Neural Signaling of Cortisol, Childhood Emotional Abuse, and Depression-Related Memory Bias

Abstract

Background: Cortisol has potent effects on learning and neuroplasticity, but little is known about its effects on negative memory biases in depression. Animal models show that aversive caregiving alters effects of glucocorticoids (primarily corticosterone in rodents and cortisol in primates) on learning and neuroplasticity into adulthood.

Methods: We investigated whether history of childhood emotional abuse (EA) moderated effects of cortisol administration (CORT) versus placebo on emotional memory formation in depression. Participants included 75 unmedicated women with varying levels of depression severity and/or EA history. In a double-blind crossover investigation, we used functional magnetic resonance imaging to measure effects of CORT (vs. placebo) on neural function during emotional memory formation.

Results: CORT eliminated the well-known relationship between depression severity and negative memory bias, a finding explained by EA severity. For women with a history of severe EA, CORT reduced depression-related negative memory bias and normalized recall for pleasant stimuli. EA severity also moderated CORT effects on neural function: in women with history of severe EA, CORT increased activation in the supplementary motor area during viewing of unpleasant relative to pleasant pictures. Additionally, supplementary motor area activation predicted reduced negative bias for pictures encoded during CORT.

Conclusions: These results suggest that increasing cortisol signaling may be neurocognitively beneficial in depressed women with a history of maltreatment. The findings corroborate prior research suggesting that presence or absence of adverse caregiving is etiologically important in depression. These findings suggest potential neurocognitive mechanisms of therapeutics targeting cortisol signaling, which show promise in treating affective disorders.

Trial registration: ClinicalTrials.gov NCT03195933.

Keywords: Cortisol; Depression; Emotional abuse; Emotional memory; Supplementary motor area; fMRI.

Figure 1. Study procedures and timeline

(A) Study timeline. Phone-based and in-person screening determined participant eligibility, after which participants completed a mock scan. In a double-blind crossover design, participants completed two memory encoding/fMRI sessions, which were typically separated by one week. During each memory encoding/fMRI session, participants were administered a pill containing either 20 mg cortisol (CORT) or placebo. Two days after each encoding/fMRI session participants returned to the lab to be tested for memory recall of encoded pictures. (B) Encoding/fMRI sessions timeline. Encoding/fMRI sessions were conducted in the evening when endogenous cortisol levels are low. Participants arrived at ~4:15 PM, received study drug at 5:05 PM, and underwent MRI scanning from ~6:05 PM to ~7:35 PM, with the encoding task beginning at ~6:35 PM. Participants departed the lab at ~8:30 PM. Saliva samples were collected throughout, including a sample immediately after the encoding task, to index salivary cortisol and alpha-amylase levels.

Figure 2. In participants with severe childhood emotional abuse (EA), CORT reversed the association between depression severity and negative memory bias

Dashed black lines represent regression fit for full sample. Colored lines represent regression fits for subjects with differing levels of childhood EA (see legend). Depression severity indexed with BDI-II (see text for details). (A) For pictures encoded following Placebo, women with greater levels of depression recalled more unpleasant relative to pleasant pictures, i.e. showed greater negative memory bias, r(74) = .38, p < .001. (B) Following CORT, there was no such correlation at the group level, r(74) = .08, n.s., illustrating a Drug (CORT vs. Placebo) × Depression Severity interaction effect, F(1,73)=5.31, p<.03, in which CORT abolishes the relation between Depression Severity and negative memory bias for the entire sample. Childhood EA moderated the effect of CORT: in women with history of severe EA, CORT reversed the relation between depression severity and negative memory bias, F(2,74) = 5.63, p < .01.

Figure 3. Brain regions showing significant Drug (CORT vs. Placebo) × EA interaction for the model using the continuous measure of EA (i.e., CTQ Emotional Abuse subscale scores)

Also see Table 3 & Figure 4, which display the Drug × EA interaction in more detail for EA groups (based on CTQ Emotional Abuse cut scores).

Figure 4. CORT-related neural response to unpleasant > pleasant pictures varied by severity of childhood emotional abuse (EA)

Shown are sagittal group difference maps for unpleasant > pleasant activations (centered on left SMA) for EA groups (Minimal, Moderate, and Severe) during Placebo and CORT conditions. Colors reflect Z-scores for CORT > Placebo and Severe > Minimal activation. At bottom-right (gray box), colors reflect F-values for significant clusters (SMA & thalamus) in the EA × Drug interaction. For cluster statistics see Table 3. Individual voxel p-value threshold for Placebo & CORT conditions was p < .005; a less stringent threshold of p < .01 was used for CORT > Placebo.