Promoting good mental health and well-being across the population is a strategic priority within the United Kingdom [1] and across the globe [2]. Good mental health influences the capacity to thrive and flourish, while conversely, poor mental health affects indices as diverse as physical well-being and health, work satisfaction and achievements, and a range of interpersonal relationships. Yet, poor mental health characterizes up to a quarter of the UK adult population [3]. Given that many adult psychosocial difficulties (e.g. depression, substance use, unemployment) can be traced to neurodevelopmental difficulties in childhood [4], investigating early risk pathways is crucial for early detection and prevention [5]. There is good evidence in animal studies, and increasing evidence in humans, that early-life adversity can promote chronic, low-grade inflammation [6] and vulnerability for later mental health problems - and may do so through the immune system’s role in brain development. The “hidden wounds hypothesis” [7] indeed proposes that early psychosocial adversity translate into biological risk for mental illness by negatively affecting the role of the immune system in brain development [8]. Of interest, inflammatory markers can cross into the brain through several routes (e.g. afferent fibers, vagus nerve, permeable blood brain barrier) and (in animals) modulate synaptogenesis, synaptic refinement and survival, as well as myelination [8, 9]. Recent evidence also suggests that DNA methylation, a type of epigenetic modification that regulates gene expression, may be a biological mechanism by which adversity can result in low-grade chronic inflammation through affecting the regulation of genes involved in inflammation [10]. However, in humans, little is known about how adversity in different developmental periods may affect immune-related DNA methylation, which in turn could influence neurodevelopmental and mental health problems.

What we have done so far:
Using DNA methylation loci from a recent independent epigenome-wide study of serum C-reactive protein (CRP) [11] – a biomarker of chronic inflammation – we [12] created inflammation-related polyepigenetic risk scores (i-ePGS; similar to polygenic risk scores) in the Avon Longitudinal Study of Parents and Children. Of interest, we replicated the previous study [11] by showing that i-ePGS scores associated with serum CRP. We then examined prospective associations with cognitive function and mental health problems. We found that higher i-ePGS at birth associated with lower cognitive function (i.e. WISC-III), which, in turn, associated with higher mental health problems between ages 7 – 15. Persisting i-ePGS in childhood (age 7) further associated with higher internalizing problems. We therefore have provided preliminary evidence that i-ePGS scores can associate with mental health problems and that the brain may be involved.

Why additional research is needed:
i) a better understanding of adversity and immune system variation with age. The changing immune-related risk environment (e.g. prenatal: maternal depression/obesity; neonatal: housing adequacy/breast feeding, etc.) coincides with a developing immune system (i.e. innate and adaptive). Environmental factors can influence adaptive changes in the immune system (e.g. potentially evidenced through DNA methylation: see [13]) and may help to explain age-correlated inflammatory responses to stress [14]. For example, in neonates only, IL-8 is shown to have specific T cell effector functions [i.e. proinflammatory; 15]. In contrast, increased concentrations of other pro-inflammatory cytokines (e.g. IL-6) are found in the circulation of adolescents/adults [14]. Research is needed to examine age-correlated “biological embedding” of environmental factors that might affect the development and long-term functioning of the immune system. ii) a more fine-tuned understanding of developmental variation in immune markers associate with changes in brain structure. Animal models show that during pregnancy and after birth peripheral inflammation can modulate the development and function of the brain for better and for worse [9]. Similar patterns are evident in humans: intrauterine inflammation associates with altered expression of placental tissue genes known to associate with cognitive impairment [16]. Adversity-related infection and inflammation are associated with impaired child cognitive function and language [17], and increased risk for depression [18]. Indeed, in an in vitro study, Prof Pariante’s group [19] reported that higher level of inflammatory markers (i.e. INF-alpha, IL-6) decreased neurogenesis and increased apoptosis in hippocampal cells – results that are highly relevant for depression. Yet, there are currently few published neuro-imaging studies. A recent paper [20] based on a small sample (n = 31) of female university students suggested increased IL-6 in response to a stressor associated with heightened connectivity in brain areas implicated in depression (e.g. amygdala, dorsomedial prefrontal cortex). Research based on large-scale epidemiological samples is needed to replicate and extend these findings. iii) testing degree to which variability in brain development help can explain (i.e. mediate) the relationship between immune function, DNA methylation and mental health. Research examining the degree to which brain-imaging can be predictive of subsequent mental health is in early stages and with mixed results [21, 22]. A recent adult brain imaging study, however, reported that an association between higher CRP levels and higher depressive symptoms was mediated by decreased functional connectivity between the ventromedial prefrontal cortex and the ventral striatum [23]. Hence, data support the idea that adversity-related inflammation can shape neurodevelopment, which in turn, can increase vulnerability for emotional problems.

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