THE IMPACT OF EARLY ADVERSITY ON TRAJECTORIES OF BRAIN MATURATION AND MENTAL HEALTH IN YOUNG ADOLESCENTS

WHAT IS THE PROPOSED STUDY ABOUT?
Psychiatric disorders, like depression, schizophrenia, bipolar disorder, and anxiety affect millions of people around the world. They disturb thinking, mood, and behaviour, and can interfere with daily life with devastating effects. They usually strike at a young age and it is very important to understand how early in the life of an individual we are still able to intervene and modify the risk of developing these disorders. For example, the risk is higher in those who have experienced trauma and adversity, and in those living in deprived social conditions. However, we do not know if the brain develops differently in those adolescents with adversity, and whether this explains why they are more likely to experience certain types of mental health problems. Furthermore, we do not know whether factors such as growing up in a very supportive family environment, or having higher general intelligence, may protect some adolescents from the effects of early adversity, preventing the brain from developing differently and from experiencing psychiatric symptoms later on.

WHAT IS ALREADY KNOWN ABOUT THIS AREA?
We know that individuals who have suffered traumatic experiences, and those with mental health problems, show alterations in the structure of the brain. For example, regions involved in memory (frontal lobe, hippocampus) are smaller in volumes. However, we do not know when these alterations start, or whether they stay the same throughout adolescence. Also, we do not know whether they particularly occur in those adolescents that have an activation of the body's response to stress. In fact, the activation of the stress system triggers a response in the "immune system", the system dedicated to fight infections in our body. This is a situation also seen in patients with depression and schizophrenia, whose bodies behave as if they were fighting an infective agent, even though they do not have an ongoing infection.

Therefore, it is possible that social adversity and this immune response interact with an underlying vulnerability in the brain, causing the brain to develop differently across adolescence, and making the person more likely to experience certain mental health problems, such as depression or psychosis. Unfortunately, the development of the brain throughout the full adolescence, and its relationship with the environment, and the immune system, in adolescents from the general community has never been studied. This is what we are planning to do in this study.

WHAT WILL THE STUDY INVOLVE?
We propose to evaluate and follow up 440 school adolescents (age 11-14 years), with and without an experience of adversity, who are already participating in other studies on risk factors for poor mental health. These studies are being conducted in the UK and in six other European countries. We will evaluate these adolescents three times, over a few years. Each time, we will assess brain structure and immune response. We will use an approach called "magnetic resonance", which allows us to look at the brain structure without using radiations, and to look at how brain changes over time. We will measure immune response in a blood sample. This study has the big advantage that more than half of these adolescents have already been evaluated with these measures in the two studies, and we will simply access the existing assessments.

HOW WILL THE STUDY HELP PEOPLE WITH MENTAL HEALTH PROBLEMS?
We are confident that this study can help us understand what are the times when adolescents are most vulnerable to mental health problems, when interventions (talking therapy or medications) can reduce risk of adverse mental health outcomes.

RESEARCH OBJECTIVES: Mental disorders usually develop in young individuals, and the risk is increased by exposure to early adversity, such as childhood maltreatment, adverse life events, and area-level disadvantage. We will establish: 1) How and when individual and area-level early adversity affects brain development (i.e., longitudinal growth trajectory of brain areas involved in psychiatric disorders, built on three longitudinal brain MRI scans); 2) Whether these alterations in growth trajectory are associated with the onset of specific psychopathology domains; and 3) If these alterations in growth trajectory are explained by persistent alterations in the levels of inflammatory markers.

EXPERIMENTAL DESIGN: We will study n=440 children and young adolescents (age 11-14) from two funded school-based longitudinal cohorts. We will enrich the existing data by collecting additional neuroimaging and immune markers measures in n=220 subjects from each cohort, selected for presence (n=110) or absence (n=110) of early adversity:
- In REACH (UK; original sample n=4010), with three MRI assessments over three years, and serum samples for immune biomarkers;
- In IMAGEN (Six EU countries; original sample n=2000) (three MRI assessments already available), with measures of immune markers in already collected serum samples;

We will model the relationship between early adversity, brain growth, psychopathology domains, and immune markers, using multivariable statistical models.

APPLICATION OF RESULTS: Characterising the biological changes associated with risk of mental health problems can ultimately provide evidence for targeting interventions to the most vulnerable individuals.

The lack of knowledge on the neurobiological link between early individual and environmental adversity and poor mental health has hindered the development of targeted, cost-effective prophylactic and therapeutic interventions for those most at risk. Therefore, the impact of this study will go far beyond that of academic research (see Academic beneficiaries for details on this aspect), starting to pave the way for novel interventions and personalised medicine where treatment decisions can be made based on the individual's characteristics.

IMPACT ON NATIONAL HEALTH:
- We will benefit young people with a history of early adversity and poor mental health, offering a model that may help identify the most vulnerable individuals, at a crucial developmental point. We will offer them a rationale for stress management and innovative pathways for potential future drug discovery (such as anti-inflammatory agents). We will benefit patients' families and loved ones will benefit from improvement in the conceptualisation of how adversity drives poor mental health and how resilience can be strengthened, with available intervention strategies. The timescale for this is medium to long-term: if brain and immune markers can reliably help identifying times of maximum vulnerability for the onset of psychopathology, anti-inflammatory agents could be trialled in this population as they are currently trialled in clinically manifest depression and psychosis; furthermore, stress-coping strategies could be delivered in a cost-effective way in the context of limited health care resources.
- The lay public will also benefit from our work: a non-stigmatising approach based on a sound biological basis to understand vulnerability to poor mental health, and an explanatory model that emphasises not only risk factors but also resilience and possible future therapeutic interventions. The time-scale for this is therefore immediate, as we intend to vigorously disseminate our findings to the general public.
- Stakeholders in health care, such as charities and non-governmental organisations, will benefit from the model we propose. Understanding how neurobiological changes at specific time points in adolescence allow early adversity to drive poor mental health can inform how interventions could be used in a more selective and personalized way, potentially improving mental health outcomes and avoiding unnecessary exposure to drugs or long-term psychological interventions. The time-scale for this is also immediate, and we have an effective communication strategy to reach stakeholders and third-sector organisations.
- Research & Development leaders, from service developers, pharmaceuticals and biotech companies, will benefit from the evidence offered by our study: it will guide them in prioritizing resources, in the difficult times ahead, identifying potential new mechanisms for novel agents relevant to brain plasticity, neurodevelopment and peripheral biomarkers, as well as biomarkers for personalised medicine and stratification. With effective communication, the time-scale for this is medium/long-term.

IMPACT ON NATIONAL WEALTH:
- Mental health problems in adolescence often persist into adulthood and consequently have long term impacts on individuals and their families and friends, with knock on effects on productivity, use of health care services, and demand for welfare assistance. That is, there are large associated direct costs to individuals, families, and health and other services, and indirect costs for the loss of productivity. Any study that can help elucidate the processes underpinning the development of mental health problems and inform strategies for prevention and intervention, will be beneficial to society at large. This is particularly important at a time when healthcare and social resources are increasingly stretched.