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

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.

Our goal is to examine the long term impact of severe early deprivation on adult brain development. Brain imaging experiments will be undertaken with a large cohort of 'orphans' who, following exposure from birth to appalling conditions in Romanian institutions of the 1980s, were adopted to homes in the UK. This sample has already given a rich longitudinal database (follow-ups at 4, 6, 11 and 15 years) and, with ESRC support, we are currently collecting further data from adoptees as they achieve adulthood. The proposed work will build both on this and on a successful imaging pilot study focusing on brain regions thought to be sensitive to early deprivation.

Our primary cohort will be compared to: (a) a native UK adopted group; (b) a group of non-adopted non-deprived controls; and-because a subset of the primary cohort have diagnoses of either Autism or ADHD-two groups of non-adopted/non-deprived clinical controls (c) with Autism and (d) with ADHD. By examining the neural impact of the deprivation in relation to its temporal parameters, and by comparing between groups as appropriate, we can address fundamental questions about brain plasticity, sensitive periods, the heterogeneity and specificity of deprivation effects, and the mechanisms of adult psychopathology.

We will assess putative adversity-sensitive brain networks using state-of-the-art MRI facilities and imaging techniques. Structural data (volume; cortical thickness and folding; white matter connectivity) will be obtained using T-1 weighted and diffusion tensor imaging. fMRI will record activation generated in networks believed sensitive to early adversity as participants undertake carefully chosen experimental tasks. Biological samples currently being collected will be used to examine whether the effects of deprivation (a) are mediated by alterations in the brain networks controlling stress reactivity; and (b) are moderated by genes controlling brain development.

Our approach to impact is best seen from the wider perspective of the English and Romanian Adoptees study as a whole. We have a strong commitment to communicating ERA's key findings to public and policy makers and work closely with professional organisations to achieve positive impact in the lives of vulnerable children and young people both currently in adversity and with adversity histories. The proposed study in combination with the ongoing ESRC funded study will deepen and extend ERA's engagement with policy makers and practitioners by intensifying our focus on disseminating messages relating to both the promotion of successful transitions to adulthood for vulnerable children with histories of adversity and the way that early adversity has fundamental impacts on brain structure and function. By highlighting the ways in which deprivation fundamentally alters brain development creating risks for poor outcomes and by studying the underlying mechanisms we hope to both draw attention to the profound difficulties faced by such individuals and also develop interventions to improve the life chances of such children thus reducing the considerable burden that they impose on families, communities, and wider society. Our communication strategy is central to our impact approach. This includes publishing in professional journals, presentations to stakeholders, and liaising with responsible media outlets. This included a recent 30 minutes documentary special on BBC Radio 4 "All in the mind" dedicated to ERA. The findings from the brain imaging study will only increase the interest of the general public, practitioners and policy makers. A key impact marker was the publication, under the auspices of British Association of Adoption and Fostering of Policy and Practice Implications from the English and Romanian Adoptees Study (Rutter, Beckett, Kreppner, & Sonuga-Barke, 2009). Targeted at national and international policy makers, and social care and clinical practitioners it identified 45 key messages - including those relating to the putative neurobiological basis of the effects of deprivation but also more generic issues such as the importance of early placement of maltreated children and the power of adoption to alter negative developmental trajectories. We also focused on the reform of institutional care around the world through a contribution to a meeting of policy makers from NGOs and governmental institutions (WHO, UNESCO, EU) with the goal of bringing the scientific work on the impact of institutional care to bear on global protection. There was a consensus at this meeting that communicating the neuro-biological consequences of maltreatment is essential to illustrate the importance of policy change to government agencies. In the current study our goal to identify neurobiological mediators of deprivation effects and also the protective and vulnerability factors made possible by its molecular genetic aspect. If this can be achieved it may be possible to start to (i) develop new therapeutic agents that specifically target deprivation-related variants of developmental disorders; (ii) identify those children in special need of intervention and (iii) target and tailor specific treatments for those children. In summary beneficiaries and users will include: a) Institutionalised, adopted, or otherwise vulnerable children who will benefit from improved care and treatment; b) Policy makers to whom the long term costs of institutional care and the importance of continuing investment in improved child protection both locally and globally, will be highlighted; c) Practitioners will be shown how to help individuals and families prepare for adult transitions and also may benefit from new therapeutic and assessment approaches that may emerge; d) Families of adopted, or otherwise vulnerable adolescents will benefit from these developments; e) Industrial partners who will help us exploit potential clinical insights from the study.