Signatures of consciousness are found in spectral and temporal properties of neuronal activity. Among these, spatiotemporal complexity after a perturbation has recently emerged as a robust metric to infer levels of consciousness. Perturbation paradigms remain, however, difficult to perform routinely. To discover alternative paradigms and metrics, we systematically explore brain stimulation and resting-state activity in a whole-brain model. We find that perturbational complexity only occurs when the brain model operates within a specific dynamical regime, in which spontaneous activity produces a large degree of functional network reorganizations referred to as being fluid. The regime of high brain fluidity is characterized by a small battery of metrics drawn from dynamical systems theory and predicts the impact of consciousness-altering drugs (Xenon, Propofol, and Ketamine). We validate the predictions in a cohort of 15 subjects at various stages of consciousness and demonstrate their agreement with previously reported perturbational complexity, but in a more accessible paradigm. Beyond the facilitation in clinical use, the metrics highlight complexity properties of brain dynamics in support of the emergence of consciousness.

Aix Marseille Université APHM Inserm INS Institut de Neurosciences des Systèmes Hôpital Sainte Marguerite Service de Pharmacologie Clinique et Pharmacosurveillance Marseille France

Aix Marseille Université Inserm Institut de Neurosciences des Systèmes UMR 1106 Marseille France

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Biomedical and Clinical Sciences University of Milan Milan Italy

IRCCS Fondazione Don Carlo Gnocchi Milan Italy

Před aktualizací

doi: 10.1101/2023.04.18.537321 PubMed

Před aktualizací

doi: 10.7554/eLife.98920.1 PubMed

Před aktualizací

doi: 10.7554/eLife.98920.2 PubMed

Zobrazit více v PubMed

Battaglia D, Boudou T, Hansen ECA, Lombardo D, Chettouf S, Daffertshofer A, McIntosh AR, Zimmermann J, Ritter P, Jirsa V. Dynamic Functional Connectivity between order and randomness and its evolution across the human adult lifespan. NeuroImage. 2020;222:117156. doi: 10.1016/j.neuroimage.2020.117156. PubMed DOI

Beggs JM, Plenz D. Neuronal avalanches in neocortical circuits. The Journal of Neuroscience. 2003;23:11167–11177. doi: 10.1523/JNEUROSCI.23-35-11167.2003. PubMed DOI PMC

Beggs JM. The criticality hypothesis: how local cortical networks might optimize information processing. Philosophical Transactions of the Royal Society A. 2008;366:329–343. doi: 10.1098/rsta.2007.2092. DOI

Breakspear M. Neuronal Dynamics and Brain Connectivity. Berlin Heidelberg: Springer; 2007. DOI

Breakspear M. Dynamic models of large-scale brain activity. Nature Neuroscience. 2017;20:340–352. doi: 10.1038/nn.4497. PubMed DOI

Brennan C, Proekt A. A quantitative model of conserved macroscopic dynamics predicts future motor commands. eLife. 2019;8:e46814. doi: 10.7554/eLife.46814. PubMed DOI PMC

Breyton M. PCI_Fluidity. swh:1:rev:2bbe4a3c44be5d03b5086e3e9ffa54a1f08f8e3bSoftware Heritage. 2025 https://archive.softwareheritage.org/swh:1:dir:f9a2920690aa85aa8ecb29e98d6d1a4bf3d18892;origin=https://github.com/ins-amu/PCI_Fluidity;visit=swh:1:snp:8b29bfda6843a92795f36195d751d12f3217e1e2;anchor=swh:1:rev:2bbe4a3c44be5d03b5086e3e9ffa54a1f08f8e3b

Casali AG, Gosseries O, Rosanova M, Boly M, Sarasso S, Casali KR, Casarotto S, Bruno MA, Laureys S, Tononi G, Massimini M. A theoretically based index of consciousness independent of sensory processing and behavior. Science Translational Medicine. 2013;5:198ra105. doi: 10.1126/scitranslmed.3006294. PubMed DOI

Casarotto S, Comanducci A, Rosanova M, Sarasso S, Fecchio M, Napolitani M, Pigorini A, G Casali A, Trimarchi PD, Boly M, Gosseries O, Bodart O, Curto F, Landi C, Mariotti M, Devalle G, Laureys S, Tononi G, Massimini M. Stratification of unresponsive patients by an independently validated index of brain complexity. Annals of Neurology. 2016;80:718–729. doi: 10.1002/ana.24779. PubMed DOI PMC

Cattani A, Galluzzi A, Fecchio M, Pigorini A, Mattia M, Massimini M. Adaptation shapes local cortical reactivity: from bifurcation diagram and simulations to human physiological and pathological responses. eNeuro. 2023;10:ENEURO.0435-22.2023. doi: 10.1523/ENEURO.0435-22.2023. PubMed DOI PMC

Chaudhuri R, Gerçek B, Pandey B, Peyrache A, Fiete I. The intrinsic attractor manifold and population dynamics of a canonical cognitive circuit across waking and sleep. Nature Neuroscience. 2019;22:1512–1520. doi: 10.1038/s41593-019-0460-x. PubMed DOI

Cocchi L, Gollo LL, Zalesky A, Breakspear M. Criticality in the brain: a synthesis of neurobiology, models and cognition. Progress in Neurobiology. 2017;158:132–152. doi: 10.1016/j.pneurobio.2017.07.002. PubMed DOI

Colombo MA, Napolitani M, Boly M, Gosseries O, Casarotto S, Rosanova M, Brichant JF, Boveroux P, Rex S, Laureys S, Massimini M, Chieregato A, Sarasso S. The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine. NeuroImage. 2019;189:631–644. doi: 10.1016/j.neuroimage.2019.01.024. PubMed DOI

Damoiseaux JS, Rombouts S, Barkhof F, Scheltens P, Stam CJ, Smith SM, Beckmann CF. Consistent resting-state networks across healthy subjects. PNAS. 2006;103:13848–13853. doi: 10.1073/pnas.0601417103. PubMed DOI PMC

Deco G, Cabral J, Saenger VM, Boly M, Tagliazucchi E, Laufs H, Van Someren E, Jobst B, Stevner A, Kringelbach ML. Perturbation of whole-brain dynamics in silico reveals mechanistic differences between brain states. NeuroImage. 2018;169:46–56. doi: 10.1016/j.neuroimage.2017.12.009. PubMed DOI

Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage. 2006;31:968–980. doi: 10.1016/j.neuroimage.2006.01.021. PubMed DOI

Edlow BL, Claassen J, Schiff ND, Greer DM. Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies. Nature Reviews. Neurology. 2021;17:135–156. doi: 10.1038/s41582-020-00428-x. PubMed DOI PMC

Fousek J, Rabuffo G, Gudibanda K, Sheheitli H, Petkoski S, Jirsa V. Symmetry breaking organizes the brain’s resting state manifold. Scientific Reports. 2024;14:31970. doi: 10.1038/s41598-024-83542-w. PubMed DOI PMC

Ghosh A, Rho Y, McIntosh AR, Kötter R, Jirsa VK. Noise during rest enables the exploration of the brain’s dynamic repertoire. PLOS Computational Biology. 2008;4:e1000196. doi: 10.1371/journal.pcbi.1000196. PubMed DOI PMC

Giacino JT, Katz DI, Schiff ND, Whyte J, Ashman EJ, Ashwal S, Barbano R, Hammond FM, Laureys S, Ling GSF, Nakase-Richardson R, Seel RT, Yablon S, Getchius TSD, Gronseth GS, Armstrong MJ. Practice guideline update recommendations summary: disorders of consciousness. Neurology. 2018;91:450–460. doi: 10.1212/WNL.0000000000005926. PubMed DOI PMC

Goldman JS, Kusch L, Yalçinkaya BH, Depannemaecker D, Nghiem TAE, Jirsa V, Destexhe A. A comprehensive neural simulation of slow-wave sleep and highly responsive wakefulness dynamics. bioRxiv. 2021 doi: 10.1101/2021.08.31.458365. DOI

Golos M, Jirsa V, Daucé E. Multistability in large scale models of brain activity. PLOS Computational Biology. 2015;11:e1004644. doi: 10.1371/journal.pcbi.1004644. PubMed DOI PMC

Haken H. Synergetics: An Introduction. Berlin, Heidelberg: Springer; 1983. DOI

Hallett M. Transcranial magnetic stimulation: a primer. Neuron. 2007;55:187–199. doi: 10.1016/j.neuron.2007.06.026. PubMed DOI

Hansen ECA, Battaglia D, Spiegler A, Deco G, Jirsa VK. Functional connectivity dynamics: modeling the switching behavior of the resting state. NeuroImage. 2015;105:525–535. doi: 10.1016/j.neuroimage.2014.11.001. PubMed DOI

Hobson JA. REM sleep and dreaming: towards a theory of protoconsciousness. Nature Reviews. Neuroscience. 2009;10:803–813. doi: 10.1038/nrn2716. PubMed DOI

Hudetz AG, Liu X, Pillay S, Boly M, Tononi G. Propofol anesthesia reduces Lempel-Ziv complexity of spontaneous brain activity in rats. Neuroscience Letters. 2016;628:132–135. doi: 10.1016/j.neulet.2016.06.017. PubMed DOI PMC

Jirsa V, Sheheitli H. Entropy, free energy, symmetry and dynamics in the brain. Journal of Physics. 2022;3:015007. doi: 10.1088/2632-072X/ac4bec. DOI

Kong X, Kong R, Orban C, Wang P, Zhang S, Anderson K, Holmes A, Murray JD, Deco G, van den Heuvel M, Yeo BTT. Sensory-motor cortices shape functional connectivity dynamics in the human brain. Nature Communications. 2021;12:6373. doi: 10.1038/s41467-021-26704-y. PubMed DOI PMC

Kringelbach ML, Cruzat J, Cabral J, Knudsen GM, Carhart-Harris R, Whybrow PC, Logothetis NK, Deco G. Dynamic coupling of whole-brain neuronal and neurotransmitter systems. PNAS. 2020;117:9566–9576. doi: 10.1073/pnas.1921475117. PubMed DOI PMC

Lavanga M, Stumme J, Yalcinkaya BH, Fousek J, Jockwitz C, Sheheitli H, Bittner N, Hashemi M, Petkoski S, Caspers S, Jirsa V. The virtual aging brain: a model-driven explanation for cognitive decline in older subjects. bioRxiv. 2022 doi: 10.1101/2022.02.17.480902. DOI

Lempel A, Ziv J. On the complexity of finite sequences. IEEE Transactions on Information Theory. 1976;22:75–81. doi: 10.1109/TIT.1976.1055501. DOI

Luppi AI, Mediano PAM, Rosas FE, Allanson J, Pickard JD, Williams GB, Craig MM, Finoia P, Peattie ARD, Coppola P, Owen AM, Naci L, Menon DK, Bor D, Stamatakis EA. Whole-brain modelling identifies distinct but convergent paths to unconsciousness in anaesthesia and disorders of consciousness. Communications Biology. 2022;5:384. doi: 10.1038/s42003-022-03330-y. PubMed DOI PMC

Montbrió E, Pazó D, Roxin A. Macroscopic description for networks of spiking neurons. Physical Review X. 2015;5:021028. doi: 10.1103/PhysRevX.5.021028. DOI

Müller EJ, Munn B, Hearne LJ, Smith JB, Fulcher B, Arnatkevičiūtė A, Lurie DJ, Cocchi L, Shine JM. Core and matrix thalamic sub-populations relate to spatio-temporal cortical connectivity gradients. NeuroImage. 2020;222:117224. doi: 10.1016/j.neuroimage.2020.117224. PubMed DOI

Murphy M, Bruno MA, Riedner BA, Boveroux P, Noirhomme Q, Landsness EC, Brichant JF, Phillips C, Massimini M, Laureys S, Tononi G, Boly M. Propofol anesthesia and sleep: a high-density EEG study. Sleep. 2011;34:283–291. doi: 10.1093/sleep/34.3.283. PubMed DOI PMC

O’Byrne J, Jerbi K. How critical is brain criticality? Trends in Neurosciences. 2022;45:820–837. doi: 10.1016/j.tins.2022.08.007. PubMed DOI

Palva JM, Zhigalov A, Hirvonen J, Korhonen O, Linkenkaer-Hansen K, Palva S. Neuronal long-range temporal correlations and avalanche dynamics are correlated with behavioral scaling laws. PNAS. 2013;110:3585–3590. doi: 10.1073/pnas.1216855110. PubMed DOI PMC

Peng X, Liu Q, Hubbard CS, Wang D, Zhu W, Fox MD, Liu H. Robust dynamic brain coactivation states estimated in individuals. Science Advances. 2023;9:eabq8566. doi: 10.1126/sciadv.abq8566. PubMed DOI PMC

Perdikis D, Sleimen-Malkoun R, Müller V, Jirsa V. Developmental and aging changes in brain network switching dynamics revealed by EEG phase synchronization. bioRxiv. 2025 doi: 10.1101/2025.07.02.662760. DOI

Petkoski S, Spiegler A, Proix T, Aram P, Temprado JJ, Jirsa VK. Heterogeneity of time delays determines synchronization of coupled oscillators. Physical Review. E. 2016;94:012209. doi: 10.1103/PhysRevE.94.012209. PubMed DOI

Petkoski S, Palva JM, Jirsa VK. Phase-lags in large scale brain synchronization: methodological considerations and in-silico analysis. PLOS Computational Biology. 2018;14:e1006160. doi: 10.1371/journal.pcbi.1006160. PubMed DOI PMC

Petkoski S, Jirsa VK. Transmission time delays organize the brain network synchronization. Philosophical Transactions of the Royal Society A. 2019;377:20180132. doi: 10.1098/rsta.2018.0132. DOI

Petkoski S, Jirsa VK. Normalizing the brain connectome for communication through synchronization. Network Neuroscience. 2022;6:722–744. doi: 10.1162/netn_a_00231. PubMed DOI PMC

Pillai AS, Jirsa VK. Symmetry breaking in space-time hierarchies shapes brain dynamics and behavior. Neuron. 2017;94:1010–1026. doi: 10.1016/j.neuron.2017.05.013. PubMed DOI

Pope M, Fukushima M, Betzel RF, Sporns O. Modular origins of high-amplitude cofluctuations in fine-scale functional connectivity dynamics. PNAS. 2021;118:e2109380118. doi: 10.1073/pnas.2109380118. PubMed DOI PMC

Preti MG, Bolton TA, Van De Ville D. The dynamic functional connectome: State-of-the-art and perspectives. NeuroImage. 2017;160:41–54. doi: 10.1016/j.neuroimage.2016.12.061. PubMed DOI

Rabuffo G, Fousek J, Bernard C, Jirsa V. Neuronal cascades shape whole-brain functional dynamics at rest. eNeuro. 2021;8:ENEURO.0283-21.2021. doi: 10.1523/ENEURO.0283-21.2021. PubMed DOI PMC

Ramsay MAE, Savege TM, Simpson BRJ, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ. 1974;2:656–659. doi: 10.1136/bmj.2.5920.656. PubMed DOI PMC

Rué-Queralt J, Stevner A, Tagliazucchi E, Laufs H, Kringelbach ML, Deco G, Atasoy S. Decoding brain states on the intrinsic manifold of human brain dynamics across wakefulness and sleep. Communications Biology. 2021;4:854. doi: 10.1038/s42003-021-02369-7. PubMed DOI PMC

Sacha M, Tesler F, Cofre R, Destexhe A. A computational approach to evaluate how molecular mechanisms impact large-scale brain activity. Nature Computational Science. 2025;5:405–417. doi: 10.1038/s43588-025-00796-8. PubMed DOI PMC

Sanders RD, Tononi G, Laureys S, Sleigh JW. Unresponsiveness ≠ unconsciousness. Anesthesiology. 2012;116:946–959. doi: 10.1097/ALN.0b013e318249d0a7. PubMed DOI PMC

Sanz Leon P, Knock SA, Woodman MM, Domide L, Mersmann J, McIntosh AR, Jirsa V. The virtual brain: a simulator of primate brain network dynamics. Frontiers in Neuroinformatics. 2013;7:10. doi: 10.3389/fninf.2013.00010. PubMed DOI PMC

Sanz-Leon P, Knock SA, Spiegler A, Jirsa VK. Mathematical framework for large-scale brain network modeling in The Virtual Brain. NeuroImage. 2015;111:385–430. doi: 10.1016/j.neuroimage.2015.01.002. PubMed DOI

Sarasso S, Boly M, Napolitani M, Gosseries O, Charland-Verville V, Casarotto S, Rosanova M, Casali AG, Brichant JF, Boveroux P, Rex S, Tononi G, Laureys S, Massimini M. Consciousness and complexity during unresponsiveness induced by Propofol, Xenon, and Ketamine. Current Biology. 2015;25:3099–3105. doi: 10.1016/j.cub.2015.10.014. PubMed DOI

Sarasso S, Casali AG, Casarotto S, Rosanova M, Sinigaglia C, Massimini M. Consciousness and complexity: a consilience of evidence. Neuroscience of Consciousness. 2021;2021:niab023. doi: 10.1093/nc/niab023. PubMed DOI PMC

Sorrentino P, Rucco R, Baselice F, De Micco R, Tessitore A, Hillebrand A, Mandolesi L, Breakspear M, Gollo LL, Sorrentino G. Flexible brain dynamics underpins complex behaviours as observed in Parkinson’s disease. Scientific Reports. 2021a;11:4051. doi: 10.1038/s41598-021-83425-4. PubMed DOI PMC

Sorrentino P, Seguin C, Rucco R, Liparoti M, Troisi Lopez E, Bonavita S, Quarantelli M, Sorrentino G, Jirsa V, Zalesky A. The structural connectome constrains fast brain dynamics. eLife. 2021b;10:e67400. doi: 10.7554/eLife.67400. PubMed DOI PMC

Sporns O. The human connectome: a complex network. Annals of the New York Academy of Sciences. 2011;1224:109–125. doi: 10.1111/j.1749-6632.2010.05888.x. PubMed DOI

Stramaglia S, Pellicoro M, Angelini L, Amico E, Aerts H, Cortés JM, Laureys S, Marinazzo D. Ising model with conserved magnetization on the human connectome: Implications on the relation structure-function in wakefulness and anesthesia. Chaos. 2017;27:047407. doi: 10.1063/1.4978999. PubMed DOI

Tagliazucchi E, Balenzuela P, Fraiman D, Chialvo DR. Criticality in large-scale brain FMRI dynamics unveiled by a novel point process analysis. Frontiers in Physiology. 2012;3:15. doi: 10.3389/fphys.2012.00015. PubMed DOI PMC

Tagliazucchi E, Chialvo DR, Siniatchkin M, Amico E, Brichant J-F, Bonhomme V, Noirhomme Q, Laufs H, Laureys S. Large-scale signatures of unconsciousness are consistent with a departure from critical dynamics. Journal of the Royal Society, Interface. 2016;13:20151027. doi: 10.1098/rsif.2015.1027. PubMed DOI PMC

Tagliazucchi E. The signatures of conscious access and its phenomenology are consistent with large-scale brain communication at criticality. Consciousness and Cognition. 2017;55:136–147. doi: 10.1016/j.concog.2017.08.008. PubMed DOI

Taylor NL, D’Souza A, Munn BR, Lv J, Zaborszky L, Müller EJ, Wainstein G, Calamante F, Shine JM. Structural connections between the noradrenergic and cholinergic system shape the dynamics of functional brain networks. NeuroImage. 2022;260:119455. doi: 10.1016/j.neuroimage.2022.119455. PubMed DOI PMC

Toker D, Pappas I, Lendner JD, Frohlich J, Mateos DM, Muthukumaraswamy S, Carhart-Harris R, Paff M, Vespa PM, Monti MM, Sommer FT, Knight RT, D’Esposito M. Consciousness is supported by near-critical slow cortical electrodynamics. PNAS. 2022;119:e2024455119. doi: 10.1073/pnas.2024455119. PubMed DOI PMC

Tononi G, Edelman GM. Consciousness and complexity. Science. 1998;282:1846–1851. doi: 10.1126/science.282.5395.1846. PubMed DOI

Tononi G, McIntosh AR, Russell DP, Edelman GM. Functional clustering: identifying strongly interactive brain regions in neuroimaging data. NeuroImage. 1998;7:133–149. doi: 10.1006/nimg.1997.0313. PubMed DOI

van den Heuvel MP, Hulshoff Pol HE. Exploring the brain network: a review on resting-state fMRI functional connectivity. European Neuropsychopharmacology. 2010;20:519–534. doi: 10.1016/j.euroneuro.2010.03.008. PubMed DOI

Van Essen DC, Smith SM, Barch DM, Behrens TEJ, Yacoub E, Ugurbil K, WU-Minn HCP Consortium The WU-Minn human connectome project: an overview. NeuroImage. 2013;80:62–79. doi: 10.1016/j.neuroimage.2013.05.041. PubMed DOI PMC

Wang P, Kong R, Kong X, Liégeois R, Orban C, Deco G, van den Heuvel MP, Thomas Yeo BT. Inversion of a large-scale circuit model reveals a cortical hierarchy in the dynamic resting human brain. Science Advances. 2019;5:eaat7854. doi: 10.1126/sciadv.aat7854. PubMed DOI PMC

Xu L, Feng J, Yu L. Avalanche criticality in individuals, fluid intelligence, and working memory. Human Brain Mapping. 2022;43:2534–2553. doi: 10.1002/hbm.25802. PubMed DOI PMC

Zamani Esfahlani F, Jo Y, Faskowitz J, Byrge L, Kennedy DP, Sporns O, Betzel RF. High-amplitude cofluctuations in cortical activity drive functional connectivity. PNAS. 2020;117:28393–28401. doi: 10.1073/pnas.2005531117. PubMed DOI PMC