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


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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    • "Improving our understanding of the neural substrate of MDD during adolescence, in its emergence, may also shed light on cognitive and neural mechanisms of the disorder that become evident in adult patient populations. Studies in adolescent MDD support dysfunction in frontal, limbic and occipital areas, in accordance with the adult literature (Halari et al., 2009; Roberson-Nay et al., 2006; Tao et al., 2012; Yang et al., 2009 Yang et al., , 2010 ). Nay et al. (2006) report reduced memory for faces and differential activation in the amygdala and anterior hippocampus during memory encoding in adolescents with MDD. "
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    ABSTRACT: Introduction: Major Depressive Disorder (MDD) is a leading cause of disease burden worldwide. Mood-congruent biases in memory tasks are frequently reported in MDD patients, with facilitated memory for negative stimuli. Most functional MRI studies to date have examined the neural correlates of these biases in depressed adults, with fewer studies in adolescents with MDD. Investigation of MDD in adolescence may aid greater understanding of the aetiology and development of the disorder. Methods: Cognitive biases were investigated in 56 MDD patients aged 11-17 years and a matched group of 30 healthy control participants with a self-referential memory task. Behavioural performance and BOLD fMRI data were collected during both encoding and retrieval stages. Results: The neural response to encoding in adolescents with MDD was found to differ significantly from controls. Additionally, neural responses during encoding and retrieval showed differential relationships with age between patient and control groups, specifically in medial, temporal, and prefrontal regions. Conclusions: These findings suggest that during adolescence neurophysiological activity associated with emotional memory differs in those with depression compared to controls and may be age sensitive.
    Full-text · Article · Dec 2015 · Developmental Cognitive Neuroscience
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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 (192 women, mean age 19.7±1.2). Perceptual processing speed was indexed by reaction times in the same task and the Trails 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
    Full-text · Article · Oct 2015 · Frontiers in Psychology
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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.
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