Neonatal Nucleus Accumbens Microstructure Modulates Individual Susceptibility to Preconception Maternal Stress in Relation to Externalizing Behaviors.

Objective: Maternal stress influences in utero brain development and is a modifiable risk factor for offspring psychopathologies. Reward circuitry dysfunction underlies various internalizing and externalizing psychopathologies. This study examined (1) the association between maternal stress and microstructural characteristics of the neonatal nucleus accumbens (NAcc), a major node of the reward circuitry, and (2) whether neonatal NAcc microstructure modulates individual susceptibility to maternal stress in relation to childhood behavioral problems.

Method: K-means longitudinal cluster analysis was performed to determine trajectories of maternal stress measures (Perceived Stress Scale [PSS], hair cortisol) from preconception to the third trimester. Neonatal NAcc microstructural measures (orientation density index [ODI] and intracellular volume fraction [ICVF]) were compared across trajectories. We then examined the interaction between maternal stress and neonatal NAcc microstructure on child internalizing and externalizing behaviors, assessed between ages 3 and 4 years.

Results: Two trajectories of maternal stress magnitude ("low"/"high") were identified for both PSS (n = 287) and hair cortisol (n = 336). Right neonatal NAcc ODI (rNAcc-ODI) was significantly lower in "low" relative to "high" PSS trajectories (n = 77, p = .04). PSS at preconception had the strongest association with rNAcc-ODI (r = 0.293, p = .029). No differences in NAcc microstructure were found between hair cortisol trajectories. A significant interaction between preconception PSS and rNAcc-ODI on externalizing behavior was observed (n = 47, p = .047).

Conclusion: Our study showed that the preconception period contributes to in utero NAcc development, and that NAcc microstructure modulates individual susceptibility to preconception maternal stress in relation to externalizing problems.

Plain Language Summary: In the S-PRESTO population-based cohort study conducted in Singapore with 351 women and their children, higher levels of maternal perceived stress within the year before pregnancy were associated with increased dendritic complexity within offsprings' nucleus accumbens, indicative of a more advanced developmental profile. Variations in right nucleus accumbens microstructure significantly modulated the association between maternal perceived stress at preconception and externalizing behaviors in early childhood. Study findings suggest that maternal stress in the preconception period accelerates in-utero nucleus accumbens development, leading to differential risk to externalizing problems in later childhood.