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

Lead Research Organisation: University College London
Department Name: Psychology and Human Development

Abstract

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.

Planned Impact

Our project findings will be of interest and, we hope, use to a number of groups. The first group are those making decisions about preventive and early treatment interventions. If our main hypothesis that early (including prenatal) stressors can lead to inflammation in children in turn leading to emotional difficulties or behaviour problems is supported, then we will have shown what reduction in type and number of early stressors can benefit children, and what reduction in inflammation can benefit children at risk. But even if it is not, our research will have shown to what extent early adversity and emotional/behavioural problems can predict inflammation, a precursor of several medical conditions. From a practice perspective, our project findings may suggest that it can be valuable for researchers to incorporate assessments of inflammation into prevention-oriented intervention studies for high-risk children (such as those whose mothers were exposed to high levels of psychosocial stress in pregnancy or those exposed to adversity themselves). This will provide insight into whether it is possible to reverse or minimise dysregulated inflammatory processes. In the future, practitioners may be able to utilise biomarkers of inflammation to identify children at high risk for long-term health problems, or to evaluate the effectiveness of social interventions to prevent future chronic disease risk among high-risk children. Given the effects of psychosocial stressors on inflammation, improvements in social environments are likely to be beneficial. Emerging data indicate that exercise, weight loss, yoga and meditation may have anti-inflammatory effects, and these approaches may be particularly appropriate components of social interventions for children exposed to adversity. If our findings show that emotional or behavioural problems cause inflammation, then we would suggest that efforts to prevent or treat emotional and behavioural problems in childhood could help prevent disease risk.

A second group to whom results will be addressed are the general public, especially parents and expectant parents. Academic researchers are a third category of users, including those with a substantive interest in child emotional and behavioural development, those interested in stressor 'effects' and those interested in advanced longitudinal modelling. Finally, we hope to inform those commissioning research in child development, who, to a large extent, continue to underestimate or neglect the interaction between the body and the mind. Our project will show if compartmentalising the domains of child functioning (into the physical and the mental, for example) in training, funding, research and social services programmes may be contraindicated.

To reach these groups, we will organise a 1-day seminar, publish accessible research briefings and press release project findings, and engage with the social media (see also Pathways to Impact). The press releases on project findings attract significant media and government interest. The research briefings will include papers for magazines (such as the Psychologist) and reports that will be available on the UCL website to download at no cost, will be targeted not only at academics but also at policy makers and the public, and will summarise research findings in non-technical language.

Publications

10 25 50

publication icon
Flouri E (2020) Neighbourhood deprivation and child behaviour across childhood and adolescence in Longitudinal and Life Course Studies

publication icon
Ji D (2021) Social cognition and cortisol in the general population: A systematic review and meta-analysis. in Stress and health : journal of the International Society for the Investigation of Stress

 
Description We have published several papers from this grant, have papers under review and in preparation. We have linked several students to our project and have supported them (note: *student author).

For example, some of the published papers:
1. Francesconi, M., *Minichino, A., Khandaker, G. M., Midouhas, E., Lewis, G., & Flouri, E. (forthcoming). Internalising symptoms mediate the longitudinal association between childhood inflammation and psychotic-like experiences in adulthood. Schizophrenia Research
2. Flouri, E., Francesconi, M., Papachristou, E., Midouhas, E., & Lewis, G. (2019). Stressful life events, inflammation and emotional and behavioural problems in children: A population-based study. Brain Behavior and Immunity, 80, 66-72
3. Papachristou, E., Flouri, E., *Kokosi, T., & Francesconi, M. (2019). Main and interactive effects of inflammation and perceived neighbourhood cohesion on psychological distress: Results from a population-based study in the UK. Quality of Life Research, 28, 2147-2157
4. Midouhas, E., Flouri, E., Papachristou, E., & *Kokosi, T. (2018). Does general intelligence moderate the association between inflammation and psychological distress? Intelligence, 68, 30-36
5. Flouri, E., Narayanan, M. K., & Nærde, A. (2018). Stressful life events and depressive symptoms in mothers and fathers of young children. Journal of Affective Disorders, 230, 22-27
6. Flouri, E., Francesconi, M., Papachristou, E., Midouhas, E., & Lewis, G. (in press). Prenatal and childhood adversity and inflammation in children: A population-based longitudinal study. Brain Behavior and Immunity
7. Flouri, E., Francesconi, M., Midouhas, E., & Lewis, G. (in press). Prenatal and childhood adverse life events, inflammation and depressive symptoms across adolescence. Journal of Affective Disorders
8. Flouri, E., Lewis, G., & Francesconi, M. (under review). Trajectories of internalising and externalising symptoms and inflammation in the general child population.
9. *Kokosi, T., Flouri, E., & Midouhas, E. (in press). Do upsetting life events explain the relationship between low socioeconomic status and systemic inflammation in childhood? Results from a longitudinal study. Brain Behavior and Immunity

In preparation:
1. Wong, K. K., Francesconi, M., & Flouri, E. (in preparation). Behavior symptom profiles in childhood predict psychotic-like experiences in adolescence.
2. *Ji, D., Flouri, E., & Papachristou, P. (in preparation): Social cognition and stress: A systematic review and meta-analysis

Our main findings are as follows.

1. The association between adverse life events and children's emotional problems is bidirectional but inflammation (IL6) mediates the effect of events on emotional problems, not the reverse. This is in line with our hypotheses.

2. Inflammation-induced internalising problems (i.e., emotional social difficulties) during childhood may be relevant for the future onset of psychotic-like experiences in adulthood.

3. At the same time, increases in emotional and social difficulties can lead to elevated levels of inflammatory markers in healthy children. Children who had increasing levels of internalising symptoms over childhood were more likely to have higher levels of CRP and IL-6 at 9 years of age, even after adjustment for confounders. A one-unit increase in the rate of annual change of internalising symptoms was related to an increase of 12% and 8% in the level of CRP and IL-6, respectively. This suggests there may be a robust pathway, via increases in emotional and social difficulties, to elevated inflammation in healthy children. Thus, successful interventions targeting children experiencing chronic emotional and social difficulties could also have physical health benefits.

4. In the general child population, increasing adversity in childhood is associated with the early onset of depressive symptoms, partly via increasing levels of plasma IL-6.

5. Independently of prenatal adversity, the number and increase in number of adverse life events experienced in childhood are associated positively with plasma levels of inflammatory markers, such as IL-6, in girls. This gender specificity warrants further research.

6. Early socioeconomic disadvantage predicted higher levels of IL-6 even after adjusting for confounders. This association was partially mediated by upsetting life events. This suggests that in the general child population, low SES is associated with increased exposure to stressful life events, in turn associated with later inflammation. These findings highlight the role of stressors associated with poverty and disadvantage in the development of inflammation among children in the general population.

Collaborations, new resources identified and used, and new directions for future research.

1. We have linked two PhD students (one of whom is ESRC-funded) to the grant, Kokosi and Ji. They have already worked on papers. Kokosi has published several.
2. We have started a collaboration with the Young Finns study team. We already have a paper in preparation where we use mendelian randomisation to test if the link we have identified between inflammation and social and emotional difficulties in children is causal ('Clemens, A.*, Elovainio, M.J., Flouri, E., & Heikkila, K. (in preparation). The association between inflammation and personality traits in children using mendelian randomization: The Cardiovascular Risk in Young Finns Study').
3. The post-doctoral researcher on the grant, Francesconi, is due to submit a bid for a fellowship to test and extend the grant's findings in another domain, cognition, also using ALSPAC (Francesconi, M. (in preparation) 'Inflammation and cognition in young adults: The roles of brain abnormalities and stressful life events').
4. We are starting a new PhD studentship which will use data from the UK Biobank to test the link between inflammation, depression and (impaired) cognition in adults, while controlling for genetic risk.
5. We have collaborated with ARUP to submit a bid (to ESRC) to explore, using data from Understanding Society, the role of inflammation in explaining the link between the built environment and cognition in adults. This was eventually unsuccessful.
6. We have collaborated with researchers from the Universities of Oxford (Minichino) and Cambridge (Khandaker) on some of our papers.
Exploitation Route 1. We show that the association between inflammation in childhood and psychotic like experiences in adult life, is partly due to inflammation-induced internalising symptoms. Thus our findings provide a background for future studies investigating tailored therapeutic approaches, which are greatly needed especially in the prodromal phase of psychotic spectrum disorders where no effective interventions are currently available.
2. If the association we observe in children is causal, i.e., stress causes child ill mental health at least partially by inflammation, then this identifies targets for prevention and treatment.
3. We show that longitudinal increases in events, irrespective of their impact, experienced in childhood are associated with IL-6 level in girls. This suggests that girls experiencing adverse experiences in childhood are a high-risk group for poor physical health. Given the links we established in this grant between physical heath (inflammation) and mental health, this suggests the importance of targeting girls experiencing increases in adversity.
4. Increasing exposure to psychosocial stressors over time during the first decade of life was related to depressive symptoms in early adolescence, partly via increased levels of inflammatory markers. Importantly, the same or very similar psychosocial stressors experienced prenatally and around birth were also related to depressive symptoms in early adolescence, but not via elevated inflammation, suggesting qualitatively different pathways to adolescent depression by early and recent psychosocial stressors.
Sectors Communities and Social Services/Policy,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Bloomsbury Colleges PhD studentship
Amount £71,000 (GBP)
Organisation Bloomsbury Colleges 
Sector Academic/University
Country United Kingdom
Start 10/2020 
End 09/2023
 
Description British Academy Small Grants Scheme
Amount £10,000 (GBP)
Organisation The British Academy 
Department British Academy/Leverhulme Trust Senior Research Fellowships
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 12/2019
 
Description Socioeconomic differences in child cognitive outcomes:The role of inflammation
Amount £71,000 (GBP)
Funding ID 1992039 
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 09/2017 
End 09/2020
 
Description The Role of Reward and Punishment Sensitivity in the Development of Eating Disorders. A Prospective Cohort Study
Amount £166,604 (GBP)
Funding ID MR/S019707/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2019 
End 02/2021
 
Description ALSPAC papers - external collaborators 1. Oxford 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a collaboration with Oxford's psychiatry department (Minichino) which resulted in a paper (now publishedf) linked to the grant (also using ALSPAC), on internalising and psychotic symptoms.
Collaborator Contribution Intellectual leadership and steer. The PDRA on our grant (Francesconi) is the first author.
Impact Paper now published.
Start Year 2018
 
Description ALSPAC papers - external collaborators 2. Cambridge 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a collaboration with Cambridge's dept of psychiatry (Khandaker), also using ALSPAC, and linked to our project. The result of this collaboration is a paper, now published, which examines the association between inflammation and psychotic symptoms, building on Khandaker's and our own work on inflammation in the ALSPAC dataset.
Collaborator Contribution Intellectual leadership and steer. I am the senior (last author)
Impact paper now published
Start Year 2018
 
Description ALSPAC papers - external collaborators 3. UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a collaboration with UCL's department of psychiatry (Solmi), again using ALSPAC, which extends some of our grant findings. The result of this is a paper (under review) and capacity building for Solmi, the early career person who is the first author.
Collaborator Contribution Mentoring and steer. I also lead on cognition.
Impact Paper is under review.
Start Year 2018
 
Description Bloomsbury Colleges PhD studentship (E. Flouri, S. Papachristou, E. Meaburn): 'Educational attainment, inflammation and depression: shared genetic aetiology or causal pathway 
Organisation Birkbeck, University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a new funded phd studentship which was inspired by this award, and which will extend the findings of this award. The topic is the association between cognition, inflammation and mental health, this time in adults. One of the main risk factors consistently associated with depression progression is low educational attainment (EA), linked to family and social circumstances but also to genetic factors. EA is also a significant predictor of inflammation which, in turn, appears to play a key role in the pathogenesis of depression via stress and other biological pathways. EA and inflammatory markers have been shown to have significant inverse genetic correlations, while twin studies additionally show that genes promoting inflammation are involved in the pathogenesis of depression. Taken together, these findings indicate either that EA, inflammation, and depression are correlated for genetic reasons, or that there are direct causal links between EA and inflammation with depression, but also between inflammation and depression. It is also likely that inflammation acts as a partial mediator for the relationship between EA and depression. This PhD project has three main objectives: first, to examine if EA is causally related to inflammation and depression, second, to investigate if inflammation is causally related to depression, and third, should the first two objectives yield positive findings, to examine if inflammation acts as a mediator of the relationship between EA and depression. To test for the shared genetic basis and causal links between EA, inflammation, and depression, we will use data derived from Understanding Society, a longitudinal study of around 40,000 UK households for which data on depression, EA, and blood inflammatory markers, and genome-wide genetic data are available.
Collaborator Contribution Our collaborator, E. Meaburn, will advise on our use of molecular genetic data.
Impact It is multidisciplinary. It has not started yet
Start Year 2020
 
Description Inflammation SNPs - the Young Finns study 
Organisation University of Helsinki
Country Finland 
Sector Academic/University 
PI Contribution This is a collaboration with LSHTM (Heikkila and Clemens) and the University of Helsinki (Elovainio) and extends some of our grant's findings, using the young finns study. The paper is being prepared and the first author is a masters student (Clemens), working under our guidance.
Collaborator Contribution The idea for the project was given by Flouri. Heikkila led on the data access and the day to day management of the work, and Elovainio facilitated data access
Impact Paper is being prepared.
Start Year 2018
 
Description MRC grant on eating disorders 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the CoI on this grant. The PI is Amy Harrison, an early career person in my department. There are no other investigators. This MRC project, also using the MCS, is linked to this ESRC grant because it was inspired by some of our grant's early findings (now published) using the CGT in MCS.
Collaborator Contribution The PI on the MRC grant is a clinical psychologist, expert in eating disorders. We will work closely with experts in computational psychiatry and epidemiology.
Impact No outputs yet, but papers submitted and in preparation
Start Year 2018
 
Description Scientific advisory network for CLS cohorts 
Organisation University College London
Department Centre for Longitudinal Studies
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been invited to join a new scientific advisory network to support the development of the CLS cohorts. I have joined a small and focussed group on the theme of 'Mental health across the life course'. The overall purpose of the network is as a resource for strategic advice and support for the development of the CLS cohorts.
Collaborator Contribution CLS runs most of the UK cohort studies. This will be a platform for discussions of the development of the cohorts. They will also call on my advice, on an ad hoc basis, for example to support the design of a new study sweep for one of their studies, or when they are developing strategic funding bids. As well as providing strategic advice and support to the cohorts, this will be a forum for developing new ideas, and collaborations.
Impact No outcomes yet. Yes, it will be multidisciplinary. The cohorts are of scientific interest to all the social sciences and most of the medical ones, too.
Start Year 2019
 
Description Royal Society valuing nature event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I was part of this invitation only event (the 'Valuing Nature' annual conference) at the Royal Society (November 2019) in which I presented and chaired. 'Valuing Nature' is the five year, £6.5m cross council programme that funds research into the role of biodiversity and ecosystem processes in human health https://valuing-nature.net/about.
Year(s) Of Engagement Activity 2019