Estradiol Modulates Neural and Behavioral Arousal in Women With Posttraumatic Stress Disorder During a Fear Learning and Extinction Task

Abstract

BackgroundFear responding in posttraumatic stress disorder (PTSD) is sexually heterogeneous and varies with hormonal fluctuations throughout the menstrual cycle. While research suggests that estrogen levels affect PTSD symptoms among women, there is a dearth of research on modulatory effects of estrogen on fear responding among women with PTSD, and neural outcome measures are lacking. MethodsA sample of 42 women with PTSD underwent 2 consecutive alternating blocks of fear conditioning and extinction training, during which a CS+ conditioned stimulus, but not a CS−, predicted the occurrence of an electric shock in an acquisition context but not in an extinction context. Assayed saliva determined estradiol levels. Skin conductance response and whole-brain voxelwise activity during functional magnetic resonance imaging were outcome variables in linear mixed-effects models, with estradiol level, PTSD severity, and task contrasts as predictors. ResultsSkin conductance response exhibited a significant estradiol × PTSD severity × habituation interaction (t = 3.180, p = .002), such that PTSD severity was correlated with increased arousal responding between training blocks among women with lower estradiol (t = −3.985, p < .001) but not higher estradiol (t = 0.550, p = .583). Voxelwise activity also demonstrated an identical three-way interaction within dorsomedial prefrontal cortex and anterior insula clusters. The skin conductance response and imaging interactions between PTSD severity and estradiol were not specific to conditioned stimulus type or context. ConclusionsEstradiol moderated the relationship between PTSD severity and arousal response habituation between fear conditioning and extinction training sessions, such that high estradiol protected against the negative impact of severe PTSD symptoms on fear habituation. These findings suggest that estrogen enhances habituation among women with severe PTSD, potentially influencing the efficacy of extinction-based therapies.