Cortisol Administration Inhibits Sadness-Related Subgenual Cingulate Activity in Depression

Sudheimer K, Heinemeyer E, O’Hara R, Duvio D, Schatzberg AF
Annual Meeting of the American College of Neuropsychopharmacology. 2015.


Background: Cortisol dysregulation has been observed in a large subpopulation of patients with major depression for over 50 years. Subgenual cingulate hyperactivity has also been observed in major depression since the advent of modern neuroimaging techniques over 20 years ago. A great deal of work has been done to demonstrate that 1) both cortisol dysregulation and subgenual cingulate hyperactivity are more pronounced in patients with more severe symptoms 2) that these findings normalize with when patients are successful treated 3) that these findings reemerge prior to relapse. However, little work has been done to integrate these findings by investigating the interactions between cortisol signaling and subgenual cingulate activity levels. Our group has previously presented evidence that cortisol inhibition of sadness induced subgenual cingulate activity is a normal neural circuit. In this study we present preliminary evidence that this circuit could be breaking down in major depression, leading to hyperactivity of the subgenual cingulate and overexpression of sadness.

Methods: A preliminary analysis included data from 9 participants suffering from major depression. All participants were medication-free for the duration of the study and all female participants were naturally cycling. Participants were scanned using functional magnetic resonance imaging on a 3 Tesla General Electric MRI scanner equipped with a custom 32-channel head-coil executing a 3X multiband acquisition pulse sequence (TR=2, 87 horizontal slices, isotropic 1.8mm voxels). Participants viewed 3 separate runs of 14 minutes and 44 seconds. Each run was divided into 3 conditions: 1) sadness induction using previously validated stimuli from the International Affective Picture System and still-frames extracted from validated film clips that the participants had previously viewed 2) control stimuli which consisted of pixel scrambled versions of the IAPS and film clip still-frames 3) fixation cross control, which consisted of a black screen with a white fixation cross. Each run contained 9 sadness induction blocks lasting 32 seconds each, 9 control stimuli blocks lasting 32 seconds each, and 19 fixation blocks lasting 16 seconds each. Between run1 and run2 participants were given either 0.65 mg/kg of orally administered cortisol or a matched placebo.

Results: Preliminary data from the first 9 participants with major depression indicate that before cortisol administration the [sadness > control] contrast produced a significant activation of the subgenual cingulate T(8)=2.615, p=0.031 . After cortisol administration this activity was significantly reduced T(8)=-2.489, p=0.0371 by an average of 78.3%.

Conclusions: The preliminary analysis indicates that cortisol-induced suppression of the subgenual cingulate activity occurs in participants with major depression. However the magnitude of this suppression is subtle compared to our previously published work with healthy control participants that showed robustly lower sadness-related subgenual cingulate activation in participants taking cortisol. Additional data are being collected from healthy control participants to allow for a direct group comparison with the depressed participants. If the sensitivity of subgenual cingulate activity to cortisol is reduced in major depression it could represent the key neural circuit breakdown that is responsible for hyperactivity of the subgenual cingulate and the overexpression of sadness.