The activity of neuroendocrine stress systems, and their effects on memory formation & neuroplasticity, are altered in depression. Research in animal models shows early life adversity alters corticosteroids' effects on memory formation and neuroplasticity into adulthood, but this is not well-established in humans. I therefore investigated the hypothesis that the effects of stress neuromodulators on depression-related cognition and neural circuitry are altered in women with history of aversive caregiving.

In a double-blind crossover study, functional magnetic resonance imaging (fMRI) was used to assess the neural correlates of the effects of cortisol administration (CORT), vs Placebo, on memory formation for emotional pictures. In addition, I used diffusion tensor imaging (DTI) to investigate relations between white matter structure and stress neuromodulators. Participants were 74 women with varying depression severity & history of childhood emotional abuse (EA). Because CORT's effects on memory formation vary by emotional arousal, we collected salivary alpha-amylase (sAA) to index task-related sympathetic activation.

Only in women with history of severe EA, CORT eliminated the relation between depression severity and negative memory bias by normalizing recall for pleasant stimuli. These women showed a related increase in BOLD activation in cortical premotor areas in response to CORT. Consistent with recent anatomical research in nonhuman primates that indicates these areas may modulate sympathetic activation via descending projections to spinal circuits innervating adrenal medulla, white matter structure in corticomotor projections to spinal cord showed opposing relations between fractional anisotropy (FA) and sAA for women with severe EA vs those without, which were normalized by CORT.

Thus, I demonstrate evidence of distinct neurocognitive responses to acute cortisol elevation in depressed women with history of EA, who may comprise an etiologically distinct subtype of depression, and whose emotional learning is partly normalized with sufficient cortisol elevation, possibly suggesting cortisol resistance at endogenous levels. Further, our functional and structural imaging results converge to suggest that in this population, cortical premotor areas may relate to these salutary neuroendocrine effects of cortisol elevation. I offer evidence from the literature that corticomotor circuits may support these effects by facilitating active emotion regulation in depressed women with history of EA. Finally, I outline future directions for basic and translational research.