Skip to main content
SpringerLink
Log in

Out-of-step: brain-heart desynchronization in anxiety disorders

  • Review Article
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

Imaging studies in anxiety disorders (AD) show abnormal functional connectivity primarily in the salience network (SN), somatomotor network (SMN), and default mode network (DMN). However, it is not clear how precisely these network changes occur including their relation to psychopathological symptoms. Here, we show that the functional networks affected in AD overlap with cortical regions that receive visceral inputs (the so-called central/visceral autonomic network). Focusing on cardiac afferents, we suggest that network changes in AD may be due to reduced phase synchronization between ongoing neural and cardiac activity. This neuro-cardiac desynchronization occurs due to the abnormal phase resetting of neural activity at the onset of each heartbeat, as measured by a lower intertrial coherence and heartbeat-evoked potential. Biochemically, cardiac afferents reach subcortical serotonergic raphe nuclei and noradrenergic locus coeruleus (among others) which, in turn, are known to reciprocally modulate the DMN and SMN/SN on the cortical level. Consistent with the network changes in AD, decreases in serotonergic and noradrenergic activity are known to increase connectivity in both SMN and SN while, at the same time, they decrease DMN connectivity. SMN and SN increases, in turn, lead to increased emotional arousal/anxiety and bodily awareness whereas decreased DMN connectivity leads to an unstable sense-of-self in AD. Finally, we integrate our proposal with interoceptive predictive processing models suggesting neuro-cardiac desynchronization as a mechanism for “noisy” bottom-up information leading to a persistently uncertain bodily state in top-down models. In sum, integrating theories on active interference and hyperarousal, we propose a precise neuro-cardiac and biochemically -driven mechanisms for key psychopathological symptoms of AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Altered resting state functional connectivity (RSFC) in different neural networks in anxiety disorders.
Fig. 2: Overlap in regions processing cardiac activity and regions affected in anxiety disorders.
Fig. 3: Neuro-cardiac desynchronization, functional networks, and symptoms of anxiety disorders.
Fig. 4: Abnormal neuro-cardiac synchronization in an interoceptive predictive coding framework.

Similar content being viewed by others

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. American Psychiatric Association; 2013.

  2. Chalmers JA, Quintana DS, Abbott MJ-A, Kemp AH. Anxiety disorders are associated with reduced heart rate variability: a meta-analysis. Front Psychiatry. 2014;5:80.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Xu J, Van Dam NT, Feng C, Luo Y, Ai H, Gu R, et al. Anxious brain networks: a coordinate-based activation likelihood estimation meta-analysis of resting-state functional connectivity studies in anxiety. Neurosci Biobehav Rev. 2019;96:21–30.

    Article  PubMed  Google Scholar 

  4. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164:1476–88.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fingelkurts AA, Fingelkurts AA. Brain space and time in mental disorders: paradigm shift in biological psychiatry. Int J Psychiatry Med. 2019;54:53–63.

    Article  PubMed  Google Scholar 

  6. Northoff G. Spatiotemporal psychopathology I: no rest for the brain’s resting state activity in depression? Spatiotemporal psychopathology of depressive symptoms. J Affect Disord. 2016;190:854–66.

    Article  PubMed  Google Scholar 

  7. Northoff G. Spatiotemporal psychopathology II: how does a psychopathology of the brain’s resting state look like? Spatiotemporal approach and the history of psychopathology. J Affect Disord. 2016;190:867–79.

    Article  PubMed  Google Scholar 

  8. Northoff G. The brain’s spontaneous activity and its psychopathological symptoms - ‘Spatiotemporal binding and integration’. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2017. https://doi.org/10.1016/j.pnpbp.2017.03.019.

  9. Northoff G, Magioncalda P, Martino M, Lee H-C, Tseng Y-C, Lane T. Too fast or too slow? Time and neuronal variability in bipolar disorder—a combined theoretical and empirical investigation. Schizophr Bull. 2018;44:54–64.

    Article  PubMed  Google Scholar 

  10. Northoff G, Duncan NW. How do abnormalities in the brain’s spontaneous activity translate into symptoms in schizophrenia? From an overview of resting state activity findings to a proposed spatiotemporal psychopathology. Prog Neurobiol. 2016. https://doi.org/10.1016/j.pneurobio.2016.08.003.

  11. Northoff G, Stanghellini G. How to link brain and experience? Spatiotemporal psychopathology of the lived body. Front Hum Neurosci. 2016;10:76.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Grupe DW, Nitschke JB. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat Rev Neurosci. 2013;14:488–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sharp PB, Miller GA, Heller W. Transdiagnostic dimensions of anxiety: neural mechanisms, executive functions, and new directions. Int J Psychophysiol J Int Organ Psychophysiol. 2015;98:365–77.

    Article  Google Scholar 

  14. Barrett LF, Simmons WK. Interoceptive predictions in the brain. Nat Rev Neurosci. 2015;16:419–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Paulus MP, Stein MB. Interoception in anxiety and depression. Brain Struct Funct. 2010;214:451–63.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stephan KE, Manjaly ZM, Mathys CD, Weber LAE, Paliwal S, Gard T, et al. Allostatic self-efficacy: a metacognitive theory of dyshomeostasis-induced fatigue and depression. Front Hum Neurosci. 2016;10:550.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Paulus MP, Feinstein JS, Khalsa SS. An active inference approach to interoceptive psychopathology. Annu Rev Clin Psychol. 2019;15:97–122.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Seth AK, Friston KJ. Active interoceptive inference and the emotional brain. Philos Trans R Soc Lond B Biol Sci. 2016;371:1708.20160007.

    Article  Google Scholar 

  19. Friston K. Hierarchical models in the brain. PLoS Comput Biol. 2008;4:e1000211.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Friston K, Schwartenbeck P, FitzGerald T, Moutoussis M, Behrens T, Dolan RJ The anatomy of choice: dopamine and decision-making. Philos Trans R Soc Lond B Biol Sci. 2014;369.

  21. Paulus MP, Stein MB. An insular view of anxiety. Biol Psychiatry. 2006;60:383–7.

    Article  PubMed  Google Scholar 

  22. Hakamata Y, Lissek S, Bar-Haim Y, Britton JC, Fox NA, Leibenluft E, et al. Attention bias modification treatment: a meta-analysis toward the establishment of novel treatment for anxiety. Biol Psychiatry. 2010;68:982–90.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Van den Bergh O, Witthöft M, Petersen S, Brown RJ. Symptoms and the body: taking the inferential leap. Neurosci Biobehav Rev. 2017;74:185–203.

    Article  PubMed  Google Scholar 

  24. Peters A, McEwen BS, Friston K. Uncertainty and stress: why it causes diseases and how it is mastered by the brain. Prog Neurobiol. 2017;156:164–88.

    Article  PubMed  Google Scholar 

  25. Sterling P. Homeostasis vs allostasis: implications for brain function and mental disorders. JAMA Psychiatry. 2014;71:1192–3.

    Article  PubMed  Google Scholar 

  26. LeDoux JE, Moscarello J, Sears R, Campese V. The birth, death and resurrection of avoidance: a reconceptualization of a troubled paradigm. Mol Psychiatry. 2017;22:24–36.

    Article  CAS  PubMed  Google Scholar 

  27. Fonzo GA, Ramsawh HJ, Flagan TM, Sullivan SG, Letamendi A, Simmons AN, et al. Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders. Br J Psychiatry J Ment Sci. 2015;206:206–15.

    Article  Google Scholar 

  28. Fonzo GA, Etkin A. Affective neuroimaging in generalized anxiety disorder: an integrated review. Dialogues Clin Neurosci. 2017;19:169–79.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kim Y-K, Yoon H-K. Common and distinct brain networks underlying panic and social anxiety disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80:115–22.

    Article  PubMed  Google Scholar 

  30. MacNamara A, DiGangi J, Phan KL. Aberrant spontaneous and task-dependent functional connections in the anxious brain. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1:278–87.

    PubMed  PubMed Central  Google Scholar 

  31. Peterson A, Thome J, Frewen P, Lanius RA. Resting-state neuroimaging studies: a new way of identifying differences and similarities among the anxiety disorders? Can J Psychiatry Rev Can Psychiatr. 2014;59:294–300.

    Article  Google Scholar 

  32. Sylvester CM, Corbetta M, Raichle ME, Rodebaugh TL, Schlaggar BL, Sheline YI, et al. Functional network dysfunction in anxiety and anxiety disorders. Trends Neurosci. 2012;35:527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci USA. 2003;100:253–8.

    Article  CAS  PubMed  Google Scholar 

  34. Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci J Soc Neurosci. 2007;27:2349–56.

    Article  CAS  Google Scholar 

  35. Pannekoek JN, Veer IM, van Tol M-J, van der Werff SJA, Demenescu LR, Aleman A, et al. Aberrant limbic and salience network resting-state functional connectivity in panic disorder without comorbidity. J Affect Disord. 2013;145:29–35.

    Article  PubMed  Google Scholar 

  36. Pannekoek JN, Veer IM, van Tol M-J, van der Werff SJA, Demenescu LR, Aleman A, et al. Resting-state functional connectivity abnormalities in limbic and salience networks in social anxiety disorder without comorbidity. Eur Neuropsychopharmacol. 2013;23:186–95.

    Article  CAS  PubMed  Google Scholar 

  37. Lai C-H, Wu Y-T. The changes in the low-frequency fluctuations of cingulate cortex and postcentral gyrus in the treatment of panic disorder: The MRI study. World J Biol Psychiatry J World Fed Soc Biol Psychiatry. 2016;17:58–65.

    Article  Google Scholar 

  38. Andreescu C, Sheu LK, Tudorascu D, Walker S, Aizenstein H. The ages of anxiety—differences across the lifespan in the default mode network functional connectivity in generalized anxiety disorder. Int J Geriatr Psychiatry. 2014;29:704–12.

    Article  PubMed  Google Scholar 

  39. Wang W, Hou J, Qian S, Liu K, Li B, Li M, et al. Aberrant regional neural fluctuations and functional connectivity in generalized anxiety disorder revealed by resting-state functional magnetic resonance imaging. Neurosci Lett. 2016;624:78–84.

    Article  CAS  PubMed  Google Scholar 

  40. Makovac E, Watson DR, Meeten F, Garfinkel SN, Cercignani M, Critchley HD, et al. Amygdala functional connectivity as a longitudinal biomarker of symptom changes in generalized anxiety. Soc Cogn Affect Neurosci. 2016;11:1719–28.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hahn A, Stein P, Windischberger C, Weissenbacher A, Spindelegger C, Moser E, et al. Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder. NeuroImage. 2011;56:881–9.

    Article  PubMed  Google Scholar 

  42. Liu F, Zhu C, Wang Y, Guo W, Li M, Wang W, et al. Disrupted cortical hubs in functional brain networks in social anxiety disorder. Clin Neurophysiol J Int Fed Clin Neurophysiol. 2015;126:1711–6.

    Article  Google Scholar 

  43. Dodhia S, Hosanagar A, Fitzgerald DA, Labuschagne I, Wood AG, Nathan PJ, et al. Modulation of resting-state amygdala-frontal functional connectivity by oxytocin in generalized social anxiety disorder. Neuropsychopharmacol Publ Am Coll Neuropsychopharmacol. 2014;39:2061–9.

    Article  CAS  Google Scholar 

  44. Liao W, Qiu C, Gentili C, Walter M, Pan Z, Ding J, et al. Altered effective connectivity network of the amygdala in social anxiety disorder: a resting-state FMRI study. PlOS ONE. 2010;5:e15238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Prater KE, Hosanagar A, Klumpp H, Angstadt M, Phan KL. Aberrant amygdala-frontal cortex connectivity during perception of fearful faces and at rest in generalized social anxiety disorder. Depress Anxiety. 2013;30:234–41.

    Article  PubMed  Google Scholar 

  46. Yuan H, Ding L, Zhu M, Zotev V, Phillips R, Bodurka J. Reconstructing large-scale brain resting-state networks from high-resolution EEG: spatial and temporal comparisons with fMRI. Brain Connect. 2016;6:122–35.

    Article  PubMed  Google Scholar 

  47. Liu F, Guo W, Fouche J-P, Wang Y, Wang W, Ding J, et al. Multivariate classification of social anxiety disorder using whole brain functional connectivity. Brain Struct Funct. 2015;220:101–15.

    Article  CAS  PubMed  Google Scholar 

  48. Shin Y-W, Dzemidzic M, Jo HJ, Long Z, Medlock C, Dydak U, et al. Increased resting-state functional connectivity between the anterior cingulate cortex and the precuneus in panic disorder: resting-state connectivity in panic disorder. J Affect Disord. 2013;150:1091–5.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Lai C-H, Wu Y-T. The alterations in inter-hemispheric functional coordination of patients with panic disorder: the findings in the posterior sub-network of default mode network. J Affect Disord. 2014;166:279–84.

    Article  PubMed  Google Scholar 

  50. Cui H, Zhang J, Liu Y, Li Q, Li H, Zhang L, et al. Differential alterations of resting-state functional connectivity in generalized anxiety disorder and panic disorder. Hum Brain Mapp. 2016;37:1459–73.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Critchley HD, Wiens S, Rotshtein P, Ohman A, Dolan RJ. Neural systems supporting interoceptive awareness. Nat Neurosci. 2004;7:189–95.

    Article  CAS  PubMed  Google Scholar 

  52. Wiebking C, Duncan NW, Qin P, Hayes DJ, Lyttelton O, Gravel P, et al. External awareness and GABA−a multimodal imaging study combining fMRI and [18F]flumazenil-PET. Hum Brain Mapp. 2014;35:173–84.

    Article  PubMed  Google Scholar 

  53. Wiebking C, Duncan NW, Tiret B, Hayes DJ, Marjaǹska M, Doyon J, et al. GABA in the insula - a predictor of the neural response to interoceptive awareness. NeuroImage 2014;86:10–18.

    Article  CAS  PubMed  Google Scholar 

  54. Kleint NI, Wittchen H-U, Lueken U. Probing the interoceptive network by listening to heartbeats: an fMRI study. PloS ONE. 2015;10:e0133164.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Quadt L, Critchley HD, Garfinkel SN. The neurobiology of interoception in health and disease. Ann N. Y. Acad Sci. 2018;1428:112–28.

    Article  PubMed  Google Scholar 

  56. Domschke K, Stevens S, Pfleiderer B, Gerlach AL. Interoceptive sensitivity in anxiety and anxiety disorders: an overview and integration of neurobiological findings. Clin Psychol Rev. 2010;30:1–11.

    Article  PubMed  Google Scholar 

  57. Caseras X, Murphy K, Mataix-Cols D, López-Solà M, Soriano-Mas C, Ortriz H, et al. Anatomical and functional overlap within the insula and anterior cingulate cortex during interoception and phobic symptom provocation. Hum Brain Mapp. 2013;34:1220–9.

    Article  PubMed  Google Scholar 

  58. Grossi D, Longarzo M, Quarantelli M, Salvatore E, Cavaliere C, De Luca P, et al. Altered functional connectivity of interoception in illness anxiety disorder. Cortex J Devoted Study Nerv Syst Behav. 2017;86:22–32.

    Article  Google Scholar 

  59. Tan Y, Wei D, Zhang M, Yang J, Jelinčić V, Qiu J. The role of mid-insula in the relationship between cardiac interoceptive attention and anxiety: evidence from an fMRI study. Sci Rep. 2018;8:17280.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Cui H, Zhang B, Li W, Li H, Pang J, Hu Q, et al. Insula shows abnormal task-evoked and resting-state activity in first-episode drug-naïve generalized anxiety disorder. Depress anxiety. 2020. https://doi.org/10.1002/da.23009.

  61. Hilbert K, Lueken U, Beesdo-Baum K. Neural structures, functioning and connectivity in Generalized Anxiety Disorder and interaction with neuroendocrine systems: a systematic review. J Affect Disord. 2014;158:114–26.

    Article  PubMed  Google Scholar 

  62. Mochcovitch MD, da Rocha Freire RC, Garcia RF, Nardi AE. A systematic review of fMRI studies in generalized anxiety disorder: evaluating its neural and cognitive basis. J Affect Disord. 2014;167:336–42.

    Article  PubMed  Google Scholar 

  63. Etkin A, Prater KE, Schatzberg AF, Menon V, Greicius MD. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch Gen Psychiatry. 2009;66:1361–72.

    Article  PubMed  Google Scholar 

  64. Fonzo GA, Ramsawh HJ, Flagan TM, Sullivan SG, Simmons AN, Paulus MP, et al. Cognitive-behavioral therapy for generalized anxiety disorder is associated with attenuation of limbic activation to threat-related facial emotions. J Affect Disord. 2014;169:76–85.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Palm ME, Elliott R, McKie S, Deakin JFW, Anderson IM. Attenuated responses to emotional expressions in women with generalized anxiety disorder. Psychol Med. 2011;41:1009–18.

    Article  CAS  PubMed  Google Scholar 

  66. Gorka SM, Fitzgerald DA, Labuschagne I, Hosanagar A, Wood AG, Nathan PJ, et al. Oxytocin modulation of amygdala functional connectivity to fearful faces in generalized social anxiety disorder. Neuropsychopharmacology. 2015;40:278–86.

    Article  CAS  PubMed  Google Scholar 

  67. Klumpp H, Angstadt M, Phan KL. Insula reactivity and connectivity to anterior cingulate cortex when processing threat in generalized social anxiety disorder. Biol Psychol. 2012;89:273–6.

    Article  PubMed  Google Scholar 

  68. Neufang S, Geiger MJ, Homola GA, Mahr M, Schiele MA, Gehrmann A, et al. Cognitive-behavioral therapy effects on alerting network activity and effective connectivity in panic disorder. Eur Arch Psychiatry Clin Neurosci. 2019;269:587–98.

    Article  PubMed  Google Scholar 

  69. Azzalini D, Rebollo I, Tallon-Baudry C. Visceral signals shape brain dynamics and cognition. Trends Cogn Sci. 2019;23:488–509.

    Article  PubMed  Google Scholar 

  70. Park H-D, Blanke O. Heartbeat-evoked cortical responses: underlying mechanisms, functional roles, and methodological considerations. NeuroImage. 2019;197:502–11.

    Article  PubMed  Google Scholar 

  71. Smith R, Thayer JF, Khalsa SS, Lane RD. The hierarchical basis of neurovisceral integration. Neurosci Biobehav Rev. 2017;75:274–96.

    Article  PubMed  Google Scholar 

  72. Park H-D, Bernasconi F, Salomon R, Tallon-Baudry C, Spinelli L, Seeck M, et al. Neural sources and underlying mechanisms of neural responses to heartbeats, and their role in bodily self-consciousness: an intracranial EEG study. Cereb Cortex. 2018;28:2351–64.

    Article  PubMed  Google Scholar 

  73. Chang C, Metzger CD, Glover GH, Duyn JH, Heinze H-J, Walter M. Association between heart rate variability and fluctuations in resting-state functional connectivity. NeuroImage 2013;68:93–104.

    Article  PubMed  Google Scholar 

  74. Rabellino D, D’Andrea W, Siegle G, Frewen PA, Minshew R, Densmore M, et al. Neural correlates of heart rate variability in PTSD during sub- and supraliminal processing of trauma-related cues. Hum Brain Mapp. 2017;38:4898–907.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Thome J, Densmore M, Frewen PA, McKinnon MC, Théberge J, Nicholson AA, et al. Desynchronization of autonomic response and central autonomic network connectivity in posttraumatic stress disorder. Hum Brain Mapp. 2017;38:27–40.

    Article  PubMed  Google Scholar 

  76. Benarroch EE. The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993;68:988–1001.

    Article  CAS  PubMed  Google Scholar 

  77. Jennings JR, Sheu LK, Kuan DC-H, Manuck SB, Gianaros PJ. Resting state connectivity of the medial prefrontal cortex covaries with individual differences in high-frequency heart rate variability. Psychophysiology. 2016;53:444–54.

    Article  PubMed  Google Scholar 

  78. Forkmann T, Scherer A, Meessen J, Michal M, Schächinger H, Vögele C, et al. Making sense of what you sense: disentangling interoceptive awareness, sensibility and accuracy. Int J Psychophysiol J Int Organ Psychophysiol. 2016;109:71–80.

    Article  Google Scholar 

  79. Garfinkel SN, Seth AK, Barrett AB, Suzuki K, Critchley HD. Knowing your own heart: distinguishing interoceptive accuracy from interoceptive awareness. Biol Psychol. 2015;104:65–74.

    Article  PubMed  Google Scholar 

  80. Kuehn E, Mueller K, Lohmann G, Schuetz-Bosbach S. Interoceptive awareness changes the posterior insula functional connectivity profile. Brain Struct Funct. 2016;221:1555–71.

    Article  PubMed  Google Scholar 

  81. Wiebking C, de Greck M, Duncan NW, Heinzel A, Tempelmann C, Northoff G. Are emotions associated with activity during rest or interoception? An exploratory fMRI study in healthy subjects. Neurosci Lett. 2011;491:87–92.

    Article  CAS  PubMed  Google Scholar 

  82. Garfinkel SN, Critchley HD. Threat and the body: how the heart supports fear processing. Trends Cogn Sci. 2016;20:34–46.

    Article  PubMed  Google Scholar 

  83. Tallon-Baudry C, Campana F, Park H-D, Babo-Rebelo M. The neural monitoring of visceral inputs, rather than attention, accounts for first-person perspective in conscious vision. Cortex J Devoted Study Nerv Syst Behav. 2018;102:139–49.

    Article  Google Scholar 

  84. Pollatos O, Yeldesbay A, Pikovsky A, Rosenblum M. How much time has passed? Ask your heart. Front Neurorobotics. 2014;8:15.

    Article  Google Scholar 

  85. Park H-D, Blanke O. Coupling inner and outer body for self-consciousness. Trends Cogn Sci. 2019;23:377–88.

    Article  PubMed  Google Scholar 

  86. Pollatos O, Herbert BM, Mai S, Kammer T. Changes in interoceptive processes following brain stimulation. Philos Trans R Soc Lond B Biol Sci. 2016;371:1708.20160016.

    Article  Google Scholar 

  87. Park H-D, Correia S, Ducorps A, Tallon-Baudry C. Spontaneous fluctuations in neural responses to heartbeats predict visual detection. Nat Neurosci. 2014;17:612–8.

    Article  CAS  PubMed  Google Scholar 

  88. Park H-D, Bernasconi F, Bello-Ruiz J, Pfeiffer C, Salomon R, Blanke O. Transient modulations of neural responses to heartbeats covary with bodily self-consciousness. J Neurosci J Soc Neurosci. 2016;36:8453–60.

    Article  CAS  Google Scholar 

  89. Park H-D, Tallon-Baudry C. The neural subjective frame: from bodily signals to perceptual consciousness. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130208.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Pfurtscheller G, Schwerdtfeger A, Seither-Preisler A, Brunner C, Aigner CS, Calisto J, et al. Synchronization of intrinsic 0.1-Hz blood-oxygen-level-dependent oscillations in amygdala and prefrontal cortex in subjects with increased state anxiety. Eur J Neurosci. 2018;47:417–26.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Pfurtscheller G, Schwerdtfeger A, Fink D, Brunner C, Aigner CS, Brito J, et al. MRI-related anxiety in healthy individuals, intrinsic BOLD oscillations at 0.1 Hz in precentral gyrus and insula, and heart rate variability in low frequency bands. PlOS ONE. 2018;13:e0206675.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Hahn G, Ponce-Alvarez A, Deco G, Aertsen A, Kumar A. Portraits of communication in neuronal networks. Nat Rev Neurosci. 2019;20:117–27.

    Article  CAS  PubMed  Google Scholar 

  93. Voloh B, Womelsdorf T. A role of phase-resetting in coordinating large scale neural networks during attention and goal-directed behavior. Front Syst Neurosci. 2016;10:18.

    Article  PubMed  PubMed Central  Google Scholar 

  94. He BJ. Spontaneous and task-evoked brain activity negatively interact. J Neurosci. 2013;33:4672–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Huang Z, Zhang J, Longtin A, Dumont G, Duncan NW, Pokorny J, et al. Is there a nonadditive interaction between spontaneous and evoked activity? Phase-dependence and its relation to the temporal structure of scale-free brain activity. Cereb Cortex. 2015. https://doi.org/10.1093/cercor/bhv288.

  96. Lakatos P, Schroeder CE, Leitman DI, Javitt DC. Predictive suppression of cortical excitability and its deficit in schizophrenia. J Neurosci J Soc Neurosci. 2013;33:11692–702.

    Article  CAS  Google Scholar 

  97. Lakatos P, Gross J, Thut G. A new unifying account of the roles of neuronal entrainment. Curr Biol CB. 2019;29:R890–R905.

    Article  CAS  PubMed  Google Scholar 

  98. Northoff G, Huang Z. How do the brain’s time and space mediate consciousness and its different dimensions? Temporo-spatial theory of consciousness (TTC). Neurosci Biobehav Rev. 2017;80:630–45.

    Article  PubMed  Google Scholar 

  99. Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety. 2000;12:2–19.

    Article  PubMed  Google Scholar 

  100. Conio B, Martino M, Magioncalda P, Escelsior A, Inglese M, Amore M, et al. Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders. Mol Psychiatry. 2020;25:82–93.

    Article  PubMed  Google Scholar 

  101. Hermans EJ, Marle HJFvan, Ossewaarde L, Henckens MJAG, Qin S, et al. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration. Science. 2011;334:1151–3.

    Article  CAS  PubMed  Google Scholar 

  102. Guedj C, Monfardini E, Reynaud AJ, Farnè A, Meunier M, Hadj-Bouziane F. Boosting norepinephrine transmission triggers flexible reconfiguration of brain networks at rest. Cereb Cortex. 2017;27:4691–4700.

    PubMed  Google Scholar 

  103. Zerbi V, Floriou-Servou A, Markicevic M, Vermeiren Y, Sturman O, Privitera M, et al. Rapid reconfiguration of the functional connectome after chemogenetic locus coeruleus activation. Neuron 2019;103:702–18.e5.

    Article  CAS  PubMed  Google Scholar 

  104. Babo-Rebelo M, Richter CG, Tallon-Baudry C. Neural responses to heartbeats in the default network encode the self in spontaneous thoughts. J Neurosci J Soc Neurosci. 2016;36:7829–40.

    Article  CAS  Google Scholar 

  105. Babo-Rebelo M, Wolpert N, Adam C, Hasboun D, Tallon-Baudry C. Is the cardiac monitoring function related to the self in both the default network and right anterior insula? Philos Trans R Soc Lond B Biol Sci. 2016;371:1708.20160004.

    Article  Google Scholar 

  106. Northoff G, Heinzel A, de Greck M, Bermpohl F, Dobrowolny H, Panksepp J. Self-referential processing in our brain−a meta-analysis of imaging studies on the self. NeuroImage 2006;31:440–57.

    Article  PubMed  Google Scholar 

  107. Northoff G, Heinzel A. First-person neuroscience: a new methodological approach for linking mental and neuronal states. Philos Ethics Humanit Med PEHM. 2006;1:E3.

    Article  PubMed  Google Scholar 

  108. Qin P, Northoff G. How is our self related to midline regions and the default-mode network? NeuroImage 2011;57:1221–33.

    Article  PubMed  Google Scholar 

  109. Blanke O. Multisensory brain mechanisms of bodily self-consciousness. Nat Rev Neurosci. 2012;13:556–71.

    Article  CAS  PubMed  Google Scholar 

  110. Enzi B, de Greck M, Prösch U, Tempelmann C, Northoff G. Is our self nothing but reward? Neuronal overlap and distinction between reward and personal relevance and its relation to human personality. PlOS ONE. 2009;4:e8429.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Northoff G, Wiebking C, Feinberg T, Panksepp J. The ‘resting-state hypothesis’ of major depressive disorder-a translational subcortical-cortical framework for a system disorder. Neurosci Biobehav Rev. 2011;35:1929–45.

    Article  PubMed  Google Scholar 

  112. Craig ADB. The sentient self. Brain Struct Funct. 2010;214:563–77.

    Article  PubMed  Google Scholar 

  113. Critchley HD, Garfinkel SN. Interoception and emotion. Curr Opin Psychol. 2017;17:7–14.

    Article  PubMed  Google Scholar 

  114. Northoff G. Anxiety disorders and the brain’s resting state networks: from altered spatiotemporal synchronization to psychopathological symptoms. Adv Exp Med Biol. 2020;1191:71–90.

    Article  CAS  PubMed  Google Scholar 

  115. Gorman JM, Sloan RP. Heart rate variability in depressive and anxiety disorders. Am Heart J. 2000;140:77–83.

    Article  CAS  PubMed  Google Scholar 

  116. Thayer JF, Ahs F, Fredrikson M, Sollers JJ, 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.

    Article  PubMed  Google Scholar 

  117. Koch C, Wilhelm M, Salzmann S, Rief W, Euteneuer F. A meta-analysis of heart rate variability in major depression. Psychol Med. 2019;49:1948–57.

    Article  PubMed  Google Scholar 

  118. Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord. 2000;61:201–16.

    Article  CAS  PubMed  Google Scholar 

  119. Thayer JF, Lane RD. Claude Bernard and the heart-brain connection: further elaboration of a model of neurovisceral integration. Neurosci Biobehav Rev. 2009;33:81–88.

    Article  PubMed  Google Scholar 

  120. Frick A, Åhs F, Engman J, Jonasson M, Alaie I, Björkstrand J, et al. Serotonin synthesis and reuptake in social anxiety disorder: a positron emission tomography study. JAMA Psychiatry. 2015;72:794–802.

    Article  PubMed  Google Scholar 

  121. Hjorth OR, Frick A, Gingnell M, Hoppe JM, Faria V, Hultberg S, et al. Expression and co-expression of serotonin and dopamine transporters in social anxiety disorder: a multitracer positron emission tomography study. Mol Psychiatry. 2019:1–10. https://doi.org/10.1038/s41380-019-0618-7.

  122. Garfinkel SN, Minati L, Gray MA, Seth AK, Dolan RJ, Critchley HD. Fear from the heart: sensitivity to fear stimuli depends on individual heartbeats. J Neurosci J Soc Neurosci. 2014;34:6573–82.

    Article  CAS  Google Scholar 

  123. Garfinkel SN, Tiley C, O’Keeffe S, Harrison NA, Seth AK, Critchley HD. Discrepancies between dimensions of interoception in autism: Implications for emotion and anxiety. Biol Psychol. 2016;114:117–26.

    Article  PubMed  Google Scholar 

  124. Pang J, Tang X, Li H, Hu Q, Cui H, Zhang L, et al. Altered interoceptive processing in generalized anxiety disorder-a heartbeat-evoked potential research. Front Psychiatry. 2019;10:616.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Judah MR, Shurkova EY, Hager NM, White EJ, Taylor DL, Grant DM. The relationship between social anxiety and heartbeat evoked potential amplitude. Biol Psychol. 2018;139:1–7.

    Article  PubMed  Google Scholar 

  126. Northoff G. Is the self a higher-order or fundamental function of the brain? The ‘basis model of self-specificity’ and its encoding by the brain’s spontaneous activity. Cogn Neurosci. 2016;7:203–22.

    Article  PubMed  Google Scholar 

  127. Riskind JH, Calvete E. Anxiety and the dynamic self as defined by the prospection and mental simulation of looming future threats. J Pers. 2020;88:31–44.

    Article  PubMed  Google Scholar 

  128. Khalsa SS, Feinstein JS, Li W, Feusner JD, Adolphs R, Hurlemann R. Panic anxiety in humans with bilateral amygdala lesions: pharmacological induction via cardiorespiratory interoceptive pathways. J Neurosci J Soc Neurosci. 2016;36:3559–66.

    Article  CAS  Google Scholar 

  129. Richter CG, Babo-Rebelo M, Schwartz D, Tallon-Baudry C. Phase-amplitude coupling at the organism level: the amplitude of spontaneous alpha rhythm fluctuations varies with the phase of the infra-slow gastric basal rhythm. NeuroImage. 2017;146:951–8.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Mind, Brain imaging, and Neuroethics, Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada

    Shankar Tumati & Georg Northoff

  2. Neuropsychopharmacology research group, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada

    Shankar Tumati

  3. Laureate Institute for Brain Research, Tulsa, OK, USA

    Martin P. Paulus

Authors
  1. Shankar Tumati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin P. Paulus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georg Northoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shankar Tumati.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tumati, S., Paulus, M.P. & Northoff, G. Out-of-step: brain-heart desynchronization in anxiety disorders. Mol Psychiatry 26, 1726–1737 (2021). https://doi.org/10.1038/s41380-021-01029-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01029-w

  • Springer Nature Limited

This article is cited by

Search

Navigation