Stress response circuitry hypoactivation related to hormonal dysfunction in women with major depression. J Affect Disord

Harvard Medical School, Department of Psychiatry, Brigham and Women's Hospital, Connors Center for Women's Health and Gender Biology, USA.
Journal of Affective Disorders (Impact Factor: 3.38). 12/2010; 131(1-3):379-87. DOI: 10.1016/j.jad.2010.11.024
Source: PubMed


Women have approximately twice the risk of major depressive disorder (MDD) than men, yet this difference remains largely unexplained. Previous MDD research suggests high rates of endocrine dysfunction, which may be related to deficits in brain activity in stress response circuitry [hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC)]. This functional magnetic resonance imaging (fMRI) study investigated the relationship between hypothalamic-pituitary-gonadal (HPG)-axis hormones and stress response circuitry dysfunction in MDD in women.
During the late follicular/midcycle phase of the menstrual cycle, female participants (10 with extensive histories of MDD, in remission, 10 healthy controls) were scanned while viewing negative and neutral arousal pictures. Group differences in blood oxygen-level dependent (BOLD) signal changes were analyzed using SPM2. Baseline gonadal hormones included estradiol, progesterone, and testosterone.
fMRI results showed greater BOLD signal intensity changes in controls versus MDD in hypothalamus, amygdala, hippocampus, OFC, ACC, and subgenual ACC, findings unrelated to medication status. MDD women had a lower serum estradiol and higher serum progesterone compared to controls. Hypoactivations in hypothalamus, subgenual ACC, amygdala and OFC in MDD were associated with low estradiol and high progesterone.
Generalizability of our findings is limited by small sample size and restriction to females, although this did not affect the internal validity of the results.
Hypoactivation of the stress response circuitry in MDD women is associated with dysregulation of the HPG-axis. Associations between brain activity deficits and hormonal disruption in MDD may ultimately contribute to understanding sex differences in MDD.

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Available from: Laura M Holsen, Jun 05, 2014
    • "This adapted set of images did not represent any particular IAPS-assessed emotion, but rather a set of images that evoked specifically quantified negative valence and high arousal levels, regardless of specific emotion and established in numerous population studies by the original Lang team (Lang et al., 1998). In numerous studies of ours, we demonstrated that this set of images evoked a stress response to negative imagery in the key brain regions of this circuitry that are associated with physiologic stress responses (e.g., Holsen et al., 2011, 2013). Fixation images were based on Fourier transformations of each neutral image to create an image with the same physical properties of the original but without recognizable content. "
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    • "Second, rats exposed to exogenous progesterone demonstrate increased spectral power from 10 to 25 Hz, which encompasses spindle range activity (Lancel et al., 1996). Third, recent data from our laboratory demonstrates women with major depressive disorder (MDD) have increased sleep spindles relative to age and sex-matched controls (Plante et al., 2013), which could potentially be due to increased progesterone during both the follicular and luteal phase in women with MDD (Hardoy et al., 2006; Holsen et al., 2011). However, because neither increased sleep spindles (Goetz et al., 1983; Reynolds et al., 1985; de Maertelaer et al., 1987; Lopez et al., 2010) nor increased progesterone (Young et al., 2000; Girdler et al., 2012) in women with MDD has been a universal finding across studies, this link is speculative, particularly since levels of progesterone and sleep spindles have not been correlated within a single MDD cohort. "
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