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，早期生活中的逆境对大脑发育有长期影响，会增加成年后不良后果的风险。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取得进展，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被克服，就有可能在人类身上测试来自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，一个独特而偶然的机会恰恰提供了这样做的机会：20世纪80年代，在罗马尼亚孤儿院度过早年时光的儿童被大规模收养到英国。这些收养创造了一个强大而合乎道德的自然实验，使早期逆境的影响得以分离出来，从而检验其对大脑发育的影响。我们正在领导英国和罗马尼亚被收养者研究（ERA），这是该队列中最大的发展研究，现已进入成年期。关于早期全球剥夺ERA影响的见解包括；(a)破坏性的初始影响；(b)调整和剥夺时间之间的联系；(c)大多数人都有显著的进步，但有些人仍然存在明显的与剥夺相关的问题（例如，准自闭症；多动症）；(d)青春期开始出现情绪问题；(g)社会认知和大脑过程的中介作用；(h)遗传因素对结果的调节作用。目前，在ESRC的支持下，我们正在建立丰富的纵向数据集，研究向早期成年生活过渡期间的社会心理适应。拟议的研究将使用成像技术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，以提供方法的证明。我们将使用最先进的核磁共振设备和结构和功能技术来检查涉及以下四个逆境敏感的大脑网络中与剥夺相关的变化；积极/消极经历的处理；执行控制;以及人际感知。我们将比较(a)罗马尼亚被收养者（总N=165）的功能；(b)英国采用的对照组（总N=52）；(c)非收养、非剥夺对照组（N=35）；(d)两组非收养/非剥夺临床（自闭症和ADHD）对照（N=35）。功能磁共振成像（fMRI）分析将重点关注直接映射到四个网络的四个实验任务所产生的激活：对金钱得失反应的激励延迟测试；积极和消极社会线索反应的情绪面孔加工测试抑制性控制的停止信号试验；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也将用于检查各组之间的结构差异，包括关键网络区域的体积，皮质厚度和折叠，以及网络内部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最近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；也就是说，从早年的极端逆境中恢复过来。此外，我们将通过比较自闭症或ADHD临床对照的神经数据与相应的剥夺相关表型的数据，来解开剥夺和共病精神病理的影响。最后，我们的生物样本数据库将允许我们检查是否(a)遗传因素缓和剥夺对大脑发育的影响，以及(b)剥夺的影响是由控制应激反应的大脑网络的变化介导的。

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.