Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n = 99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited blood oxygen-level dependent responses in the following circuitry: periaqueductal gray, hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO - R OFC, R AMYG - R OFC, and R AMYG - R HIPP. Overall, our findings demonstrated sex-dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex-dependent lens in determining these biosignatures. Hum Brain Mapp 37:3733-3744, 2016. © 2016 Wiley Periodicals, Inc.

Center for Depression Anxiety and Stress Research McLean Hospital Harvard Medical School Boston Massachusetts

Connors Center for Women's Health and Gender Biology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts

Connors Center for Women's Health and Gender Biology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts Brain and Mind Research Programme CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Connors Center for Women's Health and Gender Biology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts Division of Psychiatric Neuroscience Department of Psychiatry Athinoula a Martinos Center Massachusetts General Hospital Boston Massachusetts

Department of Community Health Brown University Providence Rhode Island

Division of Psychiatric Neuroscience Department of Psychiatry Athinoula a Martinos Center Massachusetts General Hospital Boston Massachusetts

Division of Public Psychiatry Beth Israel Deaconess Medical Center Massachusetts Mental Health Center and Harvard Medical School Boston Massachusetts

McGovern Institute for Brain Research Massachusetts Institute of Technology Boston Massachusetts

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