Early life stress and major depressive disorder : neural and cognitive mechanisms

There is increasing evidence that both major depressive disorder (MDD) and early life stress (ELS) have shared effects on cognitive and neurobiological measures, including affective (emotion-laden) cognition and brain structure. Despite the documented high prevalence of ELS in MDD and undisputed role of ELS as a key environmental risk factor for MDD, very few studies in depression have controlled for ELS. This has made it difficult to disentangle the relative effects of ELS and MDD (and possible interactions) on affective cognition and morphological measures. My PhD addressed this gap in the literature by applying a variety of methods and types of studies, including a systematic review and cross-sectional neuropsychological and neuroimaging studies. The overarching hypothesis of the PhD was that ELS at least partially mediates the effects on several cognitive and neural markers often attributed to depression, specifically affective cognition and brain structure. Study 1 comprehensively and systematically assessed affective cognition in ELS and MDD using a novel validated test battery. Results emphasised the multifaceted nature of affective cognition and revealed that specific constructs of affective cognition were affected primarily by MDD diagnosis, while others were more sensitive to ELS. A systematic review of grey matter volume (GMV) changes in MDD and ELS was provided in Study 2. This highlighted the key role ELS appears to play in GMV reductions of several brain regions, in particular the hippocampus and its subfields, independent of MDD. However, many included studies suffered from low/absent levels of ELS in the healthy control groups, limiting the ability to draw firm conclusions about the independent effect of ELS on brain structure. Furthermore, despite emerging evidence for sensitive periods during brain development and differential neurobiological effects of specific types of ELS, included studies did not measure timing of ELS and the vast majority did not specify ELS subtypes. Study 3 directly addressed these issues by investigating GMV of the hippocampus and amygdala (and their subfields) in MDD and ELS (specifically childhood sexual abuse; CSA) in a highly controlled study. Results indicated significant volume reductions in several hippocampal head subfields in CSA, independent of MDD. On the other hand, Study 4 revealed that another morphological index, cortical thickness, appears more sensitive to MDD than CSA. Specifically, MDD, independently of CSA, was associated with significantly increased cortical thickness in the medial orbitofrontal cortex and insula. Overall, studies 1-4 indicate that distinctive constructs of affective cognition and different morphological indices appear to be differentially and specifically affected by ELS or MDD. The findings of my doctoral research demonstrate the importance of measuring and controlling for ELS in studies of affective cognition and brain structure in depression to avoid misattribution of observed effects. Given that analyses all controlled for ELS and ensured matched healthy control groups with comparable ELS (or specifically CSA) levels were included, findings can be more firmly attributed to either MDD or ELS than has often been the case in previous studies. This distinction is important as it may inform mechanisms underlying ELS as a risk factor for depression and elucidate more targeted treatments/interventions.