Cortisol's effects on hippocampal activation in depressed patients are related to alterations in memory formation

Abstract

Many investigators have hypothesized that brain response to cortisol is altered in depression. However, neural activation in response to exogenously manipulated cortisol elevations has not yet been directly examined in depressed humans. Animal research shows that glucocorticoids have robust effects on hippocampal function, and can either enhance or suppress neuroplastic events in the hippocampus depending on a number of factors. We hypothesized that depressed individuals would show 1) altered hippocampal response to exogenous administration of cortisol, and 2) altered effects of cortisol on learning. In a repeated-measures design, 19 unmedicated depressed and 41 healthy individuals completed two fMRI scans. Fifteen mg oral hydrocortisone (i.e., cortisol) or placebo (order randomized and double-blind) was administered 1 h prior to encoding of emotional and neutral words during fMRI scans. Data analysis examined the effects of cortisol administration on 1) brain activation during encoding, and 2) subsequent free recall for words. Cortisol affected subsequent recall performance in depressed but not healthy individuals. We found alterations in hippocampal response to cortisol in depressed women, but not in depressed men (who showed altered response to cortisol in other regions, including subgenual prefrontal cortex). In both depressed men and women, cortisol's effects on hippocampal function were positively correlated with its effects on recall performance assessed days later. Our data provide evidence that in depressed compared to healthy women, cortisol's effects on hippocampal function are altered. Our data also show that in both depressed men and women, cortisol's effects on emotional memory formation and hippocampal function are related.

Figure 1

Salivary cortisol levels in nmol/L. Stippled lines represent salivary cortisol levels during the session in which CORT was administered. Solid lines represent salivary cortisol levels during the session in which Placebo was administered. Shaded area represents duration of time in scanner. Drug administration occurred 20–30 minutes prior to placement in scanner, and approximately 60 minutes prior to functional scanning during word encoding task. Two saliva samples were collected in the evening at home after departure from the lab. Endogenous salivary cortisol levels (at baseline on CORT day and throughout Placebo session) did not differ between depressed and control subjects, F’s < 0.1. Despite small differences apparent in the figure, depressed and control subjects did not significantly differ in salivary cortisol levels following drug administration, F(1,57) = 0.09, n.s. However, salivary cortisol levels following drug administration differed by sex, F(1,57) = 4.38, p < .05. On average, women showed greater post-drug salivary cortisol, which do not appear to be solely due to differences in weight (see text).

Figure 2

*p < .05. Free recall for words measured 4–6 days subsequent to encoding during fMRI. Analysis revealed a Drug × Group × Sex × Valence interaction, F(2,112) = 4.91, p < .01. Likewise, when examining memory bias (positive minus negative words recalled), a Drug × Group × Sex interaction is apparent, F(1,56) = 5.84, p < .02. Posthoc analyses show that interactions are due to effects of cortisol on memory for positive words in the depressed group only, which are in opposite directions for men and women. In depressed women (top left panel), CORT (compared to placebo) decreased the number of positive words subsequently recalled, t(9) = −2.47, p < .05; i.e., this sample of mildly depressed women showed a relatively positive memory bias for words encoded under placebo (similar to controls), but cortisol abolished that positive bias. In depressed men (bottom left panel), CORT (compared to placebo) increased the number of positive words subsequently recalled, t(8) = 2.48, p < .05. For words encoded under placebo, depressed men showed no bias, but CORT administration instilled a relatively positive bias.

Figure 3

Alterations in response to CORT administration in depressed women. Figure 3a: Right posterior hippocampus. Depressed compared to healthy women showed altered response to CORT in this region. Figure 3b: Altered response in this region was due to a CORT-related increase in hippocampal response to neutral words in depressed women compared to controls, F(1,30) = 9.63, p < .005. Within the depressed group, response to neutral words was greater during CORT than placebo administration, t(9) = 5.51, p < .005. Figure 3c: Altered response to CORT was related to CORT’s effects on memory in depressed women, such that women who showed greater CORT-related increase in hippocampal response to neutral (relative to emotional) words showed greater preservation of positive recall bias, r(9) = .70, p < .03.

Figure 4

For the left posterior hippocampus in depressed males, correlational findings were identical to the findings for women: the more CORT increased posterior hippocampal response to neutral (compared to emotionally arousing) words, the more CORT instilled a positive bias, r(7) = .79, p < 0.05.