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Conflict of interest
Acknowledgements The authors kindly thank Dr. Pietro Scatturin for laboratory technical support and Dr. Laura Babcock for English manuscript proof-reading. A special thank goes also to all children and their families for participating to the study. This work was supported by the grant “Progetto Giovani Studiosi” from the University of Padua (Prot. 1682/2012) to G. M. and by the FP7/2007-2013 European Research Council Starting grant LEX-MEA to A. V. (GA# 313692).
Introduction Early-life stress (ELS) has been used to refer to a host of negative experiences in childhood including exposure to stressors such as acute events, socio-economic inequalities-related stressors, and perceived stress. ELS is associated with adverse outcomes across the lifespan (Lupien et al., 2009). Retrospective studies link extreme adverse childhood experiences (e.g. maltreatment) to a range of mental health problems. More recently, multiple studies demonstrated links between exposure to mild chronic stressors and disinhibited behavior as manifest in early childhood externalizing problems (Glover, 2011). These findings suggest that ELS’ link to behavioral disinhibition can be detected early in life, but mechanisms are poorly understood. Negative effects of ELS could derive from deleterious effects of stress on neurodevelopment. However, our understanding of the relation between ELS and glutamate receptor antagonist maturation in early childhood years remains limited. Here we examine the association of ELS during early childhood to resting-state fMRI at preschool age. Rodent and nonhuman primate models and retrospective studies in human adults have revealed deleterious effects of ELS on neural function in brain networks important for memory, arousal, cognitive control, and reward processing, and other difficulties in associated cognitive functions (Lupien et al., 2009; Teicher et al., 2003; Woon and Hedges, 2008). A growing body of literature on the effects of severe adverse childhood experiences, such as maltreatment or neglect, in children reveals relations to physiological stress responses as well as structural and functional brain differences (Lupien et al., 2009; Mackey et al., 2012; Pechtel and Pizzagalli, 2011). Institutionalization and maltreatment history are associated with differences in amygdala, hippocampal, cingulate and prefrontal gray matter volume and white matter structure, and altered activation and connectivity in frontal areas, amygdala and striatal areas compared to controls (Burghy et al., 2012; Chugani et al., 2001; De Bellis et al., 2002; Eluvathingal et al., 2006; Mehta et al., 2009; Hanson et al., 2010; Mueller et al., 2010; Tottenham and Sheridan, 2009). The findings of amygdala and hippocampal differences in the literature are less consistent than differences in prefrontal cortex (which contributes to cognitive control), with some studies revealing no differences in the former set of regions as a function of early-life extreme stress (Kim et al., 2013; Mackey et al., 2012; Pechtel and Pizzagalli, 2011; Woon and Hedges, 2008). Thus, prefrontal cortex might be especially sensitive to stress as compared to amygdala and hippocampus (Mackey et al., 2012). Exposure to extreme stressors, such as institutionalization, is rare. Social inequalities-related stressors such as poverty have been recently used as a rough, distal indicator of more common, milder psychosocial stress exposure. Low childhood socioeconomic status (SES) is associated with structural and brain differences in areas central to cognitive control and verbal processing (Hackman and Farah, 2009). Directly focusing psychosocial stress exposure, Hanson and colleagues (2012) reported associations between cumulative life stress and reduced prefrontal cortex volume beginning in early childhood. Buss and colleagues (Buss et al., 2010, 2011) showed that exposure to normative types of maternal perceived stress and distress (pregnancy-specific anxiety) predicts brain and executive function alterations at school ages.