Adolescents With Major Depression Demonstrate Increased Amygdala Activation

University of California, San Diego, CA 92123, USA.
Journal of the American Academy of Child and Adolescent Psychiatry (Impact Factor: 7.26). 01/2010; 49(1):42-51. DOI: 10.1097/00004583-201001000-00008
Source: PubMed

ABSTRACT Functional neuroimaging studies have led to a significantly deeper understanding of the underlying neural correlates and the development of several mature models of depression in adults. In contrast, our current understanding of the underlying neural substrates of adolescent depression is very limited. Although numerous studies have consistently demonstrated a hyperactive amygdala in depressed adults, the few published pediatric studies have reported opposite results in the amygdala. Thus, the main purpose of this study was to further our knowledge of the underlying neural substrates of adolescent depression by examining the bilateral amygdala specifically and the whole brain in depressed adolescents compared to healthy controls.
Twelve unmedicated adolescents diagnosed with current major depressive disorder without a comorbid psychiatric disorder and 12 well-matched controls ages 13 to 17 years performed a facial-emotion matching task during functional magnetic resonance imaging at 3 T.
Region-of-interest analyses demonstrated: (1) significant bilateral amygdala activation in depressed and healthy adolescents, and (2) significantly greater left amygdala activation in depressed adolescents compared to controls. Whole-brain analysis revealed areas of significantly different brain activity in depressed adolescents compared to controls.
These results suggest that (1) depressed adolescents without a comorbid psychiatric disorder exhibit an abnormally hyperactive amygdala compared to healthy controls; (2) models of adult depression might be extended to include depressed adolescents; and (3) neuropsychiatric interventions that have been developed in depressed adults should be further examined in adolescents.

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    • "A large body of work utilizing functional magnetic resonance imaging (fMRI) in patients with MDD has revealed dysregulation within a corticolimbic circuitry involved in the perception and regulation of emotion and affect, within which the amygdala serves as a hub. The majority of these studies demonstrate relative amygdala hyperactivity in response to negative stimuli (Whalen et al., 2002; Victor et al., 2010; Yang et al., 2010). However, a notable minority of studies has associated depression (Thomas et al., 2001) or depression risk (Wolfensberger et al., 2008) with relatively blunted amygdala response to threat, suggesting there may be a depression subtype associated with reduced reactivity to environmental stimuli. "
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    ABSTRACT: The A allele of the FRAS1-related extracellular matrix protein 3 (FREM3) rs7676614 single nucleotide polymorphism (SNP) was linked to major depressive disorder (MDD) in an early genome-wide association study (GWAS), and to symptoms of psychomotor retardation in a follow-up investigation. In line with significant overlap between age-and depression-related molecular pathways, parallel work has shown that FREM3 expression in postmortem human brain decreases with age. Here, we probe the effect of rs7676614 on amygdala reactivity and perceptual processing speed, both of which are altered in depression and aging. Amygdala reactivity was assessed using a face-matching BOLD fMRI paradigm in 365 Caucasian participants in the Duke Neurogenetics Study (DNS) (192 women, mean age 19.7 ± 1.2). Perceptual processing speed was indexed by reaction times in the same task and the Trail Making Test (TMT). The effect of rs7676614 on FREM3 mRNA brain expression levels was probed in a postmortem cohort of 169 Caucasian individuals (44 women, mean age 50.8 ± 14.9). The A allele of rs7676614 was associated with blunted amygdala reactivity to faces, slower reaction times in the face-matching condition (p < 0.04), as well as marginally slower performance on TMT Part B (p = 0.056). In the postmortem cohort, the T allele of rs6537170 (proxy for the rs7676614 A allele), was associated with trend-level reductions in gene expression in Brodmann areas 11 and 47 (p = 0.066), reminiscent of patterns characteristic of older age. The low-expressing allele of another FREM3 SNP (rs1391187) was similarly associated with reduced amygdala reactivity and slower TMT Part B speed, in addition to reduced BA47 activity and extraversion (p < 0.05). Together, these results suggest common genetic variation associated with reduced FREM3 expression may confer risk for a subtype of depression characterized by reduced reactivity to environmental stimuli and slower perceptual processing speed, possibly suggestive of accelerated aging.
    Frontiers in Psychology 10/2015; 6. DOI:10.3389/fpsyg.2015.01377 · 2.80 Impact Factor
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    • "Importantly, heightened amygdala and hippocampus response to threat-related stimuli has also been observed in children, adolescents, and adults with depression (e.g. Barch et al., 2012; Beesdo et al., 2009; Bishop et al., 2004; Etkin et al., 2004; Ewbank et al., 2009; Gaffrey et al., 2011; Thomas et al., 2001b; Yang et al., 2010). Amygdala hyperresponsivity is similarly present in unaffected children at risk for depression (based on parental history of depression; Monk et al., 2008), suggesting that these differences may precede the development of psychopathology and that genetic risk and/or early environmental factors may play a key role. "
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    ABSTRACT: 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. Copyright © 2015. Published by Elsevier Inc.
    01/2015; 109. DOI:10.1016/j.neuroimage.2015.01.017
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    • "Previous work in this sample also showed that greater right amygdala sad versus neutral face activity in school-age children was related to poorer sadness regulation skills summing across all three subscales of the CEMS (Pagliaccio et al., 2013). This is highly relevant for the wellreplicated finding that people with depression show elevated amygdala responses to emotional stimuli and that greater depression severity correlates with greater amygdala responses to these stimuli (e.g., Barch et al., 2012; Beesdo et al., 2009; Gaffrey et al., 2011; Pagliaccio et al., 2011; Yang et al., 2010). First, these findings suggest that exploring individual differences in constructs, like emotion regulation, may be key to understanding the underlying neural and psychological deficits in depression (Aldao, Nolen-Hoeksema, & Schweizer, 2010; Garnefski & Kraaij, 2006; Joormann & Gotlib , 2010; Silk, Steinberg, & Morris, 2003). "
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    ABSTRACT: Structural and functional alterations in a variety of brain regions have been associated with depression and risk for depression across the life span. A majority of these regions are associated with emotion reactivity and/or regulation. However, it is generally unclear what mechanistic role these alterations play in the etiology of depression. A first step toward understanding this is to characterize the relationships between variation in brain structure/function and individual differences in depression severity and related processes, particularly emotion regulation. To this end, the current study examines how brain structure and function predict concurrent and longitudinal measures of depression symptomology and emotion regulation skills in psychiatrically healthy school-age children (N ¼ 60). Specifically, we found that smaller hippocampus volumes and greater responses to sad faces in emotion reactivity regions predict increased depressive symptoms at the time of scan, whereas larger amygdala volumes, smaller insula volumes, and greater responses in emotion reactivity regions predict decreased emotion regulation skills. In addition, larger insula volumes predict improvements in emotion regulation skills even after accounting for emotion regulation at the time of scan. Understanding brain–behavior relationships in psychiatrically healthy samples, especially early in development, will help inform normative developmental trajectories and neural alterations in depression and other affective pathology.
    Development and Psychopathology 11/2014; 26(4pt2):1289–1303. DOI:10.1017/S0954579414001035 · 4.89 Impact Factor
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