David Pagliaccio

Stress-System Genes and Life Stress Predict Cortisol Levels and Amygdala and Hippocampal Volumes in Children

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.

Shared Predisposition in the Association Between Cannabis Use and Subcortical Brain Structure

IMPORTANCE Prior neuroimaging studies have suggested that alterations in brain structure may be a consequence of cannabis use. Siblings discordant for cannabis use offer an opportunity to use cross-sectional data to disentangle such causal hypotheses from shared effects of genetics and familial environment on brain structure and cannabis use. OBJECTIVES To determine whether cannabis use is associated with differences in brain structure in a large sample of twins/siblings and to examine sibling pairs discordant for cannabis use to separate potential causal and predispositional factors linking lifetime cannabis exposure to volumetric alterations. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional diagnostic interview, behavioral, and neuroimaging data were collected from community sampling and established family registries from August 2012 to September 2014. This study included data from 483 participants (22-35 years old) enrolled in the ongoing Human Connectome Project, with 262 participants reporting cannabis exposure (ie, ever used cannabis in their lifetime). MAIN OUTCOMES AND MEASURES Cannabis exposure was measured with the Semi-Structured Assessment for the Genetics of Alcoholism. Whole-brain, hippocampus, amygdala, ventral striatum, and orbitofrontal cortex volumes were related to lifetime cannabis use (ever used, age at onset, and frequency of use) using linear regressions. Genetic (ρg) and environmental (ρe) correlations between cannabis use and brain volumes were estimated. Linear mixed models were used to examine volume differences in sex-matched concordant unexposed (n = 71 pairs), exposed (n = 81 pairs), or exposure discordant (n = 89 pairs) sibling pairs. RESULTS Among 483 study participants, cannabis exposure was related to smaller left amygdala (approximately 2.3%; P = .007) and right ventral striatum (approximately 3.5%; P < .005) volumes. These volumetric differences were within the range of normal variation. The association between left amygdala volume and cannabis use was largely owing to shared genetic factors (ρg = -0.43; P = .004), while the origin of the association with right ventral striatum volumes was unclear. Importantly, brain volumes did not differ between sex-matched siblings discordant for use (fixed effect = -7.43; t = -0.93, P = .35). Both the exposed and unexposed siblings in pairs discordant for cannabis exposure showed reduced amygdala volumes relative to members of concordant unexposed pairs (fixed effect = 12.56; t = 2.97; P = .003). CONCLUSIONS AND RELEVANCE In this study, differences in amygdala volume in cannabis users were attributable to common predispositional factors, genetic or environmental in origin, with little support for causal influences. Causal influences, in isolation or in conjunction with predispositional factors, may exist for other brain regions (eg, ventral striatum) or at more severe levels of cannabis involvement and deserve further study.

Reward Processing and Risk for Depression Across Development

Striatal response to reward has been of great interest in the typical development and psychopathology literatures. These parallel lines of inquiry demonstrate that although typically developing adolescents show robust striatal response to reward, adolescents with major depressive disorder (MDD) and those at high risk for MDD show a blunted response to reward. Understanding how these findings intersect is crucial for the development and application of early preventative interventions in at-risk children, ideally before the sharp increase in the rate of MDD onset that occurs in adolescence. Robust findings relating blunted striatal response to reward and MDD risk are reviewed and situated within a normative developmental context. We highlight the need for future studies investigating longitudinal development, specificity to MDD, and roles of potential moderators and mediators.

HPA axis genetic variation, pubertal status, and sex interact to predict amygdala and hippocampus responses to negative emotional faces in school-age children

Accumulating evidence suggests a role for stress exposure, particularly during early life, and for variation in genes involved in stress response pathways in neural responsivity to emotional stimuli. Understanding how individual differences in these factors predict differences in emotional responsivity may be important for understanding both normative emotional development and for understanding the mechanisms underlying internalizing disorders, like anxiety and depression, that have often been related to increased amygdala and hippocampus responses to negatively valenced emotional stimuli. The present study examined whether stress exposure and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predict individual differences in amygdala and hippocampus responses to fearful vs. neutral faces in school-age children (7-12 year olds; N = 107). Experience of more stressful and traumatic life events predicted greater left amygdala responses to negative emotional stimuli. Genetic profile scores interacted with sex and pubertal status to predict amygdala and hippocampus responses. Specifically, genetic profile scores were a stronger predictor of amygdala and hippocampus responses among pubertal vs. prepubertal children where they positively predicted responses to fearful faces among pubertal girls and positively predicted responses to neutral faces among pubertal boys. The current results suggest that genetic and environmental stress-related factors may be important in normative individual differences in responsivity to negative emotional stimuli, a potential mechanism underlying internalizing disorders. Further, sex and pubertal development may be key moderators of the effects of stress-system genetic variation on amygdala and hippocampus responsivity, potentially relating to sex differences in stress-related psychopathology.

Genetic Moderation of Stress Effects on Corticolimbic Circuitry.

Stress exposure is associated with individual differences in corticolimbic structure and function that often mirror patterns observed in psychopathology. Gene x environment interaction research suggests that genetic variation moderates the impact of stress on risk for psychopathology. On the basis of these findings, imaging genetics, which attempts to link variability in DNA sequence and structure to neural phenotypes, has begun to incorporate measures of the environment. This research paradigm, known as imaging gene x environment interaction (iGxE), is beginning to contribute to our understanding of the neural mechanisms through which genetic variation and stress increase psychopathology risk. Although awaiting replication, evidence suggests that genetic variation within the canonical neuroendocrine stress hormone system, the hypothalamic-pituitary-adrenal axis, contributes to variability in stress-related corticolimbic structure and function, which, in turn, confers risk for psychopathology. For iGxE research to reach its full potential it will have to address many challenges, of which we discuss: (i) small effects, (ii) measuring the environment and neural phenotypes, (iii) the absence of detailed mechanisms, and (iv) incorporating development. By actively addressing these challenges, iGxE research is poised to help identify the neural mechanisms underlying genetic and environmental associations with psychopathology.

Effect of Hippocampal and Amygdala Connectivity on the Relationship Between Preschool Poverty and School-Age Depression

OBJECTIVE In this study, the authors tested the hypothesis that poverty experienced in early childhood, as measured by income-to-needs ratio, has an impact on functional brain connectivity at school age, which in turn mediates influences on child negative mood/depression. METHOD Participants were from a prospective longitudinal study of emotion development. Preschoolers 3-5 years of age were originally ascertained from primary care and day care sites in the St. Louis area and then underwent annual behavioral assessments for up to 12 years. Healthy preschoolers and those with a history of depression symptoms underwent neuroimaging at school age. Using functional MRI, the authors examined whole brain resting-state functional connectivity with the left and right hippocampus and amygdala. RESULTS Lower income-to-needs ratio at preschool age was associated with reduced connectivity between hippocampus and amygdala and a number of regions at school age, including the superior frontal cortex, lingual gyrus, posterior cingulate, and putamen. Lower income-to-needs ratio predicted greater negative mood/depression severity at school age, as did connectivity between the left hippocampus and the right superior frontal cortex and between the right amygdala and the right lingual gyrus. Connectivity mediated the relationship between income-to-needs ratio and negative mood/depression at the time of scanning. CONCLUSIONS These findings suggest that poverty in early childhood, as assessed by at least one measure, may influence the development of hippocampal and amygdala connectivity in a manner leading to negative mood symptoms during later childhood.

Functional brain activation to emotional and nonemotional faces in healthy children: Evidence for developmentally undifferentiated amygdala function during the school-age period

The amygdala is a key region in emotion processing. In particular, fMRI studies have demonstrated that the amygdala is active during the viewing of emotional faces. Previous research has consistently found greater amygdala responses to fearful than to neutral faces in adults, convergent with a focus in the animal literature on the amygdala’s role in fear processing. Studies have shown that the amygdala also responds differentially to other facial emotion types in adults. Yet the literature regarding when this differential amygdala responsivity develops is limited and mixed. Thus, the goal of the present study was to examine amygdala responses to emotional and neutral faces in a relatively large sample of healthy school-age children (N = 52). Although the amygdala was active in response to emotional and neutral faces, the results did not support the hypothesis that the amygdala responds differentially to emotional faces in 7- to 12-year-old children. Nonetheless, amygdala activity was correlated with the severity of subclinical depression symptoms and with emotional regulation skills. Additionally, sex differences were observed in frontal, temporal, and visual regions, as well as effects of pubertal development in visual regions. These findings suggest important differences in amygdala reactivity in childhood.

Altered Gray Matter Volume and School Age Anxiety in Children Born Late Preterm

OBJECTIVES To determine if late preterm (LP) children differ from full term (FT) children in volumes of the cortex, hippocampus, corpus callosum, or amygdala and whether these differences are associated with anxiety symptoms at school-age. STUDY DESIGN LP children born between 34 and 36 weeks gestation and FT children born between 39 and 41 weeks gestation from a larger longitudinal cohort had magnetic resonance imaging scans at school-age. Brain volumes, cortical surface area, and thickness measures were obtained. Anxiety symptoms were assessed using a structured diagnostic interview annually beginning at preschool-age and following the magnetic resonance imaging. RESULTS LP children (n = 21) had a smaller percentage of total, right parietal, and right temporal lobe gray matter volume than FT children (n = 87). There were no differences in hippocampal, callosal, or amygdala volumes or cortical thickness. LP children also had a relative decrease in right parietal lobe cortical surface area. LP children had greater anxiety symptoms over all assessments. The relationship between late prematurity and school-age anxiety symptoms was mediated by the relative decrease in right temporal lobe volume. CONCLUSIONS LP children, comprising 70% of preterm children, are also at increased risk for altered brain development particularly in the right temporal and parietal cortices. Alterations in the right temporal lobe cortical volume may underlie the increased rate of anxiety symptoms among these LP children. These findings suggest that LP delivery may disrupt temporal and parietal cortical development that persists until school-age with the right temporal lobe conferring risk for elevated anxiety symptoms.

Neural Activation Associated with the Cognitive Emotion Regulation of Sadness in Healthy Children

Highlights • Childrens use of reappraisal was associated with increased prefrontal activation.• Children showed deactivation in the amygdala while reappraising sad photos.• Childrens PFC activity during reappraisal was consistent with adult findings.

Anomalous functional brain activation following negative mood induction in children with pre-school onset major depression.

While major depressive disorder has been shown to be a significant mental health issue for school-age children, recent research indicates that depression can be observed in children as early as the preschool period. Yet, little work has been done to explore the neurobiological factors associated with this early form of depression. Given research suggesting a relation between adult depression and anomalies in emotion-related neural circuitry, the goal of the current study was to elucidate changes in functional activation during negative mood induction and emotion regulation in school-age children with a history of preschool-onset depression. The results suggest that a history of depression during the preschool period is associated with decreased activity in prefrontal cortex during mood induction and regulation. Moreover, the severity of current depressed mood was associated with increased activity in limbic regions, such as the amygdala, particularly in children with a history of depression. Similar to results observed in adult depression, the current findings indicate disruptions in emotion-related neural circuitry associated with preschool-onset depression.