The third trimester of pregnancy represents a sensitive phase for infant brain plasticity when a series of fast-developing cellular events (synaptogenesis, neuronal migration, and myelination) regulates the development of neural circuits. Throughout this dynamic period of growth and development, the human brain is susceptible to stress. Preterm infants are born with an immature brain and are, while admitted to the neonatal intensive care unit, precociously exposed to stressful procedures. Postnatal stress may contribute to altered programming of the brain, including key systems such as the hypothalamic–pituitary–adrenal axis and the autonomic nervous system. These neurobiological systems are promising markers for the etiology of several affective and social psychopathologies. As preterm birth interferes with early development of stress-regulatory systems, early interventions might strengthen resilience factors and might help reduce the detrimental effects of chronic stress exposure. Here we will review the impact of stress following premature birth on the programming of neurobiological systems and discuss possible stress-related neural circuits and pathways involved in resilience and vulnerability. Finally, we discuss opportunities for early intervention and future studies.

Given the long-lasting detrimental effects of internalizing symptoms, there is great need for detecting early risk markers. One promising marker is freezing behavior.Whereas initial freezing reactions are essential for coping with threat, prolonged freezing has been associated with internalizing psychopathology. However, it remains unknown whether early life alterations in freezing reactions predict changes in internalizing symptoms during adolescent development. In a longitudinal study (N = 116), we tested prospectively whether observed freezing in infancy predicted the development of internalizing symptoms from childhood through late adolescence (until age 17). Both longer and absent infant freezing behavior during a standard challenge (robot-confrontation task) were associated with internalizing symptoms in adolescence. Specifically, absent infant freezing predicted a relative increase in internalizing symptoms consistently across development from relatively low symptom levels in childhood to relatively high levels in late adolescence. Longer infant freezing also predicted a relative increase in internalizing symptoms, but only up until early adolescence. This latter effect was moderated by peer stress and was followed by a later decrease in internalizing symptoms. The findings suggest that early deviations in defensive freezing responses signal risk for internalizing symptoms and may constitute important markers in future stress vulnerability and resilience studies. K E Y W O R D S 5-HTTLPR, adolescence, defensive stress response, infancy, internalizing symptoms, longitudinal analysis Highlights • This prospective longitudinal study investigated whether and how deviations in infant freezing predict changes in internalizing symptoms from childhood into late adolescence. • Deviations in infant freezing-both absent and longer freezing-were associated with relative increases in internalizing symptoms. • Whereas absent infant freezing predicted a continuous increase from relatively low to relatively high internalizing symptoms up until late adolescence, longer infant freezing predicted increased internalizing symptoms during early adolescence only. • Early deviations in freezing may mark an individual's risk to develop internalizing symptoms and may be important to consider in future stress vulnerability and resilience studies. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Niermann HCM, Tyborowska A, Cillessen AHN, et al. The relation between infant freezing and the development of internalizing symptoms in adolescence: A prospective longitudinal study. Dev Sci.

Stress following preterm birth can disrupt the emerging foundation of the neonatal brain. The current study examined how structural brain development is affected by a stressful early environment and whether changes in topological architecture at term-equivalent age could explain the increased vulnerability for behavioral symptoms during early childhood. Longitudinal changes in structural brain connectivity were quantified using diffusion-weighted imaging (DWI) and tractography in preterm born infants (gestational age <28 weeks), imaged at 30 and/or 40 weeks of gestation (N= 145, 43.5% female). A global index of postnatal stress was determined based on the number of invasive procedures during hospitalization (e.g., heel lance). Higher stress levels impaired structural connectivity growth in a subnetwork of 48 connections (p= 0.003), including the amygdala, insula, hippocampus, and posterior cingulate cortex. Findings were replicated in an independent validation sample (N= 123, 39.8% female,n= 91 with follow-up). Classifying infants into vulnerable and resilient based on having more or less internalizing symptoms at two to five years of age (n= 71) revealed lower connectivity in the hippocampus and amygdala for vulnerable relative to resilient infants (p< 0.001). Our findings suggest that higher stress exposure during hospital admission is associated with slower growth of structural connectivity. The preservation of global connectivity of the amygdala and hippocampus might reflect a stress-buffering or resilience-enhancing factor against a stressful early environment and early-childhood internalizing symptoms.SIGNIFICANCE STATEMENTThe preterm brain is exposed to various external stimuli following birth. The effects of early chronic stress on neonatal brain networks and the remarkable degree of resilience are not well understood. The current study aims to provide an increased understanding of the impact of postnatal stress on third-trimester brain development and describe the topological architecture of a resilient brain. We observed a sparser neonatal brain network in infants exposed to higher postnatal stress. Limbic regulatory regions, including the hippocampus and amygdala, may play a key role as crucial convergence sites of protective factors. Understanding how stress-induced alterations in early brain development might lead to brain (re)organization may provide essential insights into resilient functioning.