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    • While providing compelling evidence for associations of ELS

    2018-10-25

    While providing compelling evidence for associations of ELS with d-cycloserine and cognitive development, previous studies primarily focused on older school-aged children, compared different groups of children exposed to different forms of ELS, used cross-sectional designs, and mainly used structural brain measures. The first goal of this study is to demonstrate the relations between measures of psychosocial stress across early childhood and young children\'s resting-state fMRI in a demographically diverse sample of preschool-children. We use an interview-based measure of maternal perceived stress as our measure of ELS. We also examine whether associations with ELS are independent of other stress indicators, such as poverty, acute life events, and violence exposure. Perceived stress is a good indicator of individual differences in impact of stress, because the same stressor may have differential impact biologically and psychologically depending on how stress is appraised and experienced (Graignic-Phillippe et al., 2014). The second goal of this study is to examine effects of timing of exposure i.e., first years of life vs. concurrent preschool-age stress on neural outcomes on resting-state fMRI within the same group of children. The current study used resting-state fMRI (rs-fMRI), which is considered to reflect spontaneous connectivity in the brain during rest (Long et al., 2008). Studies with adults report atypical resting-state fMRI patterns in clinical populations suffering from mental health disorders that are associated with ELS, such as anxiety disorders and populations suffering from post-traumatic stress disorder (Sripada et al., 2012). rs-fMRI might reveal information about stress-related differences in the brain that exist at baseline in the absence of any stress-related stimuli or task demands. To our knowledge, no studies have examined how psychosocial stress exposure in early life is linked to rs-fMRI in young children. As our measure of rs-fMRI, we used regional homogeneity (ReHo) analysis that measures temporal similarity of voxels within a cluster and is considered to reflect intra-regional synchronization in a network (Song et al., 2011). We followed these ReHo analyses with network-based resting-state functional connectivity (rs-FC) analyses to identify associations with ELS for other regions that are functionally connected with those identified by the ReHo analysis. Given the past literature on ELS’ relations to brain differences in prefrontal regions, we expected ELS to associate most strongly to ReHo and fMRI connectivity in the prefrontal regions. Given the previous literature highlighting relations between ELS and prefrontal functioning, we also examined how differences in ReHo and rs-FC relate to children\'s performance on the behavioral cognitive-control task, which is associated with prefrontal functioning (e.g. Hackman and Farah, 2009; Mackey et al., 2012). Cognitive control refers to the ability to flexibly coordinate thoughts and behavior to accomplish goals. One of its basic components is the ability to adapt to shifting task demands in a flexible manner, as opposed to remaining rigid. Such task switching is supported by a wide fronto-parietal network in the brain, and resting connectivity in this network is linked to behavioral measures of cognitive control (Kim et al., 2012; Seeley et al., 2007). In the current study, we used a developmentally engaging task to measure reversal-learning (Dias et al., 1996; Finger et al., 2008; Pryce et al., 2005). On the basis of the past literature suggesting that ELS specifically associates with structural and functional brain differences in prefrontal regions, we expected ELS-related neural differences to associate with children\'s performance on the behavioral cognitive-control task (e.g. Hackman and Farah, 2009; Mackey et al., 2012).
    Materials and methods
    Results
    Discussion We used ReHo as the primary measure of resting-state fMRI, which is considered to reflect intra-regional synchronization of spontaneous activity. Children with increased levels of early ELS exhibited increased ReHo in left middle frontal gyrus. Prefrontal regions, including middle frontal gyrus, are considered to be a part of task-positive network that is commonly activated during goal-oriented cognitive tasks (Kelly et al., 2008). Previous studies have reported increased resting ReHo and resting functional connectivity in frontal regions in adults and animals with concurrent or past extreme stress exposure (Bluhm et al., 2009; Ferris and Stolberg, 2010; Yin et al., 2012). We extend the existing literature by demonstrating the association of ELS exposure with prefrontal resting-state fMRI in young children, using robust measures of maternal perceived stress that account for developmental timing of exposure. This is particularly striking because it demonstrates that even exposure to normative levels of perceived stress well within the range of normal human experience is associated with disruptions in prefrontal resting-state activity and connectivity.