Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)



First Advisor

Paul A. Newhouse


Women have greater incidence and prevalence of Major Depressive Disorder (MDD) than men during the reproductive life phase when ovarian hormones fluctuate, suggesting that ovarian hormones have a significant role in MDD etiology in women. As the core symptoms of MDD are indicative of alterations in stress responding, emotional processing, and mood regulation, examining the effects of the estrogen on these processes in women may provide a better understanding of the role of estrogen in the sex difference in MDD rates. The general aim of this dissertation was to examine neural, emotional, and attentional processes related to stress response alterations and cognitive bias in MDD in women.

To examine menstrual phase and estradiol level effects on the neural and mood response to psychosocial stress, healthy, normally cycling women were examined at either the high or low estradiol phase of the menstrual cycle. Participants were exposed to the Montreal Imaging Stress Task (MIST), with brain activity measured through functional magnetic resonance imaging (fMRI), and behavioral response assessed with subjective mood and stress measures. We found that women during the high estradiol phase showed significantly less hippocampal deactivation during psychosocial stress compared to women during the low estradiol phase. Additionally, women with higher estradiol levels also had less subjective distress in response to the MIST than women with lower estradiol levels. These results suggest that high estradiol may be protective against the shifts in brain system activity and negative mood responses associated with psychosocial stress. Periods of low estradiol may enhance the negative impact of psychosocial stress on neural activity and mood and thus contribute to MDD risk in vulnerable women.

The relation of cognitive bias to depression history in women was examined in postmenopausal women with and without a history of major depression using an emotion dot probe task during fMRI. Women with remitted MDD showed greater attentional facilitation for negative images than women with no history of MDD that was directly correlated with amygdala activity for negative images and amygdala-hippocampal connectivity in a resting scan. These findings provide evidence that differences in activity and functional connectivity in emotional processing networks may provide a neurobiological basis for continued cognitive bias in remitted MDD. Preliminary data indicate that estradiol treatment reduces amygdala-hippocampal connectivity specifically in women with a history of MDD and has interactive effects with MDD history on the mood response to psychosocial stress following the MIST such that women with a history of MDD appear to benefit from estradiol treatment while women without such history do not. Women with a history of or vulnerability to MDD may be particularly sensitive to the positive effects of estradiol on brain systems important to regulating emotional responses to psychosocial stress. The findings presented in this dissertation suggest that estrogen fluctuations across the menstrual cycle and at other reproductive events may contribute to depression risk through effects on brain systems integral to emotional evaluation and response with potential cognitive consequences.



Number of Pages

232 p.