Chronic exposure to psychosocial stress has been linked to changes in structural and functional activation of brain regions involved in the control of cardiovascular regulation. Psychosocial stress is a risk factor for coronary artery disease (CAD) and has been associated with poorer prognosis and greater mortality in women than men. We investigated sex differences in the neural correlates of mental stress in a cross-sectional study of 53 women and 112 men with stable CAD. We used [15O]H2O positron emission tomography (PET) to identify brain regions with cerebral blood flow changes with mental stress using mental arithmetic and public speaking tasks in women and men. Compared to men, women had significantly greater activation in the left superior temporal gyrus (Area 42) and greater deactivation in the anterior cingulate gyrus, bilaterally (Area 24, 32), right medial frontal gyrus (Area 8, 9), and right middle temporal gyrus (Area 21). Of interest, among those with mental stress ischemia (MSI), women had greater activation than men in the right and left anterior cingulate gyrus (Area 24, 32). In contrast, among those without MSI, there was no statistically significant increase in cerebral flow to any brain region outside of the cerebellum among women compared with men; however, there was greater hypoactivation to mental stress in women than men in the cingulate gyrus (Area 24, 32) and right middle temporal gyrus (Area 21). Among female participants, women with MSI had comparable sex differences in deactivation to mental stress as women without MSI, in addition to deactivation in the right and left prefrontal cortex (Areas 8, 11, 47). The results of our study are consistent with the hypothesis that stress is differentially associated with hyper- and hypoactivation of brain regions in men and women, particularly in the limbic system. Furthermore, our results demonstrate exaggerated stress responsivity in the prefrontal cortex, particularly the cingulate gyrus, in women with CAD and MSI.
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