HPA-axis hormone modulation of stress response circuitry activity in women with remitted major depression

Abstract

Decades of clinical and basic research indicate significant links between altered hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics and major depressive disorder (MDD). Recent neuroimaging studies of MDD highlight abnormalities in stress response circuitry regions which play a role in the regulation of the HPA-axes. However, there is a dearth of research examining these systems in parallel, especially as related to potential trait characteristics. The current study addresses this gap by investigating neural responses to a mild visual stress challenge with real-time assessment of adrenal hormones in women with MDD in remission and controls. Fifteen women with recurrent MDD in remission (rMDD) and 15 healthy control women were scanned on a 3T Siemens MR scanner while viewing neutral and negative (stress-evoking) stimuli. Blood samples were obtained before, during, and after scanning for the measurement of HPA-axis hormone levels. Compared to controls, rMDD women demonstrated higher anxiety ratings, increased cortisol levels, and hyperactivation in the amygdala and hippocampus, p<0.05, family-wise error (FWE)-corrected in response to the stress challenge. Among rMDD women, amygdala activation was negatively related to cortisol changes and positively associated with the duration of remission. Findings presented here provide evidence for differential effects of altered HPA-axis hormone dynamics on hyperactivity in stress response circuitry regions elicited by a well-validated stress paradigm in women with recurrent MDD in remission.

Keywords: ACC; ACTH; CPP; CRH; Collaborative Perinatal Project; FWE; GLM; HAM-D; HCs; HPA; HPA-axis; Hamilton Rating Scale for Depression; IAPS; International Affective Picture System; MDD; NEFS; New England Family Study; OFC; PET; POMS; PVN; Profile of Mood States; ROIs; STAI; Spielberger State-Trait Anxiety Inventory; adrenocorticotropin hormone; anterior cingulate cortex; corticotropin-releasing hormone; depression; fMRI; family-wise error; functional magnetic resonance imaging; general linear model; healthy controls; hypothalamic–pituitary–adrenal; major depressive disorder; orbitofrontal cortex; paraventricular nucleus; percent signal change; positron emission tomography; psc; regions of interest; sex differences; sgACC; stress; subgenual ACC.

Figure 1

Cortisol levels in rMDD and healthy control subjects, measured in response to mild stress paradigm during and following fMRI scanning. Error bars represent the standard error of the mean. **rMDD > HC, p<0.05.

Figure 2

Significant hyperactivation of stress response circuitry regions in rMDD women in comparison to healthy control subjects. Activations of hypothesized regions of interest were derived using restriction to within anatomical borders (defined by a manually segmented MNI brain) with the small volume correction tool in SPM8. Activations in Figure 2 are selected from Table 3, centered on the peak voxel of activation with a p<0.05 (uncorrected). Error bars indicate standard deviations.

Figure 3

Associations between amygdala hyperactivation and cortisol reactivity in response to mild stress paradigm. (a) Correlation between right amygdala psc and peak cortisol response in rMDD women (p<0.05). (b) Correlation between right amygdala psc and change in cortisol in rMDD women (p=0.071).