Cardiac autonomic dysregulation has been implicated in the comorbidity of major psychiatric disorders and cardiovascular disease, potentially through dysregulation of physiological responses to negative stressful stimuli (here, shortened to stress response). Further, sex differences in these comorbidities are substantial. Here, we tested the hypothesis that mood- and sex-dependent alterations in brain circuitry implicated in the regulation of the stress response are associated with reduced peripheral parasympathetic activity during negative emotional arousal. Fifty subjects (28 females) including healthy controls and individuals with major depression, bipolar psychosis and schizophrenia were evaluated. Functional magnetic resonance imaging and physiology (cardiac pulse) data were acquired during a mild visual stress reactivity challenge. Associations between changes in activity and functional connectivity of the stress response circuitry and variations in cardiovagal activity [normalized high frequency power of heart rate variability (HFn)] were evaluated using GLM analyses, including interactions with depressed mood and sex across disorders. Our results revealed that in women with high depressed mood, lower cardiovagal activity in response to negative affective stimuli was associated with greater activation of hypothalamus and right amygdala and reduced connectivity between hypothalamus and right orbitofrontal cortex, amygdala, and hippocampus. No significant associations were observed in women with low levels of depressed mood or men. Our results revealed mood- and sex-dependent interactions in the central regulation of cardiac autonomic activity in response to negative affective stimuli. These findings provide a potential pathophysiological mechanism for previously observed sex differences in the comorbidity of major depression and cardiovascular disease.
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García-Gómez RG, López-Jaramillo P, Tomaz C. The role played by the autonomic nervous system in the relation between depression and cardiovascular disease. Rev de neurologia. 2007;44:225–33.
Goldstein JM, Holsen L, Handa R, Tobet S. Fetal hormonal programming of sex differences in depression: linking women’s mental health with sex differences in the brain across the lifespan. Front Neurosci. 2014;8:247.
Goldstein JM, Handa RJ, Tobet SA. Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease. Front Neuroendocrinol. 2014;35:140–58.
Goldstein JM, Lancaster K, Longenecker JM, Abbs B, Holsen LM, Cherkerzian S, et al. Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses. Psychiatry Res. 2015;232:226–36.
Goldstein JM, Jerram M, Abbs B, Whitfield-Gabrieli S, Makris N. Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci. 2010;30:431–38.
Holsen LM, Spaeth SB, Lee J-H, Ogden LA, Klibanski A, Whitfield-Gabrieli S, et al. Stress response circuitry hypoactivation related to hormonal dysfunction in women with major depression. J Affect Disord. 2011;131:379–87.
Goldstein JM, Hale T, Foster SL, Tobet SA, Handa RJ. Sex differences in major depression and comorbidity of cardiometabolic disorders: impact of prenatal stress and immune exposures. Neuropsychopharmacology. 2019;44:59–70.
Tobet SA, Handa RJ, Goldstein JM. Sex-dependent pathophysiology as predictors of comorbidity of major depressive disorder and cardiovascular disease. Pflug Arch: Eur J Physiol. 2013;465:585–94.
Holsen LM, Lancaster K, Klibanski A, Whitfield-Gabrieli S, Cherkerzian S, Buka S, et al. HPA-axis hormone modulation of stress response circuitry activity in women with remitted major depression. Neuroscience. 2013;250:733–42.
Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J neuropsychiatry Clin Neurosci. 1997;9:471–81.
Dougherty D, Rauch SL. Neuroimaging and neurobiological models of depression. Harv Rev Psychiatry. 1997;5:138–59.
Goldstein JM, Jerram M, Poldrack R, Ahern T, Kennedy DN, Seidman LJ, et al. Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J Neurosci. 2005;25:9309–16.
Tobet SA, Hanna IK. Ontogeny of sex differences in the mammalian hypothalamus and preoptic area. Cell Mol Neurobiol. 1997;17:565–601.
Tobet S, Knoll JG, Hartshorn C, Aurand E, Stratton M, Kumar P, et al. Brain sex differences and hormone influences: a moving experience? J Neuroendocrinol. 2009;21:387–92.
Goldstein JM, Seidman LJ, Horton NJ, Makris N, Kennedy DN, Caviness VS, et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex. 2001;11:490–97.
McEwen BS. Gonadal steroid influences on brain development and sexual differentiation. Int Rev Physiol. 1983;27:99–145.
Domes G, Schulze L, Bottger M, Grossmann A, Hauenstein K, Wirtz PH, et al. The neural correlates of sex differences in emotional reactivity and emotion regulation. Hum Brain Mapp. 2010;31:758–69.
Whittle S, Yucel M, Yap MB, Allen NB. Sex differences in the neural correlates of emotion: evidence from neuroimaging. Biol Psychol. 2011;87:319–33.
Goldstein JM, Cherkerzian S, Buka SL, Fitzmaurice G, Hornig M, Gillman M, et al. Sex-specific impact of maternal-fetal risk factors on depression and cardiovascular risk 40 years later. J Dev Orig Health Dis. 2011;2:353–64.
Gilman SE, Cherkerzian S, Buka SL, Hahn J, Hornig M, Goldstein JM. Prenatal immune programming of the sex-dependent risk for major depression. Transl Psychiatry. 2016;6:e822.
Barefoot JC, Helms MJ, Mark DB, Blumenthal JA, Califf RM, Haney TL, et al. Depression and long-term mortality risk in patients with coronary artery disease. Am J Cardiol. 1996;78:613–7.
Kawachi I, Sparrow D, Vokonas PS, Weiss ST. Symptoms of anxiety and risk of coronary heart disease. The Normative Aging Study. Circulation 1994;90:2225–9.
Everson SA, Kaplan GA, Goldberg DE, Salonen R, Salonen JT. Hopelessness and 4-year progression of carotid atherosclerosis; the Kuopio Ischemic Heart Disease Risk Factor Study. Arteriosclerosis, Thrombosis, Vasc Biol. 1997;17:1490–95.
Glassman AH, Shapiro PA. Depression and the course of coronary artery disease. Am J Psychiatry. 1998;155:4–11.
Jones DJ, Bromberger JT, Sutton-Tyrrell K, Matthews KA. Lifetime history of depression and carotid atherosclerosis in middle-aged women. Arch Gen Psychiatry. 2003;60:153–60.
Scherrer JF, Xian H, Bucholz KK, Eisen SA, Lyons MJ, Goldberg J, et al. A twin study of depression symptoms, hypertension, and heart disease in middle-aged men. Psychosom Med. 2003;65:548–57.
Krishnan KR, Doraiswamy PM, Clary CM. Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline. Prog Neuro-Psychopharmacol Biol Psychiatry. 2001;25:347–61.
Ferguson AV, Latchford KJ, Samson WK. The paraventricular nucleus of the hypothalamus—a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets. 2008;12:717–27.
Jankord R, Herman JP. Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann N. Y. Acad Sci. 2008;1148:64–73.
Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865–71.
Ciriello J, McMurray JC, Babic T, de Oliveira CVR. Collateral axonal projections from hypothalamic hypocretin neurons to cardiovascular sites in nucleus ambiguus and nucleus tractus solitarius. Brain Res. 2003;991:133–41.
Chitravanshi VC, Kawabe K, Sapru HN. GABA and glycine receptors in the nucleus ambiguus mediate tachycardia elicited by chemical stimulation of the hypothalamic arcuate nucleus. Am J Physiol Heart Circ Physiol. 2015;309:H174–84.
Nemeroff CB, Widerlöv E, Bissette G, Walléus H, Karlsson I, Eklund K, et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984;226:1342–44.
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol. 1999;160:1–12.
Evans DL, Nemeroff CB. The clinical use of the dexamethasone suppression test in DSM-III affective disorders: correlation with the severe depressive subtypes of melancholia and psychosis. J Psychiatr Res. 1987;21:185–94.
Oquendo MA, Echavarria G, Galfalvy HC, Grunebaum MF, Burke A, Barrera A, et al. Lower cortisol levels in depressed patients with comorbid post-traumatic stress disorder. Neuropsychopharmacology. 2003;28:591–98.
Barden N. Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J Psychiatry Neurosci. 2004;29:185–93.
Goldstein JM, Holsen L, Cherkerzian S, Misra M, Handra RJ. Neuroendocrine mechanisms of depression clinical and preclinical evidence. In: Charney DS, Nestler EJ, Sklar P, Buxbaum JD eds. Charney & Nestler’s Neurobiology of Mental Illness. Oxford University Press; 2017.
Garcia RG, Zarruk JG, Guzman JC, Barrera C, Pinzon A, Trillos E, et al. Sex differences in cardiac autonomic function of depressed young adults. Biol Psychol 2012;90:179–85.
Kemp AH, Quintana DS, Gray MA, Felmingham KL, Brown K, Gatt JM. Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis. Biol Psychiatry. 2010;67:1067–74.
Stapelberg NJ, Hamilton-Craig I, Neumann DL, Shum DHK, McConnell H. Mind and heart: heart rate variability in major depressive disorder and coronary heart disease - a review and recommendations. Aust N. Z J Psychiatry. 2012;46:946–57.
Chang HA, Chang CC, Tzeng NS, Kuo TB, Lu RB, Huang SY. Cardiac autonomic dysregulation in acute schizophrenia. Acta Neuropsychiatrica. 2013;25:155–64.
Smith R, Allen JJB, Thayer JF, Lane RD. Altered functional connectivity between medial prefrontal cortex and the inferior brainstem in major depression during appraisal of subjective emotional responses: a preliminary study. Biol Psychol. 2015;108:13–24.
Garcia RGMK, Fluegel B, Holsen L, Aizley H, Remington A, Whitfield-Gabrieli S, et al. Central modulation of parasympathetic response to negative affect is disrupted in major depression: impact of sex. Neuropsychopharmacology. 2015;40:S157–8.
Lane RD, Weidenbacher H, Smith R, Fort C, Thayer JF, Allen JJB. Subgenual anterior cingulate cortex activity covariation with cardiac vagal control is altered in depression. J Affect Disord. 2013;150:565–70.
Mareckova K, Holsen LM, Admon R, Makris N, Seidman L, Buka S, et al. Brain activity and connectivity in response to negative affective stimuli: impact of dysphoric mood and sex across diagnoses. Hum Brain Mapp. 2016;37:3733–44.
Mareckova K, Holsen L, Admon R, Whitfield-Gabrieli S, Seidman LJ, Buka SL, et al. Neural - hormonal responses to negative affective stimuli: impact of dysphoric mood and sex. J Affect Disord. 2017;222:88–97.
Holsen LM, Lee J-H, Spaeth SB, Ogden LA, Klibanski A, Whitfield-Gabrieli S, et al. Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: a preliminary study. Neurosci Lett. 2012;514:57–61.
Insel TR, Cuthbert BN, Garvey MA, Heinssen RK, Pine DS, Quinn KJ, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010;167:748–51.
McNair DM, Droppleman LF, Lorr M. Edits manual for the profile of mood states: POMS. Edits; 1992.
Spielberger C, Gorsuch R, Lushene R, Vagg P, Jacobs G. Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press; 1983.
CB S. The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu Rev Neurosci. 2002;25:433–69.
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation. 1996;93:1043–65.
Weimer LH. Autonomic testing: common techniques and clinical applications. Neurologist. 2010;16:215–22.
Campos LA, Pereira VL, Muralikrishna A, Albarwani S, Brás S, Gouveia S. Mathematical biomarkers for the autonomic regulation of cardiovascular system. Front Physiol. 2013;4:279.
Barbieri R, Matten EC, Alabi AA, Brown EN. A point-process model of human heartbeat intervals: new definitions of heart rate and heart rate variability. Am J Physiol Heart Circ Physiol. 2005;288:H424–35.
Citi L, Brown EN, Barbieri R. A real-time automated point-process method for the detection and correction of erroneous and ectopic heartbeats. IEEE Trans Biomed Eng. 2012;59:2828–37.
Barbieri R, Brown EN. Analysis of heartbeat dynamics by point process adaptive filtering. IEEE Trans Biomed Eng. 2006;53:4–12.
Bradley MM, Lang PJ. Measuring emotion: the self-assessment manikin and the semantic differential. J Behav Ther Exp Psychiatry. 1994;25:49–59.
Neuroimaging WC. SPM8 Manural. London, UK: Institute of Neuroimaging; 2013.
Whitfield-Gabrieli S. REX Software. Cambridge, MA; 2009.
McLaren DG, Ries ML, Xu G, Johnson SC. A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches. NeuroImage. 2012;61:1277–86.
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage. 2003;19:1233–39.
Beissner F, Meissner K, Bär K-J, Napadow V. The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function. J Neurosci. 2013;33:10503–11.
Thayer JF, Ahs F, Fredrikson M, Sollers JJ III, Wager TD. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health. Neurosci Biobehav Rev. 2012;36:747–56.
Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993;68:988–1001.
Critchley HD. Neural mechanisms of autonomic, affective, and cognitive integration. J Comp Neurol. 2005;493:154–66.
Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol Psychiatry 2001;6:13–34.
Li Q, Zhao Y, Chen Z, Long J, Dai J, Huang X, et al. Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder. Neuropsychopharmacology. 2020;45:703–12.
Burkhouse KL, Jacobs RH, Peters AT, Ajilore O, Watkins ER, Langenecker SA. Neural correlates of rumination in adolescents with remitted major depressive disorder and healthy controls. Cogn, Affect Behav Neurosci. 2017;17:394–405.
Jones EC, Liebel SW, Hallowell ES, Sweet LH. Insula thickness asymmetry relates to risk of major depressive disorder in middle-aged to older adults. Psychiatry Res Neuroimaging. 2019;283:113–17.
Sliz D, Hayley S. Major depressive disorder and alterations in insular cortical activity: a review of current functional magnetic imaging research. Front Hum Neurosci. 2012;6:323.
Harshaw C. Interoceptive dysfunction: toward an integrated framework for understanding somatic and affective disturbance in depression. Psychological Bull. 2015;141:311–63.
Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006;7:268–77.
Eden AS, Schreiber J, Anwander A. Emotion regulation and trait anxiety are predicted by the microstructure of fibers between amygdala and prefrontal cortex. J Neurosci. 2015;35:6020–7.
De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev. 1998;19:269–301.
Chen L, Wang Y, Niu C, Zhong S, Hu H, Chen P, et al. Common and distinct abnormal frontal-limbic system structural and functional patterns in patients with major depression and bipolar disorder. NeuroImage Clin. 2018;20:42–50.
Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol. 2016;6:603–21.
Seidman LJ, Faraone SV, Goldstein JM, Kremen WS, Horton NJ, Makris N, et al. Left hippocampal volume as a vulnerability indicator for schizophrenia: a magnetic resonance imaging morphometric study of nonpsychotic first-degree relatives. Arch Gen Psychiatry. 2002;59:839–49.
McEwen BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann N. Y Acad Sci. 1998;840:33–44.
Ajayi IE, McGovern AE, Driessen AK, Kerr NF, Mills PC, Mazzone SB. Hippocampal modulation of cardiorespiratory function. Respiratory Physiol Neurobiol. 2018;252-253:18–27.
Wei L, Chen H, Wu GR. Structural covariance of the prefrontal-amygdala pathways associated with heart rate variability. Front Hum Neurosci. 2018;12:2.
Nugent AC, Bain EE, Thayer JF, Sollers JJ, Drevets WC. Sex differences in the neural correlates of autonomic arousal: a pilot PET study. Int J Psychophysiol. 2011;80:182–91.
Goldstein JM, Cherkerzian S, Seidman LJ, Donatelli JA, Remington AG, Tsuang MT, et al. Prenatal maternal immune disruption and sex-dependent risk for psychoses. Psychological Med. 2014;44:3249–61.
Garcia R, Gabriel A, Stanford A, Aizley H, Barbieri R, Gitlin D, et al. Effects of respiratory-gated auricular vagal nerve stimulation on central autonomic regulation and mood symptomatology in major depression. Neuropsychopharmacology. 2017;43:S341–2.
We would like to thank Harlyn Aizley, Ed.M., Anne Remington, M.A., Jennifer Walch, M.Ed., Sara Cherkerzian, Sc.D., and Brandon Fluegel for their substantial contributions to the collection and management of data from the original cohort studies associated with the sample.
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Garcia, R.G., Mareckova, K., Holsen, L.M. et al. Impact of sex and depressed mood on the central regulation of cardiac autonomic function. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-0651-x