors 'get under the skin'. Increases in inflammation can in turn elicit profound changes in behaviour, which include the initiation of symptoms such as sad mood, anhedonia, fatigue and social and behavioural withdrawal. This project will examine, for the first time, the role of stressor-induced inflammation in childhood in the aetiology and maintenance of emotional and behavioural problems from childhood to adolescence. This is the main aim of this project, which we will meet using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK study of more than 14,000 pregnant women in 1991-2, the children arising from the pregnancy, and their partners. Adverse life events will be measured at both the prenatal and the childhood period, in view of the evidence that prenatal and childhood adversity can affect children through different mechanisms. We will also explore the complex ways in which events may interact to predict child outcomes, investigate the importance of distinguishing events by type (e.g., dependent vs independent; chronic vs episodic), and examine the role of their perceived impact. Emotional and behavioural problems will be measured with the Strengths and Difficulties Questionnaire (SDQ) at ages around 4, 7, 8, 9, 12, 13 and 16 years. In ALSPAC, inflammation in childhood was measured at age around 9 years with levels of interleukin 6 and C-reactive protein. Our analyses will consider two important issues. First, that inflammation can be caused by a number of factors. Therefore, we will control for a diverse range of health-risk behaviours (e.g., poor diet, lack of exercise, sleep disturbance), environmental challenges (e.g., low socio-economic status) and perinatal complications, as all these can also activate inflammation, and we will exclude a small number of children with an infection at the time inflammation was measured. Second, that causal associations between inflammation, stressors and emotional/behavioural problems may be complex. For example, inflammation in children has been implicated as both the outcome of stressors and the outcome of emotional or behavioural problems. Thus we will also explore: i. the role of adverse life events in inflammation. For this part of the project, we will focus on adverse life events preceding the measurement of inflammation (that is, events that occurred at the prenatal period and at ages around 0-9 years), and ii. the role of emotional/behavioural problems in inflammation. For this, we will focus on emotional/behavioural problems preceding the measurement of inflammation (that is, at ages around 4-9 years). There is another, related, objective: to examine the reciprocal nature of the influences between adverse life events and emotional/behavioural problems. Adverse life events can be the cause but also the outcome of such problems. We will be able to examine the direction of this association using a subset of adverse life events, namely those that were measured repeatedly and at the time emotional/behavioural problems were assessed. This will enable us to test two competing hypotheses of the role of inflammation in the longitudinal link between adverse life events and emotional/behavioural problems in childhood. That is, that a) problems cause inflammation, leading to life events, or b) life events cause inflammation, leading to problems.