LONG TERM NEUROBIOLOGICAL IMPACT OF EARLY DEPRIVATION: IMAGING YOUNG ADULT BRAIN STRUCTURE AND FUNCTION IN THE ENGLISH AND ROMANIAN ADOPTEES STUDY.

动物研究表明，早期的生活逆境会对大脑发育产生长期影响，从而增加成年后不良结局的风险。原则上，了解这些过程可以指导对早期生活经历困难的个人的护理进展，但真正的进展取决于对人类早期逆境的平行研究。如果围绕这类工作的伦理困难能够克服，那么就有可能测试人类动物研究的神经生物学模型，并评估由此产生的临床干预措施。事实上，英国大规模收养早年在罗马尼亚孤儿院度过的儿童，为实现这一目标提供了一个独特而偶然的机会。这些领养创造了一个强大的、符合道德的自然实验，可以分离出暴露在早期逆境中的影响，从而检查其对大脑发育的影响。我们正在领导英国和罗马尼亚被领养人研究(ERA)，这是对这一队列进行的最大规模的发展研究，现已步入成年期。关于早期全球剥夺对ERA的影响的见解包括：(A)最初的破坏性影响；(B)适应与剥夺持续时间之间的联系；(C)大多数人显著追赶，但对一些人(如准自闭症；ADHD)而言，明显的与剥夺有关的问题；(D)青春期发作的情绪问题；(G)社会认知和大脑过程的调解作用；(H)遗传因素调节结果。目前，在ESRC的支持下，我们正在建立关于向成年早期生活过渡期间心理社会适应的丰富的纵向数据集。这项拟议的研究将使用成像来更深入地了解这种调整背后的神经生物学过程。我们已经在收集与这一目标相关的临床和生物学数据，并进行了一项成像试点研究，以提供方法的证据。我们将使用最先进的核磁共振设备以及结构和功能技术来检查与剥夺相关的变化，这些变化涉及四个逆境敏感的大脑网络：积极/消极经验的处理；执行控制；以及人际感知。我们将比较(A)罗马尼亚被领养者(总计N=165)；(B)英国收养的对照组(总计N=52)；(C)非收养的非剥夺对照组(N=35)；以及(D)两组未收养/非剥夺的临床(自闭症和ADHD)对照组(均为N=35)的功能。FMRI分析将侧重于直接映射到四个网络的四个实验任务产生的激活：对金钱得失反应的激励性延迟测试；对积极和负面社会暗示反应的情绪面孔加工测试；抑制控制的停止信号测试；以及人际信息处理的共情准确性测试。T-1加权和扩散张量成像还将用于检查组之间的结构差异，包括关键网络区域的体积、皮质厚度和折叠以及网络内和网络之间的白质连接。我们将比较不同群体的结构和功能数据，并将我们的测量与剥夺程度和较新的纵向数据联系起来。因此，我们可以探索剥夺对行为和临床结果影响的个体差异的神经基础；即，对极端早期逆境的适应能力和恢复能力。此外，我们将通过比较来自自闭症或ADHD的临床对照的神经数据和来自相应的与剥夺相关的表型的数据来解开剥夺和共病精神病理学的影响。最后，我们的生物样本数据库将允许我们检查(A)遗传因素是否缓和了剥夺对大脑发育的影响，以及(B)剥夺的影响是通过控制应激反应的大脑网络的变化来调节的。

Animal research shows that early life adversity has long-term consequences for brain development that increase risk of poor outcome in adulthood. Understanding these processes can, in principle, guide advances in the care of individuals with difficult early life experiences, but real progress depends on parallel research on early adversity in humans. If the ethical difficulties surrounding such work could be overcome, it would become possible to test neurobiological models derived from animal research in humans and evaluate clinical interventions resulting from them. In fact, a unique and serendipitous opportunity to do exactly this is afforded by the large-scale adoption to the UK of children who spent their early years in the Romanian orphanages of the 1980s. These adoptions have created a powerful and ethical natural experiment that allows the effect of exposure to early adversity to be isolated, and thus to examine its impact on brain development. We are leading The English & Romanian Adoptees Study (ERA), the largest developmental study of this cohort, now reaching adulthood. Insights into the effect of early global deprivation from ERA include; (a) a devastating initial impact; (b) a link between adjustment and deprivation duration; (c) remarkable catch-up for most individuals, but marked residual deprivation-linked problems for some (e.g., quasi-autism; ADHD); (d) adolescent onset emotional problems; (g) a mediating role for socio-cognitive and brain processes; (h) moderation of outcomes by genetic factors. Currently, with ESRC support, we are building rich longitudinal dataset on psychosocial adjustment during transition to early adult life. The proposed research will use imaging to gain deeper understanding of the neurobiological processes underlying this adjustment. We are already collecting clinical and biological data relevant to this goal, and an imaging pilot study has been conducted to provide proof of method. We will use state-of-the-art MRI facilities and structural and functional techniques to examine deprivation-related alterations in four adversity-sensitive brain networks implicated in; the processing of positive/negative experiences; executive control; and interpersonal perception. We will compare the functioning of (a) the Romanian Adoptees (total N=165); (b) a UK-adopted comparison group (total N=52); (c) a non-adopted, non-deprived control group (N=35); and (d) two groups of non-adopted/non-deprived clinical (Autism and ADHD) controls (both N=35). fMRI analysis will focus on activation generated by four experimental tasks that map directly on to the four networks: An incentive delay test of responses to monetary gain and loss; an emotional face processing test of responses to positive and negative social cues; a stop signal test of inhibitory control; and an empathic accuracy test of interpersonal information processing. T-1 weighted and diffusion tensor imaging will also be used to examine structural differences between groups, including volumes of key network regions, cortical thickness and folding, and white matter connectivity within and between networks. We will compare structural and functional data across groups and relate our measures to both extent of deprivation and more recent longitudinal data. We can thus explore the neural basis of individual variation in the effects of deprivation on behavioural and clinical outcomes; that is, resilience to, and recovery from, extreme early adversity. Furthermore, we will disentangle the effects of deprivation and co-morbid psychopathology by comparing neural data from clinically referred controls with Autism or ADHD with data from the corresponding deprivation-related phenotypes. Finally our biological sample database will allow us to examine whether (a) genetic factors moderate the effects of deprivation on brain development, and (b) the effects of deprivation are mediated by changes in the brain networks controlling stress reactivity.