It is well-established that the rate of disorders of affect exhibits a pronounced sex difference, such that susceptibility to disorders such as depression and post-traumatic stress is twice as high in women when compared to men. At present, however, the neural basis of this difference is not well understood. It has been suggested that women are at higher risk for these disorders due to a more general sex difference in the processing of affect. Multiple neuroimaging studies have supported this view, showing regional differences between men and women in the magnitude of the response to affective material. However, these studies have not converged on a consistent pattern of sex differences, nor have they related neural sex differences to pathological symptoms. Preliminary evidence from our lab has revealed a novel sex difference in affective processing, found not in the magnitude of the affective response, but rather in the persistence of that response over multiple repetitions. Our data indicate that while the response of the affective circuitry to negatively valenced stimuli does not differ between the sexes when those items are novel, the response to negative items that have been familiarized through repeated presentation is significantly greater in women than it is in men. This suggests that the affective systems of women habituate significantly more slowly to negative stimuli than do men's. Studies of individuals with high anxiety have shown similarly sustained activity in the affective network during the extinction of fear relative to healthy controls. Thus, it may be the case that the persistence of the affective response in women explains their greater susceptibility to affective disorder. In this proposal, we will test that possibility. Using fMRI, we will first fully characteize the habituation curves for the response to emotion-inducing material in various affective regions of interest in women and men, confirming the sex difference. These data will then be compared to various measures of affective disruption, including multiple inventories measuring depression and anxiety, tests of HPA axis responsiveness, and self-reported rumination. We predict that women will show longer-lasting responses in regions including amygdala, insula, and anterior cingulate relative to men, and that the magnitude of these responses after numerous repetitions will correlate with measures of affective dysfunction, such that those with the most persistent affective responses will also show the most symptoms. We further predict that women will have greater responses in the affective network than men when familiar affective material is visualized one week later. If these predictions are confirmed, it would indicate that the rate of habituation to negative stimuli predicts symptoms of affective disorder. Thus, as a slower rate of habituation is more common in women, they are more susceptible to disorders of affect as a group. A better understanding of the factors underlying sex differences in affective disorder could lead to more personalized and effective treatment.

Public Health Relevance

This study will compare the persistence of the brain's response to negative material over multiple repetitions between women and men, and test whether an enduring neural response to negativity is related to various symptoms of affective disorder. Based on preliminary data, we predict that women will exhibit a more persistent neural response to negative experience, such that their brains continue to respond to repeated presentation of a negative stimulus after the brains of men have ceased to respond, and that this persistence will be correlated with symptoms of anxiety and depression. The results of this experiment may help to explain the significantly higher susceptibility to disorders of affect in women relative to men, and could lead to more customized and effective treatments.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZMH1-ERB-L (07))
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Simmons, Janine M
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Massachusetts General Hospital
United States
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Bickart, Kevin C; Dickerson, Bradford C; Barrett, Lisa Feldman (2014) The amygdala as a hub in brain networks that support social life. Neuropsychologia 63:235-48