Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood.
ABSTRACT: Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.
Project description:Childhood trauma exposure is a potent risk factor for psychopathology. Emerging research suggests that aberrant saliency processing underlies the link between early trauma exposure and later cognitive and socioemotional deficits that are hallmark of several psychiatric disorders. Here, we examine brain and behavioral responses during a face categorization conflict task, and relate these to intrinsic connectivity of the salience network (SN). The results demonstrate a unique pattern of SN dysfunction in youth exposed to trauma (n = 14) relative to comparison youth (n = 19) matched on age, sex, IQ, and sociodemographic risk. We find that trauma-exposed youth are more susceptible to conflict interference and this correlates with higher fronto-insular responses during conflict. Resting-state functional connectivity data collected in the same participants reveal increased connectivity of the insula to SN seed regions that is associated with diminished reward sensitivity, a critical risk/resilience trait following stress. In addition to altered intrinsic connectivity of the SN, we observed altered connectivity between the SN and default mode network (DMN) in trauma-exposed youth. These data uncover network-level disruptions in brain organization following one of the strongest predictors of illness, early life trauma, and demonstrate the relevance of observed neural effects for behavior and specific symptom dimensions. SN dysfunction may serve as a diathesis that contributes to illness and negative outcomes following childhood trauma.
Project description:Psychopathy-related paralimbic and limbic structural brain abnormalities have been implicated in incarcerated adult and adolescent male samples. However, there have been few neuroimaging studies of psychopathic traits in females in general and no studies from incarcerated female youth in particular. Here we present the first study to examine the relationship between brain gray matter volumes and psychopathic traits (assessed using the Psychopathy Checklist-Youth Version [PCL-YV]) in a sample of maximum-security incarcerated female adolescents (N?=?39; mean age?=?17.6 years). Consistent with male samples, regional gray matter volumes were negatively related to psychopathic traits in female youth offenders in limbic and paralimbic areas, including orbitofrontal cortex, parahippocampal cortex, temporal poles, and left hippocampus. These results provide evidence that psychopathic traits manifest similar neural abnormalities across sex and age.
Project description:Exposure to childhood adversities (CA) is associated with subsequent alterations in regional brain grey matter volume (GMV). Prior studies have focused mainly on severe neglect and maltreatment. The aim of this study was to determine in currently healthy adolescents if exposure to more common forms of CA results in reduced GMV. Effects on brain structure were investigated using voxel-based morphometry in a cross-sectional study of youth recruited from a population-based longitudinal cohort. 58 participants (mean age = 18.4) with (n = 27) or without (n = 31) CA exposure measured retrospectively from maternal interview were included in the study. Measures of recent negative life events (RNLE) recorded at 14 and 17 years, current depressive symptoms, gender, participant/parental psychiatric history, current family functioning perception and 5-HTTLPR genotype were covariates in analyses. A multivariate analysis of adversities demonstrated a general association with a widespread distributed neural network consisting of cortical midline, lateral frontal, temporal, limbic, and cerebellar regions. Univariate analyses showed more specific associations between adversity measures and regional GMV: CA specifically demonstrated reduced vermis GMV and past psychiatric history with reduced medial temporal lobe volume. In contrast RNLE aged 14 was associated with increased lateral cerebellar and anterior cingulate GMV. We conclude that exposure to moderate levels of childhood adversities occurring during childhood and early adolescence exerts effects on the developing adolescent brain. Reducing exposure to adverse social environments during early life may optimize typical brain development and reduce subsequent mental health risks in adult life.
Project description:Youth with severe conduct problems impose a significant cost on society by engaging in high levels of antisocial and aggressive behavior. Within this group, adolescents with high levels of callous- unemotional traits have been found to exhibit more severe and persistent patterns of antisocial behavior than youth with severe conduct problems but normative levels of callous-unemotional traits. Existing neuroimaging studies, along with theoretical accounts of psychopathology, suggest that dysfunction within the paralimbic cortex and limbic system may underlie elevated levels of callous-unemotional traits. The present study examines this hypothesis by investigating gray matter correlates associated with callous-unemotional traits. A sample of incarcerated male adolescents (N = 269), were assessed using voxel-based morphometry. Callous-unemotional traits were assessed using the Inventory of Callous-Unemotional traits (Frick 2004). Total callous-unemotional traits were negatively correlated with anterior temporal lobe gray matter volume (GMV). Callous traits in particular exhibited a reliable negative correlation with gray matter volume in nearly every paralimbic brain region examined. Uncaring traits were positively correlated with GMV in the orbitofrontal and anterior cingulate cortices. These findings demonstrate specific neural features within the paralimbic cortex and limbic system that accompany elevated callous-unemotional traits and serves to expand our understanding of pathophysiological mechanisms that may give rise to severe conduct problems in youth.
Project description:Trauma and related fear exert significant influence on mental and physical health throughout the lifespan and are associated with intergenerational patterns of development, health, and behavior. DNA methylation and gene expression are involved in our developmental adaptations to our experiences and can be influenced by social interventions. Patterns of DNA methylation and expression of a gene involved in neurodevelopment and psychiatric risk (BDNF) have been linked with childhood trauma. Given the intergenerational patterns of health and behavior, and previous links between childhood trauma and BDNF methylation and expression, this study investigated the potential for maternal history of traumatic experiences to influence development in her newborn, via changes in her newborn's BDNF methylation and expression. We found that mothers' trauma history was associated with epigenetic regulation of BDNF in their newborns. Moreover, the association between maternal trauma and BDNF methylation and expression patterns were moderated by newborn sex. Male newborns showed increased BDNF expression with maternal exposure to child abuse (p = .001), and increased BDNF methylation with greater maternal fear (p = .001). Female newborns showed reduced BDNF expression with greater maternal fear (p = .004). Practitioners strive to identify prevention and intervention avenues that will reduce the harmful effects of trauma. Future research should consider the potential for maternal historical trauma experiences to influence offspring DNA methylation and gene expression in a manner that could alter development and inform novel prevention strategies.
Project description:OBJECTIVE: Psychotic experiences occur at a much greater prevalence in the population than psychotic disorders. There has been little research to date, however, on genetic risk for this extended psychosis phenotype. We examined whether COMT or BDNF genotypes were associated with psychotic experiences or interacted with childhood trauma in predicting psychotic experiences. METHOD: Psychiatric interviews and genotyping for COMT-Val158Met and BDNF-Val66Met were carried out on two population-based samples of 237 individuals aged 11-15 years. Logistic regression was used to examine for main effects by genotype and childhood trauma, controlling for important covariates. This was then compared to a model with a term for interaction between genotype and childhood trauma. Where a possible interaction was detected, this was further explored in stratified analyses. RESULTS: While childhood trauma showed a borderline association with psychotic experiences, COMT-Val158Met and BDNF-Val66Met genotypes were not directly associated with psychotic experiences in the population. Testing for gene x environment interaction was borderline significant in the case of COMT-Val158Met with individuals with the COMT-Val158Met Val-Val genotype, who had been exposed to childhood trauma borderline significantly more likely to report psychotic experiences than those with Val-Met or Met-Met genotypes. There was no similar interaction by BDNF-Val66Met genotype. CONCLUSION: The COMT-Val158Met Val-Val genotype may be a genetic moderator of risk for psychotic experiences in individuals exposed to childhood traumatic experiences.
Project description:Childhood maltreatment (CM) is a strong risk factor for development of posttraumatic stress disorder (PTSD) upon adult exposure to extreme adverse events. However, the neural underpinnings of this relationship are not well understood. Here, we test the hypothesis that severity of CM history is positively correlated with emotion-processing limbic and prefrontal brain activation/connectivity and negatively correlated with prefrontal gray matter volumes in women with PTSD due to intimate-partner violence (IPV-PTSD). Thirty-three women with IPV-PTSD underwent structural and functional magnetic resonance imaging while completing a facial emotion processing task. Multivariate regressions examined the relationship of CM to patterns of activation, connectivity, and gray matter volumes. CM severity was: (a) positively correlated with ventral ACC activation while processing angry faces; (b) negatively correlated with dorsal ACC and insula activation while processing fear and angry faces, arising from positive correlations with the shape-matching baseline; (c) positively correlated with limbic-prefrontal connectivity while processing fear faces but negatively correlated with amygdalo-insular connectivity while processing fear and angry; and (d) negatively correlated with prefrontal gray matter volumes. These results suggest CM exposure may account for variability in limbic/prefrontal brain function and prefrontal structure in adulthood PTSD and offer one potential mechanism through which CM confers risk to future development of PTSD.
Project description:BACKGROUND:Early childhood trauma is known to independently increase adverse outcome risk in coronary artery disease (CAD) patients, although the neurological correlates are not well understood. The purpose of this study was to examine whether early childhood trauma alters neural responses to acute mental stress in CAD patients. METHODS:Participants (n?=?152) with CAD underwent brain imaging with High Resolution Positron Emission Tomography and radiolabeled water during control (verbal counting, neutral speaking) and mental stress (mental arithmetic, public speaking). Traumatic events in childhood were assessed with the Early Trauma Inventory (ETI-SR-SF) and participants were separated by presence (ETI+) or absence (ETI-) of early childhood trauma. Brain activity during mental stress was compared between ETI+ and ETI-. RESULTS:Compared to ETI-, ETI+ experienced greater (p < 0.005) activations during mental stress within the left anterior cingulate, bilateral frontal lobe and deactivations (p < 0.005) within the left insula, left parahippocampal gyrus, right dorsal anterior cingulate, bilateral cerebellum, bilateral fusiform gyrus, left inferior temporal gyrus, and right parietal lobe. Significant (p < 0.005) positive correlations between brain activation and ETI-SR-SF scores were observed within the left hippocampus, bilateral frontal lobe, left occipital cuneus, and bilateral temporal lobe. LIMITATIONS:Results in non-CAD samples may differ and ETI may be subject to recall bias. CONCLUSION:Early childhood trauma exacerbated activations in stress-responsive limbic and cognitive brain areas with direct and indirect connections to the heart, potentially contributing to adverse outcomes in CAD patients.
Project description:Previous studies have found childhood trauma to be associated with functional and structural abnormalities in corticostriatal-limbic brain regions, which may explain the associations between trauma and negative mental and physical health outcomes. However, functional neuroimaging of maltreatment-related trauma has been limited by largely using generic and predominantly aversive stimuli. Personalized stress, favorite-food, and neutral/relaxing cues during functional magnetic resonance imaging were used to probe the neural correlates of emotional/motivational states in adolescents with varying exposure to maltreatment-related trauma. Sixty-four adolescents were stratified into high- or low-trauma-exposed groups. Cue-related measures of subjective anxiety and craving were collected. Relative to the low-trauma-exposed group, high-trauma-exposed adolescents displayed an increased activation of insula, anterior cingulate, and prefrontal cortex in response to stress cues. Activation in subcortical structures, including the hippocampus, was inversely correlated with subjective anxiety in the high- but not the low-trauma-exposed group. The high-trauma-exposed group displayed hypoactivity of cerebellar regions in response to neutral/relaxing cues. No group differences were observed in response to favorite-food cues. The relationship between trauma exposure and altered cortico-limbic circuitry may in part explain the association between childhood trauma and heightened vulnerability to emotional disturbances and risky behaviour. This may be particularly pertinent during adolescence when such difficulties often emerge. Further work is needed to elucidate the mechanism linking trauma to obesity.
Project description:Interaction between childhood trauma and genetic factors influences the pathophysiology of posttraumatic stress disorder (PTSD). This study examined the interaction effect of childhood trauma and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on PTSD symptoms and brain cortical thickness. A total of 216 participants (133 healthy volunteers and 83 PTSD patients) were recruited. T1-weighted structural magnetic resonance imaging, BDNF rs6265 genotyping through blood sampling, and clinical assessments including the childhood trauma questionnaire (CTQ) and posttraumatic stress disorder Checklist (PCL) were performed. A moderated regression analysis, two-way multivariate analysis of covariance, and correlation analysis were conducted. An interaction between the CTQ and the BDNF polymorphism significantly influenced PTSD symptom severity. In fact, people with rs6265 Val/Val genotype and higher CTQ scores showed higher PCL scores. Additionally, this interaction was significant on both left fusiform and transverse temporal gyri thickness. Furthermore, the thickness of both brain regions was significantly correlated with psychological symptoms including depression, anxiety, rumination, and cognitive emotion regulation methods; yet this was mainly observed in people with the Val/Val genotype. The interaction between childhood trauma and BDNF polymorphism significantly influences both PTSD symptoms and cortical thickness and the Val/Val genotype may increase the risk in Korean population.