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.

Brain and Mind Research Programme CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

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

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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Alonso SJ, Damas C, Navarro E (2000): Behavioral despair in mice after prenatal stress. J Physiol Biochem 56:77–82. PubMed

Anthenelli RM (2010): Focus on: Comorbid mental health disorders. Alcohol Res Health 33:109. PubMed PMC

Beauregard M, Paquette V, Levesque J (2006): Dysfunction in the neural circuitry of emotional self‐regulation in major depressive disorder. Neuroreport 17:843–846. PubMed

Bradley MM, Lang PJ (1994): Measuring emotion: The self‐assessment manikin and the semantic differential. J Behav Ther Exp Psychiatry 25:49–59. PubMed

Brett M, Anton J‐L, Valabregue R, Poline JB. Region of Interest Analysis Using an SPM Toolbox. 8th International Conference on Functional Mapping of the Human Brain; Sendai, Japan. 2002.

Carbone DL, Handa RJ (2013): Sex and stress hormone influences on the expression and activity of brain‐derived neurotrophic factor. Neuroscience 239:295–303. PubMed PMC

Clewett D, Schoeke A, Mather M (2013): Amygdala functional connectivity is reduced after the cold pressor task. Cogn Affect Behav Neurosci 13:501–518. PubMed PMC

Cunningham‐Bussel AC, Root JC, Butler T, Tuescher O, Pan H, Epstein J, Weisholtz DS, Pavony M, Silverman ME, Goldstein MS, Altemus M, Cloitre M, Ledoux J, McEwen B, Stern E, Silbersweig D (2009): Diurnal cortisol amplitude and fronto‐limbic activity in response to stressful stimuli. Psychoneuroendocrinology 34:694–704. PubMed PMC

Dedovic K, Duchesne A, Andrews J, Engert V, Pruessner JC (2009): The brain and the stress axis: The neural correlates of cortisol regulation in response to stress. NeuroImage 47:864–871. PubMed

Derntl B, Kryspin‐Exner I, Fernbach E, Moser E, Habel U (2008): Emotion recognition accuracy in healthy young females is associated with cycle phase. Horm Behav 53:90–95. PubMed

Doehrmann O, Ghosh SS, Polli FE, Reynolds GO, Horn F, Keshavan A, Triantafyllou C, Saygin ZM, Whitfield‐Gabrieli S, Hofmann SG, Pollack M, Gabrieli JD (2013): Predicting treatment response in social anxiety disorder from functional magnetic resonance imaging. JAMA Psychiatry 70:87–97. PubMed PMC

Domes G, Schulze L, Bottger M, Grossmann A, Hauenstein K, Wirtz PH, Heinrichs M, Herpertz SC (2010): The neural correlates of sex differences in emotional reactivity and emotion regulation. Hum Brain Mapp 31:758–769. PubMed PMC

Dougherty D, Rauch SL (1997): Neuroimaging and neurobiological models of depression. Harv Rev Psychiatry 5:138–159. PubMed

Engman J, Linnman C, Van Dijk KR, Milad MR (2016): Amygdala subnuclei resting‐state functional connectivity sex and estrogen differences. Psychoneuroendocrinology 63:34–42. PubMed

Gilman SE, Cherkerzian S, Buka SL, Hahn J, Horing M, Goldstein M (2016). Prenatal immune programming of the sex‐dependent risk for major depression, Transl Psychiatry, doi:10.1038/tp.2016.91 PubMed DOI PMC

Goldstein JM (2006): Sex, hormones and affective arousal circuitry dysfunction in schizophrenia. Horm Behav 50:612–622. PubMed

Goldstein JM, Seidman LJ, Horton NJ, Makris N, Kennedy DN, Caviness VS Jr, Faraone SV, Tsuang MT (2001): Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex 11:490–497. PubMed

Goldstein JM, Jerram M, Poldrack R, Ahern T, Kennedy DN, Seidman LJ, Makris N (2005): Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J Neurosci 25:9309–9316. PubMed PMC

Goldstein JM, Buka SL, Seidman LJ, Tsuang MT (2010a): Specificity of familial transmission of schizophrenia psychosis spectrum and affective psychoses in the New England family study's high‐risk design. Arch Gen Psychiatry 67:458–467. PubMed PMC

Goldstein JM, Jerram M, Abbs B, Whitfield‐Gabrieli S, Makris N (2010b): Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci 30:431–438. PubMed PMC

Goldstein J, Cherkerzian S, Seidman L, Donatelli JA, Remington AG, Tsuang MT, Hornig M, Buka SL (2014): Prenatal maternal immune disruption and sex‐dependent risk for psychoses. Psychol Med 44:3249–3261. PubMed PMC

Goldstein JM, Holsen L, Handa R, Tobet S (2014): Fetal hormonal programming of sex differences in depression: Linking women's mental health with sex differences in the brain across the lifespan. Front Neurosci 8:1–8. PubMed PMC

Goldstein JM, Lancaster K, Longenecker JM, Abbs B, Holsen LM, Cherkerzian S, Whitfield‐Gabrieli S, Makris N, Tsuang MT, Buka SL, Seidman LJ, Klibanski A (2015): Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses. Psychiatry Res 232:226–236. PubMed PMC

Herman JP, Cullinan WE (1997): Neurocircuitry of stress: Central control of the hypothalamo–pituitary–adrenocortical axis. Trends Neurosci 20:78–84. PubMed

Holmes AJ, Lee PH, Hollinshead MO, Bakst L, Roffman JL, Smoller JW, Buckner R (2012): Individual differences in amygdala‐medial prefrontal anatomy link negative affect, impaired social functioning, and polygenic depression risk. J. Neurosci 32:18087–18100. PubMed PMC

Holsen LM, Lee JH, Spaeth SB, Ogden LA, Klibanski A, Whitfield‐Gabrieli S, Sloan RP, Goldstein JM (2012): Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: A preliminary study. Neurosci Lett 514:57–61. PubMed PMC

Holsen L, Lancaster K, Klibanski A, Whitfield‐Gabrieli S, Cherkerzian S, Buka S, Goldstein JM (2013): HPA‐Axis hormone modulation of stress response circuitry activity in women with remitted major depression. Neuroscience 250:733–742. PubMed PMC

Insel TR, Cuthbert BN, Garvey MA, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P (2010): Research domain criteria (RDoC): Toward a new classification framework for research on mental disorders. Am J Psychiatry 167:748–751. PubMed

Jacobs EG, Holsen LM, Lancaster K, Makris N, Whitfield‐Gabrieli S, Remington A, Weiss B, Buka S, Klibanski A, Goldstein JM (2015): 17β‐Estradiol differentially regulates stress circuitry activity in healthy and depressed women. Neuropsychopharmacology 40:566–576. PubMed PMC

Kendler K, Gatz M, Gardner C, Pedersen N (2006): A Swedish national twin study of lifetime major depression. Am J Psychiatry 163:109–114. PubMed

Kern S, Oakes TR, Stone CK, McAuliff EM, Kirschbaum C, Davidson RJ (2008): Glucose metabolic changes in the prefrontal cortex are associated with HPA axis response to a psychosocial stressor. Psychoneuroendocrinology 33:517–529. PubMed PMC

Kessler RC (2003): Epidemiology of women and depression. J Affect Disord 74:5–13. PubMed

Kilpatrick L, Zald D, Pardo J, Cahill L (2006): Sex‐related differences in amygdala functional connectivity during resting conditions. NeuroImage 30:452–461. PubMed

Lang PJ, Bradley MM, Cuthbert MM (1997): Motivated attention: Affect, activation, and action In: Lang PJ, Simons RF, Balaban MT, editors. Attention and Orienting: Sensory and Motivational Processes. Hillsdale, NJ: Erlbaum; pp 97–135.

Lebron‐Milad K, Abbs B, Milad MR, Linnman C, Rougemount‐Bücking A, Zeidan MA, Holt DJ, Goldstein JM (2012): Sex differences in the neurobiology of fear conditioning and extinction: A preliminary fMRI study of shared sex differences with stress‐arousal circuitry. Biol Mood Anxiety Disord 2:1–10. PubMed PMC

Liberzon I, King AP, Britton JC,K, Luan Phan M, Abelson JL, Taylor SF (2007): Paralimbic and medial prefrontal cortical involvement in neuroendocrine responses to traumatic stimuli. Am J Psychiatry 164:1250–1258. PubMed

Lo CC, Cheng TC, de la Rosa IA (2015): Depression and substance use: A temporal‐ordered model. Subst Use Misuse 50:1274–1283. PubMed

Lungu O, Potvin S, Tikàsz A, Mendrek A (2015): Sex differences in effective fronto‐limbic connectivity during negative emotion processing. Psychoneuroendocrinology 62:180–188. PubMed

Mayberg HS (1997): Limbic‐cortical dysregulation: A proposed model of depression. J Neuropsychiatry Clin Neurosci 9:471–481. PubMed

McCormick CM, Smythe JW, Sharma S, Meaney MJ (1995): Sex‐specific effects of prenatal stress on hypothalamic‐pituitary‐adrenal responses to stress and brain glucocorticoid receptor density in adult rats. Brain Res Dev Brain Res 84:55–61. PubMed

McEwen BS, De Kloet ER, Rostene W (1986): Adrenal steroid receptors and actions in the nervous system. Physiol Rev 66:1121–1188. PubMed

McLaren DG, Ries ML, Xu G, Johnson SC (2012): A generalized form of context‐dependent psychophysiological interactions (gPPI): A comparison to standard approaches. NeuroImage 61:1277–1286. PubMed PMC

McNair D, Lorr M, Droppleman L (1992): Revised Manual for the Profile of Mood States, Vol. 731 San Diego, CA: Educational and Industrial Testing Services; pp 732–733.

Monroe SM, Harkness KL (2005): Life stress, the “kindling” hypothesis, and the recurrence of depression: Considerations from a life stress perspective. Psychol Rev 112:417. PubMed

Myin‐Germeys I, Peeters F, Havermans R, Nicolson NA, DeVries MW, Delespaul P, Van Os J (2003): Emotional reactivity to daily life stress in psychosis and affective disorder: An experience sampling study. Acta Psychiatry Scand 107:124–131. PubMed

Myrianthopoulos NC, French KS (1968): An application of the US Bureau of the Census socioeconomic index to a large, diversified patient population. Soc Sci Med 2:283–299. PubMed

NIMH Center for Emotion and Attention (1999): International Affective Picture System [digitized photographs] [digitized photographs]. Gainesville, Florida: Center for Research in Psychophysiology, NIMH Center for Emotion & Attention, University of Florida.

Niswander KR, Gordon M (1972): The Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke: The Women and Their Pregnancies. Washington, D.C: Government Printing Office, U.S. Department of Health, Education, and Welfare.

NITRC (2011): Artifact Detection Tools (ART) [computer program]. Cambridge, MA. Release version 07/19/11.

Northoff G, Schneider F, Rotte M, Matthiae C, Tempelmann C, Wiebking C, Bermpohl F, Heinzel A, Danos P, Heinze HJ, Bogerts B, Walter M, Panksepp J (2009): Differential parametric modulation of self‐relatedness and emotions in different brain regions. Hum Brain Mapp 30:369–382. PubMed PMC

Ossewaarde L, Hermans EJ, van Wingen GA, Kooijman SC, Johansson IM, Bäckström T, Fernández G (2010): Neural mechanisms underlying changes in stress‐sensitivity across the menstrual cycle. Psychoneuroendocrinology 35:47–55. PubMed

Pacak K, Palkovits M, Kopin IJ, Goldstein DS (1995): Stress‐induced norepinephrine release in the hypothalamic paraventricular nucleus and pituitary‐adrenocortical and sympathoadrenal activity: In vivo microdialysis studies. Front Neuroendocrinol 16:89–150. PubMed

Phelps EA (2006): Emotion and cognition: Insights from studies of the human amygdala. Annu Rev Psychol 57:27–53. PubMed

Phelps EA, LeDoux JE (2005): Contributions of the amygdala to emotion processing: From animal models to human behavior. Neuron 48:175–187. PubMed

Price JL, Drevets WC (2010): Neurocircuitry of mood disorders. Neuropsychopharmacology 35:192–216. PubMed PMC

Quaedflieg C, van de Ven V, Meyer T, Siep N, Merckelbach H, Smeets T (2015): Temporal dynamics of stress‐induced alternations of intrinsic amygdala connectivity and neuroendocrine levels. PLoS One 10:e0124141. PubMed PMC

REX Software (2009): REX Software [computer program]. Cambridge, MA.

Rhodes ME, Rubin RT (1999): Functional sex differences ('sexual diergism') of central nervous system cholinergic systems, vasopressin, and hypothalamic‐pituitary‐adrenal axis activity in mammals: A selective review. Brain Res Brain Res Rev 30:135–152. PubMed

Rowland JE, Hamilton MK, Lino BJ, Ly P, Denny K, Hwang EJ, Mitchell PB, Carr VJ, Green MJ (2013): Cognitive regulation of negative affect in schizophrenia and bipolar disorder. Psychiatry Res 208:21–28. PubMed

Schuler MS, Vasilenko SA, Lanza ST (2015): Age‐varying associations between substance use behaviors and depressive symptoms during adolescence and young adulthood. Drug Alcohol Depend 157:75–82. PubMed PMC

Seney ML, Sibille E (2014): Sex differences in mood disorders: Perspectives from humans and rodent models. Biol Sex Differ 5:1–10. PubMed PMC

Shin LM, Wright CI, Cannistraro PA, Cannistraro PA, Wedig MM, McMullin K, Martis B, Macklin ML, Lasko NB, Cavanagh SR, Krangel TS, Orr SP, Pitman RK, Whalen PJ, Rauch SL (2005): A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 62:273–281. PubMed

Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA (1983): Manual for the State‐Trait Anxiety Inventory Palo Alto, CA: Consulting Psychologists Press.

Stratton MS, Staros M, Budefeld T, Searcy BT, Nash C, Eitel C, Carbone D, Handa RJ, Majdic G, Tobet SA (2014): Embryonic GABA(B) receptor blockade alters cell migration, adult hypothalamic structure, and anxiety‐ and depression‐like behaviors sex specifically in mice. PLoS One 9:e106015. PubMed PMC

The FIL Methods Group (2013): Neuroimaging WTCf. SPM8 Manural. London, UK: Institute of Neuroimaging; 2013.

Tobet SA, Hanna IK (1997): Ontogeny of sex differences in the mammalian hypothalamus and preoptic area. Cell Mol Neurobiol 17:565–601. PubMed PMC

Urry HL, Van Reekum CM, Johnstone T, Kalin NH, Thurow ME, Schaefer HS, Jackson CA, Frye CJ, Greischar LL, Alexander AL, Davidson RJ (2006): Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. J Neurosci 26:4415–4425. PubMed PMC

Van Os J, Kapur S (2009): Schizophrenia. Lancet 374:635–645. PubMed

Veer IM, Oei NY, Spinhoven P, van Buchem MA, Elzinga BM, Rombouts SA (2012): Endogenous cortisol is associated with functional connectivity between the amygdala and medial prefrontal cortex. Psychoneuroendocrinology 37:1039–1047. PubMed

Weinstock M, Matlina E, Maor GI, Rosen H, McEwen BS (1992): Prenatal stress selectively alters the reactivity of the hypothalamic‐pituitary adrenal system in the female rat. Brain Res 595:195–200. PubMed

Zald DH, McHugo M, Ray KL, Glahn DC, Eickhoff SB, Laird AR (2014): Meta‐analytic connectivity modeling reveals differential functional connectivity of the medial and lateral orbitofrontal cortex. Cereb Cortex 24:232–248. PubMed PMC

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later

Impact of sex and depressed mood on the central regulation of cardiac autonomic function

Perinatal stress and human hippocampal volume: Findings from typically developing young adults

Neural - hormonal responses to negative affective stimuli: Impact of dysphoric mood and sex