Reduced hippocampal and amygdala volume as a mechanism underlying stress sensitization to depression following childhood trauma.
ABSTRACT: BACKGROUND:Stressful life events are more likely to trigger depression among individuals exposed to childhood adversity. However, the mechanisms underlying this stress sensitization remain largely unknown. Any such mechanism must be altered by childhood adversity and interact with recent stressful life events, magnifying their association with depression. AIM:This study investigated whether reduced hippocampal and amygdala volume are potential mechanisms underlying stress sensitization following childhood violence exposure. METHOD:A sample of 149 youth (aged 8-17 years), with (N?=?75) and without (N?=?74) exposure to physical abuse, sexual abuse, or domestic violence participated. Participants completed a structural MRI scan and assessments of depression. Approximately 2 years later, stressful life events were assessed along with depression symptoms in 120 participants (57 violence exposed). RESULTS:Childhood violence exposure was associated with smaller hippocampal and amygdala volume. Stressful life events occurring during the follow-up period predicted worsening depression over time, and this association was magnified among those with smaller hippocampal and amygdala volumes. Significant moderated mediation models revealed the indirect effects of violence exposure on increasing depression over time through hippocampal and amygdala volumes, particularly among youths who experienced more stressful life events. CONCLUSIONS:These results provide evidence for reduced hippocampal and amygdala volume as potential mechanisms of stress sensitization to depression following exposure to violence. More broadly, these patterns suggest that hippocampal and amygdala-mediated emotional and cognitive processes may confer vulnerability to stressful life events among children who have experienced violence.
Project description:BACKGROUND:Childhood maltreatment is one of the most potent predictors of future psychopathology, including internalizing disorders. It remains unclear whether heightened amygdala reactivity to threat and elevated stress exposure may be implicated in the pathogenesis and maintenance of internalizing disorders among individuals with a history of childhood maltreatment. METHODS:Using data from a sample of 1,144 young adults, we investigated the contribution of baseline threat-related amygdala reactivity and prospective major stressful life events to internalizing symptoms severity 1 year later (on average) in individuals with a history of maltreatment (n = 100) and propensity score matched nonmaltreated peers (n = 96). RESULTS:Even after stringently matching for several potentially confounding variables - including baseline internalizing symptoms, socioeconomic status and IQ - childhood maltreatment status predicted increased amygdala reactivity at baseline, elevated post-baseline exposure to major stressful life events and internalizing symptoms at follow-up. We also showed, for the first time, that amygdala reactivity at baseline and also post-baseline exposure to major stressful life events mediated the association between a history of maltreatment and future internalizing symptoms. CONCLUSIONS:These findings provide support for the view that maltreatment is a potent developmental insult leading to long-lasting neurocognitive recalibrations of the threat processing system. It is possible that such alterations, over time, may impact mental health functioning by compromising the ability to effectively negotiate everyday challenges (stress susceptibility). These alterations were not, however, found to sensitize an individual to the impact of major stressful life events. The results of this study also lend compelling support to the view that increased psychiatric risk, in the context of childhood maltreatment, follows from an increased propensity to experience major stressful life events (stress generation).
Project description:IMPORTANCE The study provides novel data to inform the mechanisms by which poverty negatively impacts childhood brain development. OBJECTIVE To investigate whether the income-to-needs ratio experienced in early childhood impacts brain development at school age and to explore the mediators of this effect. DESIGN, SETTING, AND PARTICIPANTS This study was conducted at an academic research unit at the Washington University School of Medicine in St Louis. Data from a prospective longitudinal study of emotion development in preschool children who participated in neuroimaging at school age were used to investigate the effects of poverty on brain development. Children were assessed annually for 3 to 6 years prior to the time of a magnetic resonance imaging scan, during which they were evaluated on psychosocial, behavioral, and other developmental dimensions. Preschoolers included in the study were 3 to 6 years of age and were recruited from primary care and day care sites in the St Louis metropolitan area; they were annually assessed behaviorally for 5 to 10 years. Healthy preschoolers and those with clinical symptoms of depression participated in neuroimaging at school age/early adolescence. EXPOSURE Household poverty as measured by the income-to-needs ratio. MAIN OUTCOMES AND MEASURES Brain volumes of children's white matter and cortical gray matter, as well as hippocampus and amygdala volumes, obtained using magnetic resonance imaging. Mediators of interest were caregiver support/hostility measured observationally during the preschool period and stressful life events measured prospectively. RESULTS Poverty was associated with smaller white and cortical gray matter and hippocampal and amygdala volumes. The effects of poverty on hippocampal volume were mediated by caregiving support/hostility on the left and right, as well as stressful life events on the left. CONCLUSIONS AND RELEVANCE The finding that exposure to poverty in early childhood materially impacts brain development at school age further underscores the importance of attention to the well-established deleterious effects of poverty on child development. Findings that these effects on the hippocampus are mediated by caregiving and stressful life events suggest that attempts to enhance early caregiving should be a focused public health target for prevention and early intervention. Findings substantiate the behavioral literature on the negative effects of poverty on child development and provide new data confirming that effects extend to brain development. Mechanisms for these effects on the hippocampus are suggested to inform intervention.
Project description:<h4>Objective</h4>To identify the clinical and psychosocial factors associated with psychiatric comorbidity in patients consulting for depression in Primary Health Care (PHC) in Chile.<h4>Methods</h4>394 patients with a diagnosis of major depression being treated in a Chilean PHC were evaluated using a sociodemographic and clinical interview, the mini-international neuropsychiatric interview (MINI), a childhood trauma events (CTEs) screening, the intimate partner violence (IPV) scale, the Life Experiences Survey (LES), and the Hamilton Depression Rating Scale (HDRS).<h4>Results</h4>Positive correlations were established between higher number of psychiatric comorbidities and severity of depressive symptoms (r = 0.358), frequency of CTEs (r = 0.228), frequency of IPV events (r = 0.218), frequency of recent stressful life events (r = 0.188), number of previous depressive episodes (r = 0.340), and duration of these (r = 0.120). Inverse correlations were determined with age at the time of the first consultation (r = -0.168), age of onset of depression (r = -0.320), and number of medical comorbidities (r = -0.140). Of all associated factors, early age of the first depressive episode, CTEs antecedents, and recent stressful life events explain 13.6% of total variability in psychiatric comorbidities.<h4>Conclusions</h4>A higher prevalence of psychiatric comorbidity among subjects seeking help for depression in Chilean PHCs is associated with early onset of depression, clinical severity, chronicity, and interpersonal adversity experienced since childhood.
Project description:UNLABELLED:Major depression has been repeatedly associated with amygdala hyper-responsiveness to negative (but not positive) facial expressions at early, automatic stages of emotion processing using subliminally presented stimuli. However, it is not clear whether this "limbic bias" is a correlate of depression or represents a vulnerability marker preceding the onset of the disease. Because childhood maltreatment is a potent risk factor for the development of major depression in later life, we explored whether childhood maltreatment is associated with amygdalar emotion processing bias in maltreated but healthy subjects. Amygdala responsiveness to subliminally presented sad and happy faces was measured by means of fMRI at 3 T in N = 150 healthy subjects carefully screened for psychiatric disorders. Childhood maltreatment was assessed by the 25-item childhood trauma questionnaire (CTQ). A strong association of CTQ-scores with amygdala responsiveness to sad, but not happy facial expressions emerged. This result was further qualified by an interaction of emotional valence and CTQ-scores and was not confounded by trait anxiety, current depression level, age, gender, intelligence, education level, and more recent stressful life-events. Childhood maltreatment is apparently associated with detectable changes in amygdala function during early stages of emotion processing which resemble findings described in major depression. Limbic hyper-responsiveness to negative facial cues could be a consequence of the experience of maltreatment during childhood increasing the risk of depression in later life. LIMITATION:the present association of limbic bias and maltreatment was demonstrated in the absence of psychopathological abnormalities, thereby limiting strong conclusions.
Project description:We have previously reported that threat-related amygdala activity measured during a baseline fMRI scan predicts the experience of depression and anxiety associated with stressful life events years later. Here, we examine whether two broad measures of childhood environmental enrichment, namely parental educational achievement and subjective parental socioeconomic status, buffer against the effects of amygdala activity on future vulnerability to stress. Analyses of data available from 579 young adults revealed that maternal, but not paternal, educational achievement moderates the association between amygdala activity, recent life stress, and changes in mood and anxiety symptoms, even when controlling for participants' current subjective socioeconomic status. Specifically, only participants reporting lower maternal educational achievement exhibited our previously observed interaction between amygdala activity and future life stress predicting increases in depression and anxiety. These results suggest that higher maternal educational achievement may help buffer stress sensitivity associated with heightened threat-related amygdala activity.
Project description:Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structures. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, and FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3-5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7-12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3-5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.
Project description:Variations in people's vulnerability to stressful life events may rise from a predated neural sensitivity as well as from differential neural modifications in response to the event. Because the occurrence of a stressful life event cannot be foreseen, characterizing the temporal trajectory of its neural manifestations in humans has been a real challenge. The current prospective study examined the emotional experience and brain responses of 50 a priori healthy new recruits to the Israeli Defense Forces at 2 time points: before they entered their mandatory military service and after their subsequent exposure to stressful events while deployed in combat units. Over time, soldiers reported on increase in stress symptoms that was correlated with greater amygdala and hippocampus responsiveness to stress-related content. However, these closely situated core limbic regions exhibited different temporal trajectories with regard to the stress effect; whereas amygdala's reactivity before stress predicted the increase in stress symptoms, the hippocampal change in activation over time correlated with the increase in such symptoms. Hippocampal plasticity was also reflected by a modification over time of its functional coupling with the ventromedial prefrontal cortex, and this coupling magnitude was again predicted by predated amygdala reactivity. Together, these findings suggest that variations in human's likelihood to develop symptomatic phenomena following stressful life events may depend on a balanced interplay between their amygdala's predisposing reactivity and hippocampal posteriori intra- and interregional plasticity. Accordingly, an individually tailored therapeutic approach for trauma survivors should target these 2 neural probes while considering their unique temporal prints.
Project description:Childhood adversity is heterogeneous with potentially distinct dimensions of violence exposure and social deprivation. These dimensions may differentially shape emotion-based neural circuitry, such as amygdala-PFC white matter connectivity. Amygdala-orbitofrontal cortex (OFC) white matter connectivity has been linked to regulation of the amygdala's response to emotional stimuli. Using a preregistered analysis plan, we prospectively examined the effects of childhood exposure to two dimensions of adversity, violence exposure and social deprivation, on the adolescent amygdala-PFC white matter connectivity. We also reproduced the negative correlation between amygdala-PFC white matter connectivity and amygdala activation to threat faces. 183 15-17-year-olds were recruited from the Fragile Families and Child Wellbeing Study - a longitudinal, birth cohort, sample of predominantly low-income youth. Probabilistic tractography revealed that childhood violence exposure and social deprivation interacted to predict the probability of adolescent right hemisphere amygdala-OFC white matter connectivity. High violence exposure with high social deprivation related to less amygdala-OFC white matter connectivity. Violence exposure was not associated with white matter connectivity when social deprivation was at mean or low levels (i.e., relatively socially supportive contexts). Therefore, social deprivation may exacerbate the effects of childhood violence exposure on the development of white matter connections involved in emotion processing and regulation. Conversely, social support may buffer against them.
Project description:Clinical depression can occur in young children as early as age three. This very early onset variant of depression shows the same clinical features with developmental adjustments as depression that onsets later in life. One robust neural feature of adult depression is reduced hippocampal volume. We measured hippocampal volume in a sample of 35 children aged 4-7 who were either in a clinical trial for preschool onset depression or were recruited from the community. We used T1 MPRAGE acquisitions on a Siemen's Scanner, with Freesurfer 5.3 used to segment the hippocampus. Depression was measured using the K-SADS early childhood (K-SADS-EC) to create a dimensional depression severity score and the Child Behavior Checklist (CBCL) Depression T-Score. Multilevel models indicated that greater depression severity as measured by either the CBCL Depression Score or the K-SADS-EC was associated with lower hippocampal volume, even controlling for total gray matter, maternal depression, income-to-needs ratio, and stressful life events. These data indicate evidence for reduced hippocampal volume among children with PO-MDD who were more severely depressed. Findings are consistent with the idea that hippocampal volume reductions are an early occurring associated neural marker of MDD, particularly for more severe depression.
Project description:Major depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction.A literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method.The results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051).The interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.