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.     

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.     

Default mode network connectivity in children with a history of preschool onset depression

Background: Atypical Default Mode Network (DMN) functional connectivity has been previously reported in depressed adults. However, there is relatively little data informing the developmental nature of this phenomenon. The current case‐control study examined the DMN in a unique prospective sample of school‐age children with a previous history of preschool depression. Methods: DMN functional connectivity was assessed using resting state functional connectivity magnetic resonance imaging data and the posterior cingulate (PCC) as a seed region of interest. Thirty‐nine medication naïve school age children (21 with a history of preschool depression and 18 healthy peers) and their families who were ascertained as preschoolers and prospectively assessed over at least 4 annual waves as part of a federally funded study of preschool depression were included. Results: Decreased connectivity between the PCC and regions within the middle temporal gyrus (MTG), inferior parietal lobule, and cerebellum was found in children with known depression during the preschool period. Increased connectivity between the PCC and regions within the subgenual and anterior cingulate cortices and anterior MTG bilaterally was also found in these children. Additionally, a clinically relevant ‘brain‐behavior’ relationship between atypical functional connectivity of the PCC and disruptions in emotion regulation was identified. Conclusions: To our knowledge, this is the first study to examine the DMN in children known to have experienced the onset of a clinically significant depressive syndrome during preschool. Results suggest that a history of preschool depression is associated with atypical DMN connectivity. However, longitudinal studies are needed to clarify whether the current findings of atypical DMN connectivity are a precursor or a consequence of preschool depression.     

Etiology and genetics of early-onset mood disorders

Most studies dealing with the familiality and genetics of mood disorders have been limited to adults, but several studies suggest that there is continuity between childhood- and adolescence-onset depression and mania and adult illness. More direct estimates of the heritability of depressive symptoms or episodes in children and adolescents indicate that the genetic contributions may be greater than 50%. A number of functional and structural imaging studies have identified particular circuitry as being involved in the generation of emotion and mood disorders. Imaging studies of twins have suggested that regional brain volume and characteristics of brain shape are heritable. A potentially important new avenue of research will be the correlation of the genetics of brain structure or function with the genetics of mood disorders. Preliminary studies of adolescent and young adult twins suggest a significant correspondence between the genetic contributions to some regional brain volumes and early-onset mood disorders.     

Potential Risk Factors for the Development of Self-Injurious Behavior among Infants at Risk for Autism Spectrum Disorder

Prevalence of self-injurious behavior (SIB) is as high as 50% among children with autism spectrum disorder (ASD). Identification of risk factors for the development of SIB is critical to early intervention and prevention. However, there is little empirical research utilizing a prospective design to identify early risk factors for SIB. The purpose of this study was to evaluate behavioral characteristics predicting SIB at age 2 years among 235 infants at high familial risk for ASD. Logistic regression results indicated that presence of SIB or proto-SIB and lower developmental functioning at age 12 months significantly predicted SIB at 24 months. A pattern of persistent SIB over this period was associated with a diagnosis of autism and poorer cognitive and adaptive outcomes.     

Sex‐specific contribution of DHEA‐cortisol ratio to prefrontal‐hippocampal structural development,cognitive abilities and personality traits

Although dehydroepiandrosterone (DHEA) may exert neuroprotective effects in the developing brain, prolonged or excessive elevations in cortisol may exert neurotoxic effects. The ratio between DHEA and cortisol (DC ratio) has been linked to internalising and externalising disorders, as well as cognitive performance, supporting the clinical relevance of this hormonal ratio during development. However, the brain mechanisms by which these effects may be mediated have not yet been identified. Furthermore, although there is evidence that the effects of cortisol in the central nervous system may be sexually dimorphic in humans, the opposite is true for DHEA, with human studies showing no sex‐specific associations in cortical thickness, cortico‐amygdalar or cortico‐hippocampal structural covariance. Therefore, it remains unclear whether sex moderates the developmental associations between DC ratio, brain structure, cognition and behaviour. In the present study, we examined the associations between DC ratio, structural covariance of the hippocampus with whole‐brain cortical thickness, and measures of personality, behaviour and cognition in a longitudinal sample of typically developing children, adolescents and young adults aged 6‐22 years (N = 225 participants [F = 128]; 355 scans [F = 208]), using mixed effects models that accounted for both within‐ and between‐subject variances. We found sex‐specific interactions between DC ratio and anterior cingulate cortex‐hippocampal structural covariance, with higher DC ratios being associated with a more negative covariance between these structures in girls, and a more positive covariance in boys. Furthermore, the negative prefrontal‐hippocampal structural covariance found in girls was associated with higher verbal memory and mathematical ability, whereas the positive covariance found in boys was associated with lower cooperativeness and reward dependence personality traits. These findings support the notion that the ratio between DHEA and cortisol levels may contribute, at least in part, to the development of sex differences in cognitive abilities, as well as risk for internalising/externalising disorders, via an alteration in prefrontal‐hippocampal structure during the transition from childhood to adulthood.     

The treatment of late age onset psychoses with electroconvulsive therapy

The authors describe the clinical course and the brain imaging findings of six patients with late age onset psychoses who were treated with electroconvulsive therapy (ECT). In all five patients who failed to respond to ECT, one or more structural brain changes (lateral ventricular enlargement and/or subcortical structural changes) were observed. In addition, all six patients developed an interictal ECT-induced delirium. Consistent with previous ECT-induced delirium studies, caudate hyperintensities were present in the three patients who received brain MRI scans. The potential clinical correlates of structural brain changes in LAOP patients will be described, along with proposed areas of future research.     

Volumetric reduction in left subgenual prefrontal cortex in early onset depression.

BACKGROUND: Subgenual prefrontal cortex (SGPFC) volume reduction has been reported in middle age adults with major depression (MD) or bipolar affective disorder. In this study, the authors test the hypothesis that SGPFC reduction is present in adolescent onset MD, and examine differences in the magnitude of reduction in younger versus older women. METHODS: Subgenual prefrontal cortex volume was measured from T1 weighted MR images in (1) 30 young women with early onset MD versus eight age-matched controls, and (2) 18 middle aged women with recurrent MD versus nine age-matched controls. RESULTS: Left SGPFC volume was reduced in adolescent and middle aged females with depression. The magnitude of the difference between depressed and control groups (average 19% difference) was similar in younger and older women. CONCLUSIONS: Left subgenual cingulate volume reductions are present in young women with adolescent onset MD.