Increasing evidence suggests that mental health and physical health are linked by neural systems that jointly regulate somatic physiology and high-level cognition. Key systems include the ventromedial prefrontal cortex and the related default-mode network. These systems help to construct models of the ‘self-in-context’, compressing information across time and sensory modalities into conceptions of the underlying causes of experience. Self-in-context models endow events with personal meaning and allow predictive control over behaviour and peripheral physiology, including autonomic, neuroendocrine and immune function. They guide learning from experience and the formation of narratives about the self and one’s world. Disorders of mental and physical health, especially those with high co-occurrence and convergent alterations in the functionality of the ventromedial prefrontal cortex and the default-mode network, could benefit from interventions focused on understanding and shaping mindsets and beliefs about the self, illness and treatment.
This is a preview of subscription content
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Engel, G. L. The need for a new medical model: a challenge for biomedicine. Science 196, 129–136 (1977).
Suls, J. & Green, P. A. Multimorbidity in health psychology and behavioral medicine. Health Psychol. 38, 769–771 (2019).
Kapur, S., Phillips, A. G. & Insel, T. R. Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol. Psychiatry 17, 1174 (2012).
Barrett, L. F. & Simmons, W. K. Interoceptive predictions in the brain. Nat. Rev. Neurosci. 16, 419–429 (2015).
Kleckner, I. R. et al. Evidence for a large-scale brain system supporting allostasis and interoception in humans. Nat. Hum. Behav. 1, 0069 (2017).
Behrens, T. E. J. et al. What is a cognitive map? Organizing knowledge for flexible behavior. Neuron 100, 490–509 (2018).
Schuck, N. W., Cai, M. B., Wilson, R. C. & Niv, Y. Human orbitofrontal cortex represents a cognitive map of state space. Neuron 91, 1402–1412 (2016).
Seth, A. K. Interoceptive inference, emotion, and the embodied self. Trends Cogn. Sci. 17, 565–573 (2013).
Friston, K. The free-energy principle: a unified brain theory? Nat. Rev. Neurosci. 11, 127–138 (2010).
Stalnaker, T. A., Cooch, N. K. & Schoenbaum, G. What the orbitofrontal cortex does not do. Nat. Neurosci. 18, 620–627 (2015).
Barrett, L. F. The theory of constructed emotion: an active inference account of interoception and categorization. Soc. Cogn. Affect. Neurosci. 12, 1833 (2017).
Gershman, S. J., Norman, K. A. & Niv, Y. Discovering latent causes in reinforcement learning. Curr. Opin. Behav. Sci. 5, 43–50 (2015).
Tolman, E. C. Cognitive maps in rats and men. Psychol. Rev. 55, 189–208 (1948).
Constantinescu, A. O., O’Reilly, J. X. & Behrens, T. E. J. Organizing conceptual knowledge in humans with a gridlike code. Science 352, 1464–1468 (2016).
Buckner, R. L. & DiNicola, L. M. The brain’s default network: updated anatomy, physiology and evolving insights. Nat. Rev. Neurosci. 20, 593–608 (2019).
Raichle, M. E. The brain’s default mode network. Annu. Rev. Neurosci. 38, 433–447 (2015).
van den Heuvel, M. P. & Sporns, O. An anatomical substrate for integration among functional networks in human cortex. J. Neurosci. 33, 14489–14500 (2013).
Dum, R. P., Levinthal, D. J. & Strick, P. L. Motor, cognitive, and affective areas of the cerebral cortex influence the adrenal medulla. Proc. Natl Acad. Sci. USA 113, 9922–9927 (2016).
Ulrich-Lai, Y. M. & Herman, J. P. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 10, 397–409 (2009).
Haber, S. N. & Knutson, B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35, 4–26 (2010).
Alexander, L. et al. Over-activation of primate subgenual cingulate cortex enhances the cardiovascular, behavioral and neural responses to threat. Nat. Commun. 11, 5386 (2020).
Öngür, D. & Price, J. L. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb. Cortex 10, 206–219 (2000).
Kraynak, T. E., Marsland, A. L., Wager, T. D. & Gianaros, P. J. Functional neuroanatomy of peripheral inflammatory physiology: a meta-analysis of human neuroimaging studies. Neurosci. Biobehav. Rev. 94, 76–92 (2018).
Ben-Shaanan, T. L. et al. Modulation of anti-tumor immunity by the brain’s reward system. Nat. Commun. 9, 2723 (2018).
Hiser, J. & Koenigs, M. The multifaceted role of the ventromedial prefrontal cortex in emotion, decision making, social cognition, and psychopathology. Biol. Psychiatry 83, 638–647 (2017).
Volkow, N. D., Koob, G. F. & McLellan, A. T. Neurobiologic advances from the brain disease model of addiction. N. Engl. J. Med. 374, 363–371 (2016).
Zhou, J. et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease. Brain 133, 1352–1367 (2010).
Geha, P. Y. et al. The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron 60, 570–581 (2008).
Kessler, R. C. et al. Development of lifetime comorbidity in the World Health Organization World Mental Health Surveys. Arch. Gen. Psychiatry 68, 90–100 (2011).
Caspi, A. et al. The p factor: one general psychopathology factor in the structure of psychiatric disorders? Clin. Psychol. Sci. 2, 119–137 (2014).
Lo, M.-T. et al. Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders. Nat. Genet. 49, 152–156 (2017).
Brainstorm, C. et al. Analysis of shared heritability in common disorders of the brain. Science 360, eaap8757 (2018).
Insel, T. R. & Cuthbert, B. N. Medicine. Brain disorders? Precisely. Science 348, 499–500 (2015).
Wang, I. M. et al. Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers. Mol. Syst. Biol. 8, 594 (2012).
Demyttenaere, K. et al. Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA 291, 2581–2590 (2004).
Tsang, A. et al. Common chronic pain conditions in developed and developing countries: gender and age differences and comorbidity with depression-anxiety disorders. J. Pain 9, 883–891 (2008).
Davidson, K. W., Alcántara, C. & Miller, G. E. Selected psychological comorbidities in coronary heart disease: challenges and grand opportunities. Am. Psychol. 73, 1019–1030 (2018).
Ginty, A. T., Kraynak, T. E., Fisher, J. P. & Gianaros, P. J. Cardiovascular and autonomic reactivity to psychological stress: neurophysiological substrates and links to cardiovascular disease. Auton. Neurosci. 207, 2–9 (2017).
Kraynak, T. E., Marsland, A. L. & Gianaros, P. J. Neural mechanisms linking emotion with cardiovascular disease. Curr. Cardiol. Rep. 20, 128 (2018).
Kim, H.-G., Cheon, E.-J., Bai, D.-S., Lee, Y. H. & Koo, B.-H. Stress and heart rate variability: a meta-analysis and review of the literature. Psychiatry Investig. 15, 235–245 (2018).
Thayer, J. F., Åhs, F., Fredrikson, M., Sollers, J. J. & Wager, T. D. 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. 36, 747–756 (2012).
Alvares, G. A., Quintana, D. S., Hickie, I. B. & Guastella, A. J. Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis. J. Psychiatry Neurosci. 41, 89–104 (2016).
Chalmers, J. A., Quintana, D. S., Abbott, M. J. A. & Kemp, A. H. Anxiety disorders are associated with reduced heart rate variability: a meta-analysis. Front. Psychiatry 5, 80 (2014).
Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008).
Valkanova, V., Ebmeier, K. P. & Allan, C. L. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J. Affect. Disord. 150, 736–744 (2013).
Pradhan, A. D., Manson, J. E., Rifai, N., Buring, J. E. & Ridker, P. M. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286, 327–334 (2001).
Danesh, J. et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med. 5, e78 (2008).
Ji, R.-R., Chamessian, A. & Zhang, Y.-Q. Pain regulation by non-neuronal cells and inflammation. Science 354, 572–577 (2016).
Kappelmann, N., Lewis, G., Dantzer, R., Jones, P. B. & Khandaker, G. M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatry 23, 335–343 (2018).
Cole, S. W. et al. Loneliness, eudaimonia, and the human conserved transcriptional response to adversity. Psychoneuroendocrinology 62, 11–17 (2015).
Cole, S. W. Human social genomics. PLoS Genet. 10, e1004601 (2014).
Pariante, C. M. Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation. Eur. Neuropsychopharmacol. 27, 554–559 (2017).
Tracey, K. J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).
Ben-Shaanan, T. L. et al. Activation of the reward system boosts innate and adaptive immunity. Nat. Med. 22, 940–944 (2016).
Kirschbaum, C., Pirke, K. M. & Hellhammer, D. H. The ‘Trier Social Stress Test’ — a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28, 76–81 (1993).
Marsland, A. L., Walsh, C., Lockwood, K. & John-Henderson, N. A. The effects of acute psychological stress on circulating and stimulated inflammatory markers: a systematic review and meta-analysis. Brain Behav. Immun. 64, 208–219 (2017).
Spicer, J. et al. Prevention of stress-provoked endothelial injury by values affirmation: A proof of principle study. Ann. Behav. Med. 50, 471–479 (2015).
Rozanski, A. Behavioral cardiology: current advances and future directions. J. Am. Coll. Cardiol. 64, 100–110 (2014).
Jiang, W. et al. Mental stress — induced myocardial ischemia and cardiac events. JAMA 275, 1651–1656 (1996).
Cacioppo, J. T. et al. Loneliness and health: potential mechanisms. Psychosom. Med. 64, 407–417 (2002).
Wampold, B. E. How important are the common factors in psychotherapy? An update. World Psychiatry 14, 270–277 (2015).
Benedetti, F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron 84, 623–637 (2014).
Enck, P., Bingel, U., Schedlowski, M. & Rief, W. The placebo response in medicine: minimize, maximize or personalize? Nat. Rev. Drug Discov. 12, 191–204 (2013).
Ashar, Y. K., Chang, L. J. & Wager, T. D. Brain mechanisms of the placebo effect: an affective appraisal account. Annu. Rev. Clin. Psychol. 13, 73–98 (2017).
Wager, T. D., Scott, D. J. & Zubieta, J. K. Placebo effects on human μ-opioid activity during pain. Proc. Natl Acad. Sci. USA 104, 11056–11061 (2007).
Kirsch, I. Placebo effect in the treatment of depression and anxiety. Front. Psychiatry 10, 407 (2019).
Zahrt, O. H. & Crum, A. J. Perceived physical activity and mortality: evidence from three nationally representative U.S. samples. Health Psychol. 36, 1017–1025 (2017).
Schoenbaum, G., Roesch, M. R., Stalnaker, T. A. & Takahashi, Y. K. A new perspective on the role of the orbitofrontal cortex in adaptive behaviour. Nat. Rev. Neurosci. 10, 885–892 (2009).
Crum, A. J., Leibowitz, K. A. & Verghese, A. Making mindset matter. BMJ 356, j674 (2017).
Lissek, S. et al. Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study. Soc. Cogn. Affect. Neurosci. 9, 1134–1142 (2014).
Koban, L., Kusko, D. & Wager, T. D. Generalization of learned pain modulation depends on explicit learning. Acta Psychol. 184, 75–84 (2018).
Wilson, R. C., Takahashi, Y. K., Schoenbaum, G. & Niv, Y. Orbitofrontal cortex as a cognitive map of task space. Neuron 81, 267–279 (2014).
Hutchinson, J. B. & Barrett, L. F. The power of predictions: an emerging paradigm for psychological research. Curr. Dir. Psychol. Sci. 28, 280–291 (2019).
Lazarus, R. S. & Folkman, S. Stress, Appraisal, and Coping (Springer Publishing Company, 1984).
Summerfield, C. & de Lange, F. P. Expectation in perceptual decision making: neural and computational mechanisms. Nat. Rev. Neurosci. 15, 745–756 (2014).
Rao, R. P. & Ballard, D. H. Predictive coding in the visual cortex: a functional interpretation of some extra-classical receptive-field effects. Nat. Neurosci. 2, 79–87 (1999).
Barrett, L. F., Quigley, K. S. & Hamilton, P. An active inference theory of allostasis and interoception in depression. Philos. Trans. R. Soc. Lond. B Biol. Sci. 371, 20160011 (2016).
Büchel, C., Geuter, S., Sprenger, C. & Eippert, F. Placebo analgesia: a predictive coding perspective. Neuron 81, 1223–1239 (2014).
Sterling, P. Allostasis: a model of predictive regulation. Physiol. Behav. 106, 5–15 (2012).
Tamir, D. I. & Thornton, M. A. Modeling the predictive social mind. Trends Cogn. Sci. 22, 201–212 (2018).
Koban, L., Ramamoorthy, A. & Konvalinka, I. Why do we fall into sync with others? Interpersonal synchronization and the brain’s optimization principle. Soc. Neurosci. 14, 1–9 (2017).
van Heukelum, S. et al. Where is cingulate cortex? A cross-species view. Trends Neurosci. 43, 285–299 (2020).
Dum, R. P., Levinthal, D. J. & Strick, P. L. The mind–body problem: Circuits that link the cerebral cortex to the adrenal medulla. Proc. Natl Acad. Sci. USA 116, 26321–26328 (2019).
Price, J. L. Definition of the orbital cortex in relation to specific connections with limbic and visceral structures and other cortical regions. Ann. N. Y. Acad. Sci. 1121, 54–71 (2007).
Saper, C. B. The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu. Rev. Neurosci. 25, 433–469 (2002).
Yeo, B. T. T. et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J. Neurophysiol. 106, 1125–1165 (2011).
Eisenbarth, H., Chang, L. J. & Wager, T. D. Multivariate brain prediction of heart rate and skin conductance responses to social threat. J. Neurosci. 36, 11987–11998 (2016).
Schaefer, A. et al. Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity MRI. Cereb. Cortex 28, 3095–3114 (2018).
Andrews-Hanna, J. R., Reidler, J. S., Sepulcre, J., Poulin, R. & Buckner, R. L. Functional-anatomic fractionation of the brain’s default network. Neuron 65, 550–562 (2010).
Christoff, K., Irving, Z. C., Fox, K. C. R., Spreng, R. N. & Andrews-Hanna, J. R. Mind-wandering as spontaneous thought: a dynamic framework. Nat. Rev. Neurosci. 17, 718–731 (2016).
Hunt, L. T. et al. Triple dissociation of attention and decision computations across prefrontal cortex. Nat. Neurosci. 21, 1471–1481 (2018).
Barbas, H. General cortical and special prefrontal connections: principles from structure to function. Annu. Rev. Neurosci. 38, 269–289 (2015).
Margulies, D. S. et al. Situating the default-mode network along a principal gradient of macroscale cortical organization. Proc. Natl Acad. Sci. USA 113, 12574–12579 (2016).
Raichle, M. E. et al. A default mode of brain function. Proc. Natl Acad. Sci. USA 98, 676–682 (2001).
Fox, K. C. R., Spreng, R. N., Ellamil, M., Andrews-Hanna, J. R. & Christoff, K. The wandering brain: meta-analysis of functional neuroimaging studies of mind-wandering and related spontaneous thought processes. Neuroimage 111, 611–621 (2015).
Mason, M. F. et al. Wandering minds: the default network and stimulus-independent thought. Science 315, 393–395 (2007).
Spreng, R. N., Mar, R. A. & Kim, A. S. N. The common neural basis of autobiographical memory, prospection, navigation, theory of mind, and the default mode: a quantitative meta-analysis. J. Cogn. Neurosci. 21, 489–510 (2009).
Cabeza, R. & St Jacques, P. Functional neuroimaging of autobiographical memory. Trends Cogn. Sci. 11, 219–227 (2007).
Binder, J. R., Desai, R. H., Graves, W. W. & Conant, L. L. Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies. Cereb. Cortex 19, 2767–2796 (2009).
Benoit, R. G., Szpunar, K. K. & Schacter, D. L. Ventromedial prefrontal cortex supports affective future simulation by integrating distributed knowledge. Proc. Natl Acad. Sci. USA 111, 16550–16555 (2014).
Schacter, D. L., Addis, D. R. & Buckner, R. L. Remembering the past to imagine the future: the prospective brain. Nat. Rev. Neurosci. 8, 657–661 (2007).
Bertossi, E., Aleo, F., Braghittoni, D. & Ciaramelli, E. Stuck in the here and now: construction of fictitious and future experiences following ventromedial prefrontal damage. Neuropsychologia 81, 107–116 (2016).
Baldassano, C., Hasson, U. & Norman, K. A. Representation of real-world event schemas during narrative perception. J. Neurosci. 38, 9689–9699 (2018).
Honey, C. J. et al. Slow cortical dynamics and the accumulation of information over long timescales. Neuron 76, 423–434 (2012).
Jain, S. & Huth, A. in Advances in Neural Information Processing Systems 31 (eds Bengio, S. et al.) 6628–6637 (Curran Associates Inc., 2018).
Milivojevic, B., Vicente-Grabovetsky, A. & Doeller, C. F. Insight reconfigures hippocampal-prefrontal memories. Curr. Biol. 25, 821–830 (2015).
Gabora, L., Rosch, E. & Aerts, D. Toward an ecological theory of concepts. Ecol. Psychol. 20, 84–116 (2008).
Doeller, C. F., Barry, C. & Burgess, N. Evidence for grid cells in a human memory network. Nature 463, 657–661 (2010).
Viganò, S. & Piazza, M. Distance and direction codes underlie navigation of a novel semantic space in the human brain. J. Neurosci. 40, 2727–2736 (2020).
Tavares, R. M. et al. A map for social navigation in the human brain. Neuron 87, 231–243 (2015).
Bradfield, L. A., Dezfouli, A., van Holstein, M., Chieng, B. & Balleine, B. W. Medial orbitofrontal cortex mediates outcome retrieval in partially observable task situations. Neuron 88, 1268–1280 (2015).
Burke, K. A., Franz, T. M., Miller, D. N. & Schoenbaum, G. The role of the orbitofrontal cortex in the pursuit of happiness and more specific rewards. Nature 454, 340–344 (2008).
Coricelli, G. et al. Regret and its avoidance: a neuroimaging study of choice behavior. Nat. Neurosci. 8, 1255–1262 (2005).
Camille, N. et al. The involvement of the orbitofrontal cortex in the experience of regret. Science 304, 1167–1170 (2004).
Northoff, G. et al. Self-referential processing in our brain — a meta-analysis of imaging studies on the self. Neuroimage 31, 440–457 (2006).
Denny, B. T., Kober, H., Wager, T. D. & Ochsner, K. N. A meta-analysis of functional neuroimaging studies of self- and other judgments reveals a spatial gradient for mentalizing in medial prefrontal cortex. J. Cogn. Neurosci. 24, 1742–1752 (2012).
Blanke, O. Multisensory brain mechanisms of bodily self-consciousness. Nat. Rev. Neurosci. 13, 556–571 (2012).
Ochsner, K. N. et al. Reflecting upon feelings: an fMRI study of neural systems supporting the attribution of emotion to self and other. J. Cogn. Neurosci. 16, 1746–1772 (2004).
Lockwood, P. L. et al. Neural mechanisms for learning self and other ownership. Nat. Commun. 9, 4747 (2018).
Farb, N. A. S. et al. Attending to the present: mindfulness meditation reveals distinct neural modes of self-reference. Soc. Cogn. Affect. Neurosci. 2, 313–322 (2007).
Chavez, R. S. & Heatherton, T. F. Multimodal frontostriatal connectivity underlies individual differences in self-esteem. Soc. Cogn. Affect. Neurosci. 10, 364–370 (2015).
Amodio, D. M. & Frith, C. D. Meeting of minds: the medial frontal cortex and social cognition. Nat. Rev. Neurosci. 7, 268–277 (2006).
Lombardo, M. V. et al. Shared neural circuits for mentalizing about the self and others. J. Cogn. Neurosci. 22, 1623–1635 (2009).
Tamir, D. I. & Mitchell, J. P. Neural correlates of anchoring-and-adjustment during mentalizing. Proc. Natl Acad. Sci. USA 107, 10827–10832 (2010).
Krienen, F. M., Tu, P.-C. & Buckner, R. L. Clan mentality: evidence that the medial prefrontal cortex responds to close others. J. Neurosci. 30, 13906–13915 (2010).
Kable, J. W. & Glimcher, P. W. The neural correlates of subjective value during intertemporal choice. Nat. Neurosci. 10, 1625–1633 (2007).
Nicolle, A. et al. An agent independent axis for executed and modeled choice in medial prefrontal cortex. Neuron 75, 1114–1121 (2012).
Parkinson, C., Kleinbaum, A. M. & Wheatley, T. Spontaneous neural encoding of social network position. Nat. Hum. Behav. 1, 0072 (2017).
Morelli, S. A., Leong, Y. C., Carlson, R. W., Kullar, M. & Zaki, J. Neural detection of socially valued community members. Proc. Natl Acad. Sci USA 115, 8149–8154 (2018).
Ashar, Y. K., Andrews-Hanna, J. R., Dimidjian, S. & Wager, T. D. Empathic care and distress: predictive brain markers and dissociable brain systems. Neuron 94, 1263–1273 e1264 (2017).
Shamay-Tsoory, S. G. & Aharon-Peretz, J. Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia 45, 3054–3067 (2007).
Anderson, S. W., Barrash, J., Bechara, A. & Tranel, D. Impairments of emotion and real-world complex behavior following childhood- or adult-onset damage to ventromedial prefrontal cortex. J. Int. Neuropsychol. Soc. 12, 224–235 (2006).
Ermer, E., Cope, L. M., Nyalakanti, P. K., Calhoun, V. D. & Kiehl, K. A. Aberrant paralimbic gray matter in criminal psychopathy. J. Abnorm. Psychol. 121, 649–658 (2012).
Levy, D. J. & Glimcher, P. W. The root of all value: a neural common currency for choice. Curr. Opin. Neurobiol. 22, 1027–1038 (2012).
Plassmann, H., O’Doherty, J., Shiv, B. & Rangel, A. Marketing actions can modulate neural representations of experienced pleasantness. Proc. Natl Acad. Sci. USA 105, 1050–1054 (2008).
Hare, T. A., Camerer, C. F. & Rangel, A. Self-control in decision-making involves modulation of the vmPFC valuation system. Science 324, 646–648 (2009).
Hutcherson, C. A., Plassmann, H., Gross, J. J. & Rangel, A. Cognitive regulation during decision making shifts behavioral control between ventromedial and dorsolateral prefrontal value systems. J. Neurosci. 32, 13543–13554 (2012).
Lindquist, K. A., Wager, T. D., Kober, H., Bliss-Moreau, E. & Barrett, L. F. The brain basis of emotion: a meta-analytic review. Behav. Brain Sci. 35, 121–143 (2012).
Etkin, A., Egner, T. & Kalisch, R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn. Sci. 15, 85–93 (2011).
Satpute, A. B. & Lindquist, K. A. The default mode network’s role in discrete emotion. Trends Cogn. Sci. 23, 851–864 (2019).
Kringelbach, M. L., O’Doherty, J., Rolls, E. T. & Andrews, C. Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cereb. Cortex 13, 1064–1071 (2003).
Hartley, C. A. & Phelps, E. A. Changing fear: the neurocircuitry of emotion regulation. Neuropsychopharmacology 35, 136–146 (2010).
Roy, M., Shohamy, D. & Wager, T. D. Ventromedial prefrontal-subcortical systems and the generation of affective meaning. Trends Cognit. Sci. 16, 147–156 (2012).
Benoit, R. G., Paulus, P. C. & Schacter, D. L. Forming attitudes via neural activity supporting affective episodic simulations. Nat. Commun. 10, 2215 (2019).
Stolier, R. M. & Freeman, J. B. Neural pattern similarity reveals the inherent intersection of social categories. Nat. Neurosci. 19, 795–797 (2016).
Losin, E. A. R. et al. Neural and sociocultural mediators of ethnic differences in pain. Nat. Hum. Behav. 4, 517–530 (2020).
Eldar, E., Rutledge, R. B., Dolan, R. J. & Niv, Y. Mood as representation of momentum. Trends Cogn. Sci. 20, 15–24 (2016).
Koban, L. et al. Social anxiety is characterized by biased learning about performance and the self. Emotion 17, 1144–1155 (2017).
Morrison, S. E. & Salzman, C. D. The convergence of information about rewarding and aversive stimuli in single neurons. J. Neurosci. 29, 11471–11483 (2009).
Milad, M. R. & Quirk, G. J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).
Amat, J. et al. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat. Neurosci. 8, 365–371 (2005).
Murray, E. A. & Rudebeck, P. H. Specializations for reward-guided decision-making in the primate ventral prefrontal cortex. Nat. Rev. Neurosci. 19, 404–417 (2018).
Kim, H. F. & Hikosaka, O. Distinct basal ganglia circuits controlling behaviors guided by flexible and stable values. Neuron 79, 1001–1010 (2013).
Damasio, A. R., Tranel, D. & Damasio, H. Individuals with sociopathic behavior caused by frontal damage fail to respond autonomically to social stimuli. Behav. Brain Res. 41, 81–94 (1990).
Beer, J. S., John, O. P., Scabini, D. & Knight, R. T. Orbitofrontal cortex and social behavior: integrating self-monitoring and emotion-cognition interactions. J. Cogn. Neurosci. 18, 871–879 (2006).
Milad, M. R. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).
Schiller, D., Levy, I., Niv, Y., LeDoux, J. E. & Phelps, E. A. From fear to safety and back: reversal of fear in the human brain. J. Neurosci. 28, 11517–11525 (2008).
Tinnermann, A., Geuter, S., Sprenger, C., Finsterbusch, J. & Büchel, C. Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia. Science 358, 105–108 (2017).
Howard, J. D. & Kahnt, T. Identity-specific reward representations in orbitofrontal cortex are modulated by selective devaluation. J. Neurosci. 37, 2627–2638 (2017).
Nook, E. C. & Zaki, J. Social norms shift behavioral and neural responses to foods. J. Cogn. Neurosci. 27, 1412–1426 (2015).
Zaki, J., Schirmer, J. & Mitchell, J. P. Social influence modulates the neural computation of value. Psychol. Sci. 22, 894–900 (2011).
Harris, L. T. & Fiske, S. T. Dehumanizing the lowest of the low: neuroimaging responses to extreme out-groups. Psychol. Sci. 17, 847–853 (2006).
Schmidt, L. et al. Neuroanatomy of the vmPFC and dlPFC predicts individual differences in cognitive regulation during dietary self-control across regulation strategies. J. Neurosci. 38, 3402–3417 (2018).
Maier, S. U., Makwana, A. B. & Hare, T. A. Acute stress impairs self-control in goal-directed choice by altering multiple functional connections within the brain’s decision circuits. Neuron 87, 621–631 (2015).
Kober, H. et al. Prefrontal-striatal pathway underlies cognitive regulation of craving. Proc. Natl Acad. Sci. USA 107, 14811–14816 (2010).
Peters, J. & Büchel, C. Episodic future thinking reduces reward delay discounting through an enhancement of prefrontal-mediotemporal interactions. Neuron 66, 138–148 (2010).
Lempert, K. M., Speer, M. E., Delgado, M. R. & Phelps, E. A. Positive autobiographical memory retrieval reduces temporal discounting. Soc. Cogn. Affect. Neurosci. 12, 1584–1593 (2017).
Woo, C. W., Roy, M., Buhle, J. T. & Wager, T. D. Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain. PLoS Biol. 13, e1002036 (2015).
Wager, T. D., Davidson, M. L., Hughes, B. L., Lindquist, M. A. & Ochsner, K. N. Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron 59, 1037–1050 (2008).
Falk, E. B. et al. Functional brain imaging predicts public health campaign success. Soc. Cogn. Affect. Neurosci. 11, 204–214 (2016).
Berkman, E. T. & Falk, E. B. Beyond brain mapping: using neural measures to predict real-world outcomes. Curr. Dir. Psychol. Sci. 22, 45–50 (2013).
McEwen, B. S. et al. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res. Brain Res. Rev. 23, 79–133 (1997).
McEwen, B. S. & Gianaros, P. J. Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann. N. Y. Acad. Sci. 1186, 190–222 (2010).
Crum, A. J., Salovey, P. & Achor, S. Rethinking stress: the role of mindsets in determining the stress response. J. Pers. Soc. Psychol. 104, 716–733 (2013).
Levy, B. R. & Myers, L. M. Preventive health behaviors influenced by self-perceptions of aging. Prev. Med. 39, 625–629 (2004).
Levy, B. R., Slade, M. D., Kunkel, S. R. & Kasl, S. V. Longevity increased by positive self-perceptions of aging. J. Pers. Soc. Psychol. 83, 261–270 (2002).
Hughes, K. et al. The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis. Lancet Public. Health 2, e356–e366 (2017).
Williams, D. R., Neighbors, H. W. & Jackson, J. S. Racial/ethnic discrimination and health: findings from community studies. Am. J. Public. Health 98, S29–37 (2008).
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. 33, 10503–10511 (2013).
Reichlin, S. Neuroendocrine-immune interactions. N. Engl. J. Med. 329, 1246–1253 (1993).
Gianaros, P. J. et al. A brain phenotype for stressor-evoked blood pressure reactivity. J. Am. Heart Assoc. 6, e006053 (2017).
Bandler, R., Keay, K. A., Floyd, N. & Price, J. Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res. Bull. 53, 95–104 (2000).
Price, J. L. & Drevets, W. C. Neurocircuitry of mood disorders. Neuropsychopharmacology 35, 192–216 (2010).
Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).
Sha, Z., Wager, T. D., Mechelli, A. & He, Y. Common dysfunction of large-scale neurocognitive networks across psychiatric disorders. Biol. Psychiatry 85, 379–388 (2019).
Goodkind, M. et al. Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry 72, 305–315 (2015).
Smallwood, R. F. et al. Structural brain anomalies and chronic pain: a quantitative meta-analysis of gray matter volume. J. Pain 14, 663–675 (2013).
Thompson, J. M. & Neugebauer, V. Cortico-limbic pain mechanisms. Neurosci. Lett. 702, 15–23 (2019).
Turnwald, B. P. et al. Learning one’s genetic risk changes physiology independent of actual genetic risk. Nat. Hum. Behav. 3, 48–56 (2019).
Crum, A. J., Akinola, M., Martin, A. & Fath, S. The role of stress mindset in shaping cognitive, emotional, and physiological responses to challenging and threatening stress. Anxiety Stress. Coping 30, 379–395 (2017).
Keller, A. et al. Does the perception that stress affects health matter? The association with health and mortality. Health Psychol. 31, 677–684 (2012).
Bhanji, J. P. & Beer, J. S. Taking a different perspective: mindset influences neural regions that represent value and choice. Soc. Cogn. Affect. Neurosci. 7, 782–793 (2012).
Hege, M. A. et al. Eating less or more — mindset induced changes in neural correlates of pre-meal planning. Appetite 125, 492–501 (2018).
Koban, L., Jepma, M., López-Solà, M. & Wager, T. D. Different brain networks mediate the effects of social and conditioned expectations on pain. Nat. Commun. 10, 4096 (2019).
Koban, L. & Wager, T. D. Beyond conformity: social influences on pain reports and physiology. Emotion 16, 24–32 (2016).
López-Solà, M., Geuter, S., Koban, L., Coan, J. A. & Wager, T. D. Brain mechanisms of social touch-induced analgesia in females. PAIN 160, 2072–2085 (2019).
López-Solà, M., Koban, L. & Wager, T. D. Transforming pain with prosocial meaning: a functional magnetic resonance imaging study. Psychosom. Med. 80, 814–825 (2018).
Kober, H., Buhle, J., Weber, J., Ochsner, K. N. & Wager, T. D. Let it be: mindful-acceptance down-regulates pain and negative emotion. Soc. Cogn. Affect. Neurosci. 14, 1147–1158 (2020).
Zeidan, F. et al. Mindfulness meditation-based pain relief employs different neural mechanisms than placebo and sham mindfulness meditation-induced analgesia. J. Neurosci. 35, 15307–15325 (2015).
Zunhammer, M. et al. Placebo effects on the neurologic pain signature: a meta-analysis of individual participant functional magnetic resonance imaging data. JAMA Neurol. 75, 1321–1330 (2018).
Jepma, M., Koban, L., van Doorn, J., Jones, M. & Wager, T. D. Behavioural and neural evidence for self-reinforcing expectancy effects on pain. Nat. Hum. Behav. 2, 838–855 (2018).
Barsaglini, A., Sartori, G., Benetti, S., Pettersson-Yeo, W. & Mechelli, A. The effects of psychotherapy on brain function: a systematic and critical review. Prog. Neurobiol. 114, 1–14 (2014).
Quidé, Y., Witteveen, A. B., El-Hage, W., Veltman, D. J. & Olff, M. Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: a systematic review. Neurosci. Biobehav. Rev. 36, 626–644 (2012).
Pollo, A., Carlino, E. & Benedetti, F. Placebo mechanisms across different conditions: from the clinical setting to physical performance. Philos. Trans. R. Soc. B 366, 1790–1798 (2011).
Antoni, M. H. Psychosocial intervention effects on adaptation, disease course and biobehavioral processes in cancer. Brain Behav. Immun. 30 (Suppl), S88–S98 (2013).
Kroenke, C. H., Kubzansky, L. D., Schernhammer, E. S., Holmes, M. D. & Kawachi, I. Social networks, social support, and survival after breast cancer diagnosis. J. Clin. Oncol. 24, 1105–1111 (2006).
Mirosevic, S. et al. “Not just another meta-analysis”: sources of heterogeneity in psychosocial treatment effect on cancer survival. Cancer Med. 8, 363–373 (2019).
Lutgendorf, S. K. & Sood, A. K. Biobehavioral factors and cancer progression: physiological pathways and mechanisms. Psychosom. Med. 73, 724–730 (2011).
Fawzy, F. I., Canada, A. L. & Fawzy, N. W. Malignant melanoma: effects of a brief, structured psychiatric intervention on survival and recurrence at 10-year follow-up. Arch. Gen. Psychiatry 60, 100–103 (2003).
Andersen, B. L. et al. Biobehavioral, immune, and health benefits following recurrence for psychological intervention participants. Clin. Cancer Res. 16, 3270–3278 (2010).
Chida, Y. & Steptoe, A. The association of anger and hostility with future coronary heart disease: a meta-analytic review of prospective evidence. J. Am. Coll. Cardiol. 53, 936–946 (2009).
Miller, T. Q., Smith, T. W., Turner, C. W., Guijarro, M. L. & Hallet, A. J. A meta-analytic review of research on hostility and physical health. Psychol. Bull. 119, 322–348 (1996).
Rozanski, A., Blumenthal, J. A. & Kaplan, J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99, 2192–2217 (1999).
Suls, J. & Bunde, J. Anger, anxiety, and depression as risk factors for cardiovascular disease: the problems and implications of overlapping affective dispositions. Psychol. Bull. 131, 260–300 (2005).
Matthews, K. A. Psychological perspectives on the development of coronary heart disease. Am. Psychol. 60, 783–796 (2005).
Stetler, C. & Miller, G. E. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom. Med. 73, 114–126 (2011).
Rotella, F. & Mannucci, E. Depression as a risk factor for diabetes: a meta-analysis of longitudinal studies. J. Clin. Psychiatry 74, 31–37 (2013).
Nicholson, A., Kuper, H. & Hemingway, H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur. Heart J. 27, 2763–2774 (2006).
van Melle, J. P. et al. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom. Med. 66, 814–822 (2004).
Everson-Rose, S. A. & Lewis, T. T. Psychosocial factors and cardiovascular diseases. Annu. Rev. Public Health 26, 469–500 (2005).
Kawachi, I. et al. Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 89, 1992–1997 (1994).
Roest, A. M., Martens, E. J., de Jonge, P. & Denollet, J. Anxiety and risk of incident coronary heart disease: a meta-analysis. J. Am. Coll. Cardiol. 56, 38–46 (2010).
Thurston, R. C., Rewak, M. & Kubzansky, L. D. An anxious heart: anxiety and the onset of cardiovascular diseases. Prog. Cardiovasc. Dis. 55, 524–537 (2013).
Cohen, S. et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc. Natl Acad. Sci. USA 109, 5995–5999 (2012).
Segerstrom, S. C. & Miller, G. E. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol. Bull. 130, 601–630 (2004).
Steptoe, A. & Kivimäki, M. Stress and cardiovascular disease: an update on current knowledge. Annu. Rev. Public. Health 34, 337–354 (2013).
Chida, Y. & Steptoe, A. Positive psychological well-being and mortality: a quantitative review of prospective observational studies. Psychosom. Med. 70, 741–756 (2008).
Ostir, G. V., Markides, K. S., Peek, M. K. & Goodwin, J. S. The association between emotional well-being and the incidence of stroke in older adults. Psychosom. Med. 63, 210–215 (2001).
Cohen, S., Alper, C. M., Doyle, W. J., Treanor, J. J. & Turner, R. B. Positive emotional style predicts resistance to illness after experimental exposure to rhinovirus or influenza a virus. Psychosom. Med. 68, 809–815 (2006).
Steptoe, A., Wardle, J. & Marmot, M. Positive affect and health-related neuroendocrine, cardiovascular, and inflammatory processes. Proc. Natl Acad. Sci. USA 102, 6508–6512 (2005).
Holt-Lunstad, J., Smith, T. B. & Layton, J. B. Social relationships and mortality risk: a meta-analytic review. PLoS Med. 7, e1000316 (2010).
Berkman, L. F., Leo-Summers, L. & Horwitz, R. I. Emotional support and survival after myocardial infarction. A prospective, population-based study of the elderly. Ann. Intern. Med. 117, 1003–1009 (1992).
Falagas, M. E. et al. The effect of psychosocial factors on breast cancer outcome: a systematic review. Breast Cancer Res. 9, R44 (2007).
Cohen, S., Doyle, W. J., Skoner, D. P., Rabin, B. S. & Gwaltney, J. M. Jr. Social ties and susceptibility to the common cold. JAMA 277, 1940–1944 (1997).
Heffner, K. L., Waring, M. E., Roberts, M. B., Eaton, C. B. & Gramling, R. Social isolation, C-reactive protein, and coronary heart disease mortality among community-dwelling adults. Soc. Sci. Med. 72, 1482–1488 (2011).
House, J. S., Robbins, C. & Metzner, H. L. The association of social relationships and activities with mortality: prospective evidence from the Tecumseh Community Health Study. Am. J. Epidemiol. 116, 123–140 (1982).
Beasley, J. M. et al. Social networks and survival after breast cancer diagnosis. J. Cancer Surviv. 4, 372–380 (2010).
Fratiglioni, L., Paillard-Borg, S. & Winblad, B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 3, 343–353 (2004).
Rutledge, T. et al. Social networks and incident stroke among women with suspected myocardial ischemia. Psychosom. Med. 70, 282–287 (2008).
Chida, Y. & Steptoe, A. Greater cardiovascular responses to laboratory mental stress are associated with poor subsequent cardiovascular risk status: a meta-analysis of prospective evidence. Hypertension 55, 1026–1032 (2010).
Sheps, D. S. et al. Mental stress-induced ischemia and all-cause mortality in patients with coronary artery disease: results from the psychophysiological investigations of myocardial ischemia study. Circulation 105, 1780–1784 (2002).
Hamer, M. & Steptoe, A. Cortisol responses to mental stress and incident hypertension in healthy men and women. J. Clin. Endocrinol. Metab. 97, E29–34 (2012).
Cacioppo, J. T. et al. Heterogeneity in neuroendocrine and immune responses to brief psychological stressors as a function of autonomic cardiac activation. Psychosom. Med. 57, 154–164 (1995).
Glasser, M. F. et al. A multi-modal parcellation of human cerebral cortex. Nature 536, 171–178 (2016).
Iversen, S., Iversen, L. & Saper, C. B. The autonomic nervous system and the hypothalamus. Princ. Neural Sci. 4, 960–981 (2000).
Critchley, H. D. & Harrison, N. A. Visceral influences on brain and behavior. Neuron 77, 624–638 (2013).
Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C. & Wager, T. D. Large-scale automated synthesis of human functional neuroimaging data. Nat. Methods 8, 665–670 (2011).
Koster-Hale, J. et al. Mentalizing regions represent distributed, continuous, and abstract dimensions of others’ beliefs. Neuroimage 161, 9–18 (2017).
Soutschek, A., Moisa, M., Ruff, C. C. & Tobler, P. N. The right temporoparietal junction enables delay of gratification by allowing decision makers to focus on future events. PLoS Biol. 18, e3000800 (2020).
Seeley, W. W. The salience network: a neural system for perceiving and responding to homeostatic demands. J. Neurosci. 39, 9878–9882 (2019).
The authors are grateful for support from the US National Institutes of Health, including grants R01MH076136 and R01DA035484 (T.D.W.), R01DA043690 and R01DA042911 (H.K.) and NHLBI P01 040962 (P.J.G.), and for a Marie-Skłodowska-Curie/PRESTIGE fellowship (PRESTIGE-2018-2-0023) from Campus France (L.K.). The authors thank M. Meyer for helpful feedback, and L. Feldman Barrett and two anonymous reviewers for constructive peer-review comments on prior drafts of the manuscript.
The authors declare no competing interests.
Peer review information
Nature Reviews Neuroscience thanks L. Feldman Barrett and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Koban, L., Gianaros, P.J., Kober, H. et al. The self in context: brain systems linking mental and physical health. Nat Rev Neurosci 22, 309–322 (2021). https://doi.org/10.1038/s41583-021-00446-8
Nature Aging (2022)
Multivariate Brain Activity while Viewing and Reappraising Affective Scenes Does Not Predict the Multiyear Progression of Preclinical Atherosclerosis in Otherwise Healthy Midlife Adults
Affective Science (2022)
Wiener klinische Wochenschrift (2022)
Structural brain differences in recovering and weight-recovered adult outpatient women with anorexia nervosa
Journal of Eating Disorders (2021)