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Randomized Controlled Trial
, 38 (5), 826-45

Exogenous Glucocorticoids Decrease Subgenual Cingulate Activity Evoked by Sadness

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Randomized Controlled Trial

Exogenous Glucocorticoids Decrease Subgenual Cingulate Activity Evoked by Sadness

Keith D Sudheimer et al. Neuropsychopharmacology.

Abstract

The glucocorticoid hormone cortisol is known to have wide-ranging effects on a variety of physiological systems, including the morphology and physiology of the amygdala and hippocampus. Disruptions of cortisol regulation and signaling are also linked with psychiatric disorders involving emotional disturbances. Although there is much evidence to suggest a relationship between cortisol signaling and the brain physiology underlying emotion, few studies have attempted to test for direct effects of cortisol on the neurophysiology of emotion. We administered exogenous synthetic cortisol (hydrocortisone, HCT) using two different dosing regimens (25 mg/day over 4 days, 100 mg single dose), in a double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study. During fMRI scanning, healthy subjects viewed images designed to induce happy, sad, and neutral emotional states. Subjective emotional reactions were collected for each experimental stimulus after fMRI scanning. Mood ratings were also collected throughout the 4 days of the study. Both dose regimens of HCT resulted in decreased subgenual cingulate activation during sadness conditions. The 25 mg/day regimen also resulted in higher arousal ratings of sad stimuli. No effects of HCT were observed on any mood ratings. Few reliable effects of HCT were observed on brain activity patterns or subjective emotional responses to stimuli that were not sad. The inhibitory effects of cortisol on sadness-induced subgenual cingulate activity may have critical relevance to the pathophysiology of major depression, as both subgenual hyperactivity and decreased sensitivity to cortisol signaling have been documented in patients with depression.

Figures

Figure 1
Figure 1
Regions of interest extractions from the subgenual cingulate (panel 1) ventral medial prefrontal cortex (panel 2), and the amygdala (panel 3). Significant group differences were detected for contrasts involving sad stimuli in the subgenual cingulate and the ventral medial prefrontal cortex (VMPFC). *p<0.05 after Bonferroni correction.
Figure 2
Figure 2
Decreased activation of the subgenual cingulate cortex in groups receiving hydrocortisone (HCT) on contrasts involving sad stimuli. Qualitatively similar effects were seen in both HCT groups. Voxel-wise statistical tests at p<0.05 after family-wise error and small volume correction are only significant for peak voxels in the extended dose group on the sad vs neutral contrast (upper-right panel). The maps above are subject to a p<0.05 threshold and a cluster threshold of five voxels for qualitative display purposes. See Table 2 for statistics.
Figure 3
Figure 3
Subjective ratings are displayed for each type of experimental stimuli. The first column displays data for the each kind of emotional stimuli (happy, sad, neutral). The second and third column displays the same data when only faces or only International Affective Picture System (IAPS) stimuli are considered. The dashed line above the valence measure denotes the neutral valence rating. Stimuli ratings above 5 indicate a positive valence and below 5 indicate a negative valence. In the hydrocortisone groups, the ratings of arousal across all stimuli are elevated. However, this elevation in arousal only achieves statistical significance for sad stimuli rated by the extended dose group. *p<0.05 after Bonferroni correction.
Figure 4
Figure 4
Subjective ratings of each of the experimental stimuli are plotted in valence/arousal space for the placebo group. Arrows indicate the vector of shifts toward increasing arousal in the hydrocortisone groups. The left panel quiver plot demonstrates placebo group to single-dose group change vectors. The right panel demonstrates placebo group to extended dose group change vectors. In the extended dose group, the most prominent shifts are in the stimuli occupying the low valence portions of the valence/arousal space, which correspond to sad stimuli. IAPS, International Affective Picture System.

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