The societal impact of conduct problems (e.g., fighting, stealing) is profound, but the degree of impact is related to when conduct problems start (1). Compared with their later onset counterparts, individuals with an onset of conduct problems in early childhood are at high risk for persistent criminal behaviors and the development of antisocial personality disorder (2); these youth are often also impaired in multiple settings (social, educational and interpersonal) and are at increased risk for developing mental and physical health problems in adulthood (3). Research has highlighted that childhood onset individuals can present impaired cognitive (e.g., IQ, attention, inhibition) and emotional (e.g., callousness, anxiety, depression) function (4-6), and the role of neurobiological factors in explaining persistent offending in the early onset group has attracted attention. However, only a handful of neuroimaging studies to date have focused on children with conduct problems and these have often identified structural and functional atypicalities in affect processing and affect regulation areas of the brain (e.g. amygdala, orbitofrontal cortex and anterior cingulate cortex) (7). Most brain imaging studies, however, have either not assessed the timing of onset of conduct problems (8, 9), or are based on cross-sectional designs with retrospective reporting used to establish childhood onset (10). Moreover, few published neuroimaging studies have taken into account the risk environments (e.g., poverty, stressful life events, poor parenting) that associate with abnormal brain structure and/or function, and potential biological mechanisms (e.g., DNA methylation) that could at least partially explain brain differences for those exposed to chronic risk. These two limitations are important to redress, for at least three reasons. First, childhood onset children are shown to be exposed to a high incidence of prenatal and early postnatal risks that also associate with impaired (long-term) brain function and structure (11). Second, in certain studies, risk exposures explain differences in the cognitive functioning of delinquents (12). Third, a potential biological mechanism that can affect both the structure and function of the brain, on the experience of chronic risk, is epigenetics (13, 14). The potentially modifiable nature of environmental and epigenetic risk holds particular relevance for clinical and public health policies aimed at reducing the prevalence of conduct problems.

This application proposes the first systematic cross-national examination of potential neurobiological differences in different onsets of conduct problems in two comparable longitudinal epidemiological birth cohorts: The Avon Longitudinal Study of Parents and Children (ALSPAC; UK) and Generation R (GenR; The Netherlands). The proposal includes extensive measures of environmental stress exposures beginning prenatally and extending to late-childhood; DNA sampling from the same individuals at birth, age 7, age 9 (ALSPAC) and age 10 (GenR); brain imaging at ages 10 (GenR) and age 18 (ALSPAC); and the construction of developmental phenotypes of conduct problem trajectories between ages 4 and 13 (ALSPAC), and age 3 and 10 (GenR). This novel and innovative application has five specific aims:

Aim 1. Does structural and functional brain imaging differ between early childhood onset and later onset conduct problem trajectories?

Aim 2. Do any identified differences in brain structure and/or function associate with environmental risk exposure (prenatal and/or postnatal)?

Aim 3. Are risk exposure-to-brain associations at least partially explained by DNA methylation differences?

Aim 4. Is the impact of risk on brain structure/function and DNA methylation greater the earlier and more chronic the experience? (e.g., prenatal vs. postnatal).

Aim 5. Are the above Aims replicable in ALSPAC and GenR?

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