Unraveling the Longstanding Scars of Early Neurodevelopmental Stress

Abstract

Early neurodevelopment, both in utero and in the postnatal phase, is a time when stressors can produce long-lasting changes that significantly increase the risk of mental health problems in adulthood (1). Pregnancy complications such as depression in the mother and childhood trauma can impact on neurodevelopment and increase the likelihood of psychiatric illnesses, such as major depression together with anxiety and personality disorders. Large-scale prospective studies indicate that the increased risk of these disorders following early adversity persists into old age. It is equally clear that not everyone who experiences early stressors develops psychiatric illness in adulthood and neither is there a relationship between any specific stress and a particular psychiatric disorder. If we are to ameliorate the impact of early stress, it is important that we gain an increased understanding of the manner in which such stress impacts on biological development and the psychosocial and genetic factors that help decrease the toxic effects of stress. In this regard, two articles in this issue of Biological Psychiatry focus on the underlying persistent neuronal alterations in subjects who have been exposed to, albeit qualitatively different and potent, early-life stressors (2,3). Interestingly, both articles highlight an important role for the amygdala in these effects. Olsavsky et al. (2) provide evidence in a functional magnetic resonance imaging experiment that altered activation of the amygdala plays a role in long-term behavioral problems in maternally deprived children that had been subsequently adopted (children were aged between 6 and 15 years at the time of scanning). Behaviorally, they found that this cohort had indiscriminate friendliness, which can be defined as an uncharacteristic reduced reticence and atypical approach behaviors towards adults, including strangers, being unable to distinguish adopted mothers from strangers and that this was also demonstrable in terms of amygdala discrimination to both types of stimuli. Interestingly, there was a positive correlation between age at adoption and hence duration of maternal deprivation and extent of the amygdala discrimination and behavioral response in terms of indiscriminate friendliness. On the other hand, Rifkin-Graboi et al. (3) takes a different approach, but once again, this study highlights the role of the amygdala in the long-term effects of early-life stress. They show that microstructural changes in the right amygdala (as assessed within the first 2 weeks of life) can be induced as a result of depression in the mother. The study adds further to our understanding of the toxic effect of maternal depression on the developing fetus. It is also worth noting that recent studies are pointing to a link between maternal childhood maltreatment and maternal antenatal depression (4), thus continuing the cycle of stress-induced effects across the generations with the cooccurrence of both insults significantly increasing the risk of offspring adversity. The mechanism for both of these associations is unclear and may include genomic and environmental influences both during fetal development and postnatally. Experimental studies in animals involving gestation stress or in early life are proving invaluable in uncovering key changes in the neurodevelopment of limbic structures, including alteration in amygdala size, neuronal activity, and expression of key stress-related genes (5). Moreover, starting with the work of Levine et al. (6) in Stanford and Meaney et al. (7) in McGill, a growing body of preclinical data in both rodents and nonhuman primates has been focused on understanding the consequences of alterations in maternal care in early life to both the susceptibility and resilience to psychopathology [see (1) for review].