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Regional entropy of functional imaging signals varies differently in sensory and cognitive systems during propofol-modulated loss and return of behavioral responsiveness

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Abstract

The level and richness of consciousness depend on information integration in the brain. Altered interregional functional interactions may indicate disrupted information integration during anesthetic-induced unconsciousness. How anesthetics modulate the amount of information in various brain regions has received less attention. Here, we propose a novel approach to quantify regional information content in the brain by the entropy of the principal components of regional blood oxygen-dependent imaging signals during graded propofol sedation. Fifteen healthy individuals underwent resting-state scans in wakeful baseline, light sedation (conscious), deep sedation (unconscious), and recovery (conscious). Light sedation characterized by lethargic behavioral responses was associated with global reduction of entropy in the brain. Deep sedation with completely suppressed overt responsiveness was associated with further reductions of entropy in sensory (primary and higher sensory plus orbital prefrontal cortices) but not high-order cognitive (dorsal and medial prefrontal, cingulate, parietotemporal cortices and hippocampal areas) systems. Upon recovery of responsiveness, entropy was restored in the sensory but not in high-order cognitive systems. These findings provide novel evidence for a reduction of information content of the brain as a potential systems-level mechanism of reduced consciousness during propofol anesthesia. The differential changes of entropy in the sensory and high-order cognitive systems associated with losing and regaining overt responsiveness are consistent with the notion of “disconnected consciousness”, in which a complete sensory-motor disconnection from the environment occurs with preserved internal mentation.

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Fig. 1: The regional number of PCs and entropy in the four states of consciousness
Fig. 2: Pairwise comparisons of group mean entropy among the states of consciousness
Fig. 3: State-dependent changes of the number of PCs and entropy in the sensory and high-order cognitive systems

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References

  • Agnati, L. F., Santarossa, L., Genedani, S., Canela, E. I., Leo, G., Franco, R., Woofs, A., Lluis, C., et al. (2004). On the nested hierarchical organization of CNS: Basic characteristics of neuronal molecular organization. In P. Erdi (Ed.), Cortical Dynamics LNCS 3146 (pp. 24–54). Berlin: Springer.

    Google Scholar 

  • Alkire, M. T. (2008). Loss of effective connectivity during general anesthesia. International Anesthesiology Clinics, 46(3), 55–73.

    Article  CAS  Google Scholar 

  • Alkire, M. T., Hudetz, A. G., & Tononi, G. (2008). Consciousness and anesthesia. Science, 322(5903), 876–880.

    Article  CAS  Google Scholar 

  • Allen, E. A., Damaraju, E., Plis, S. M., Erhardt, E. B., Eichele, T., & Calhoun, V. D. (2014). Tracking whole-brain connectivity dynamics in the resting state. Cerebral Cortex, 24(3), 663–676.

    Article  Google Scholar 

  • Barttfeld, P., Uhrig, L., Sitt, J. D., Sigman, M., Jarraya, B., & Dehaene, S. (2015). Signature of consciousness in the dynamics of resting-state brain activity. Proceedings of the National Academy of Sciences of the United States of America, 112(3), 887–892.

    Article  CAS  Google Scholar 

  • Ben-Naim, A. (2012). Entropy and the second law: interpretation and misss-interpretationsss. New Jersey; London: World Scientific.

    Book  Google Scholar 

  • Biswal, B. B. (2012). Resting state fMRI: A personal history. NeuroImage, 62(2), 938–944.

    Article  Google Scholar 

  • Bokde, A. L., Lopez-Bayo, P., Meindl, T., Pechler, S., Born, C., Faltraco, F., Teipel, S. J., Moller, H. J., et al. (2006). Functional connectivity of the fusiform gyrus during a face-matching task in subjects with mild cognitive impairment. Brain, 129(Pt 5), 1113–1124.

    Article  CAS  Google Scholar 

  • Boly, M., Sanders, R. D., Mashour, G. A., & Laureys, S. (2013). Consciousness and responsiveness: Lessons from anaesthesia and the vegetative state. Current Opinion in Anaesthesiology, 26(4), 444–449.

    Article  CAS  Google Scholar 

  • Bonhomme, V., Boveroux, P., Hans, P., Brichant, J. F., Vanhaudenhuyse, A., Boly, M., & Laureys, S. (2011). Influence of anesthesia on cerebral blood flow, cerebral metabolic rate, and brain functional connectivity. Current Opinion in Anaesthesiology, 24(5), 474–479.

    Article  Google Scholar 

  • Bonhomme, V., Boveroux, P., Brichant, J. F., Laureys, S., & Boly, M. (2012). Neural correlates of consciousness during general anesthesia using functional magnetic resonance imaging (fMRI). Archives Italiennes de Biologie, 150(2–3), 155–163.

    CAS  PubMed  Google Scholar 

  • Britz, J., Van De Ville, D., & Michel, C. M. (2010). BOLD correlates of EEG topography reveal rapid resting-state network dynamics. NeuroImage, 52(4), 1162–1170.

    Article  Google Scholar 

  • Bruhn, J., Ropcke, H., & Hoeft, A. (2000). Approximate entropy as an electroencephalographic measure of anesthetic drug effect during desflurane anesthesia. Anesthesiology, 92(3), 715–726.

    Article  CAS  Google Scholar 

  • Carhart-Harris, R. L., Leech, R., Hellyer, P. J., Shanahan, M., Feilding, A., Tagliazucchi, E., Chialvo, D. R., & Nutt, D. (2014). The entropic brain: A theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in Human Neuroscience, 8, 20.

    Article  Google Scholar 

  • Casali, A. G., Gosseries, O., Rosanova, M., Boly, M., Sarasso, S., Casali, K. R., Casarotto, S., Bruno, M. A., et al. (2013). A theoretically based index of consciousness independent of sensory processing and behavior. Sci Transl Med, 5(198), 198ra105.

    Article  Google Scholar 

  • Casarotto, S., Comanducci, A., Rosanova, M., Sarasso, S., Fecchio, M., Napolitani, M., Pigorini, A., A, G. C., et al. (2016). Stratification of unresponsive patients by an independently validated index of brain complexity. Annals of Neurology, 80(5), 718–729.

    Article  Google Scholar 

  • Chang, C., & Glover, G. H. (2010). Time-frequency dynamics of resting-state brain connectivity measured with fMRI. NeuroImage, 50(1), 81–98.

    Article  Google Scholar 

  • Chernik, D. A., Gillings, D., Laine, H., Hendler, J., Silver, J. M., Davidson, A. B., Schwam, E. M., & Siegel, J. L. (1990). Validity and reliability of the Observer's assessment of alertness/sedation scale: study with intravenous midazolam. Journal of Clinical Psychopharmacology, 10(4), 244–251.

    Article  CAS  Google Scholar 

  • Davis, M. H., Coleman, M. R., Absalom, A. R., Rodd, J. M., Johnsrude, I. S., Matta, B. F., Owen, A. M., & Menon, D. K. (2007). Dissociating speech perception and comprehension at reduced levels of awareness. Proceedings of the National Academy of Sciences of the United States of America, 104(41), 16032–16037.

    Article  CAS  Google Scholar 

  • Di, X., & Biswal, B. B. (2015). Dynamic brain functional connectivity modulated by resting-state networks. Brain Structure & Function, 220(1), 37–46.

    Article  Google Scholar 

  • Eer, A. S., Padmanabhan, U., & Leslie, K. (2009). Propofol dose and incidence of dreaming during sedation. European Journal of Anaesthesiology, 26(10), 833–836.

    Article  CAS  Google Scholar 

  • Farras-Permanyer, L., Guardia-Olmos, J., & Pero-Cebollero, M. (2015). Mild cognitive impairment and fMRI studies of brain functional connectivity: The state of the art. Frontiers in Psychology, 6, 1095.

    Article  Google Scholar 

  • Ferenets, R., Lipping, T., Anier, A., Jantti, V., Melto, S., & Hovilehto, S. (2006). Comparison of entropy and complexity measures for the assessment of depth of sedation. IEEE Transactions on Biomedical Engineering, 53(6), 1067–1077.

    Article  Google Scholar 

  • Ferrarelli, F., Massimini, M., Sarasso, S., Casali, A., Riedner, B. A., Angelini, G., Tononi, G., & Pearce, R. A. (2010). Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proceedings of the National Academy of Sciences of the United States of America, 107(6), 2681–2686.

    Article  CAS  Google Scholar 

  • Gokhale, D. V., Ahmed, N. A., Res, B. C., & Piscataway, N. J. (1989). Entropy expressions and their estimators for multivariate distributions. IEEE Transactions on Information Theory, 5(3), 688–692.

    Google Scholar 

  • Haimovici, A., Tagliazucchi, E., Balenzuela, P., & Chialvo, D. R. (2013). Brain organization into resting state networks emerges at criticality on a model of the human connectome. Physical Review Letters, 110(17), 178101.

    Article  Google Scholar 

  • Haldeman, C., & Beggs, J. M. (2005). Critical branching captures activity in living neural networks and maximizes the number of metastable states. Physical Review Letters, 94(5), 058101.

    Article  Google Scholar 

  • Huang, Z., Zhang, J., Wu, J., Qin, P., Wu, X., Wang, Z., Dai, R., Li, Y., et al. (2016). Decoupled temporal variability and signal synchronization of spontaneous brain activity in loss of consciousness: An fMRI study in anesthesia. Neuroimage, 124(Pt A), 693–703.

    Article  Google Scholar 

  • Hudetz, A. G. (2012). General anesthesia and human brain connectivity. Brain Connectivity, 2(6), 291–302.

    Article  Google Scholar 

  • Hudetz, A. G., & Mashour, G. A. (2016). Disconnecting consciousness: Is there a common anesthetic end point? Anesthesia and Analgesia, 123(5), 1228–1240.

    Article  Google Scholar 

  • Hudetz, A. G., Humphries, C. J., & Binder, J. R. (2014). Spin-glass model predicts metastable brain states that diminish in anesthesia. Frontiers in Systems Neuroscience, 8, 234.

    Article  Google Scholar 

  • Hudetz, A. G., Liu, X., & Pillay, S. (2015). Dynamic repertoire of intrinsic brain states is reduced in propofol-induced unconsciousness. Brain Connectivity, 5(1), 10–22.

    Article  Google Scholar 

  • Hudetz, A. G., Liu, X., Pillay, S., Boly, M., & Tononi, G. (2016). Propofol anesthesia reduces Lempel-Ziv complexity of spontaneous brain activity in rats. Neuroscience Letters, 628, 132–135.

    Article  CAS  Google Scholar 

  • Hutchison, R. M., Womelsdorf, T., Allen, E. A., Bandettini, P. A., Calhoun, V. D., Corbetta, M., Della Penna, S., Duyn, J. H., Glover, G. H., Gonzalez-Castillo, J., Handwerker, D. A., Keilholz, S., Kiviniemi, V., Leopold, D. A., de Pasquale, F., Sporns, O., Walter, M., & Chang, C. (2013). Dynamic functional connectivity: Promise, issues, and interpretations. NeuroImage, 80, 360–378.

    Article  Google Scholar 

  • Leslie, K., Sleigh, J., Paech, M. J., Voss, L., Lim, C. W., & Sleigh, C. (2009). Dreaming and electroencephalographic changes during anesthesia maintained with propofol or desflurane. Anesthesiology, 111(3), 547–555.

    Article  CAS  Google Scholar 

  • Liu, X., Lauer, K. K., Ward, B. D., Rao, S. M., Li, S. J., & Hudetz, A. G. (2012). Propofol disrupts functional interactions between sensory and high-order processing of auditory verbal memory. Human Brain Mapping, 33(10), 2487–2498.

    Article  Google Scholar 

  • Liu, X., Lauer, K. K., Ward, B. D., Li, S. J., & Hudetz, A. G. (2013). Differential effects of deep sedation with propofol on the specific and nonspecific thalamocortical systems: A functional magnetic resonance imaging study. Anesthesiology, 118(1), 59–69.

    Article  CAS  Google Scholar 

  • Liu, X., Lauer, K. K., Douglas Ward, B., Roberts, C., Liu, S., Gollapudy, S., Rohloff, R., Gross, W., Chen, G., Xu, Z., Binder, J. R., Li, S. J., & Hudetz, A. G. (2017). Propofol attenuates low-frequency fluctuations of resting-state fMRI BOLD signal in the anterior frontal cortex upon loss of consciousness. NeuroImage, 147, 295–301.

    Article  CAS  Google Scholar 

  • Llinas, R., Ribary, U., Contreras, D., & Pedroarena, C. (1998). The neuronal basis for consciousness. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 353(1377), 1841–1849.

    Article  CAS  Google Scholar 

  • Logothetis, N. K. (2008). What we can do and what we cannot do with fMRI. Nature, 453(7197), 869–878.

    Article  CAS  Google Scholar 

  • Ma, Y., Hamilton, C., & Zhang, N. (2017). Dynamic connectivity patterns in conscious and unconscious brain. Brain Connectivity, 7(1), 1–12.

    Article  Google Scholar 

  • Maksimow, A., Sarkela, M., Langsjo, J. W., Salmi, E., Kaisti, K. K., Yli-Hankala, A., Hinkka-Yli-Salomaki, S., Scheinin, H., et al. (2006). Increase in high frequency EEG activity explains the poor performance of EEG spectral entropy monitor during S-ketamine anesthesia. Clinical Neurophysiology, 117(8), 1660–1668.

    Article  CAS  Google Scholar 

  • Mashour, G. A. (2014). Top-down mechanisms of anesthetic-induced unconsciousness. Frontiers in Systems Neuroscience, 8, 115.

    Article  Google Scholar 

  • Mashour, G. A., & Alkire, M. T. (2013). Consciousness, anesthesia, and the thalamocortical system. Anesthesiology, 118(1), 13–15.

    Article  Google Scholar 

  • Mason, M. F., Norton, M. I., Van Horn, J. D., Wegner, D. M., Grafton, S. T., & Macrae, C. N. (2007). Wandering minds: The default network and stimulus-independent thought. Science, 315(5810), 393–395.

    Article  CAS  Google Scholar 

  • Massimini, M., Ferrarelli, F., Huber, R., Esser, S. K., Singh, H., & Tononi, G. (2005). Breakdown of cortical effective connectivity during sleep. Science, 309(5744), 2228–2232.

    Article  CAS  Google Scholar 

  • Oizumi, M., Albantakis, L., & Tononi, G. (2014). From the phenomenology to the mechanisms of consciousness: Integrated information theory 3.0. PLoS Computational Biology, 10(5), e1003588.

    Article  Google Scholar 

  • Plourde, G., Belin, P., Chartrand, D., Fiset, P., Backman, S. B., Xie, G., & Zatorre, R. J. (2006). Cortical processing of complex auditory stimuli during alterations of consciousness with the general anesthetic propofol. Anesthesiology, 104(3), 448–457.

    Article  Google Scholar 

  • Sanders, R. D., Tononi, G., Laureys, S., & Sleigh, J. W. (2012). Unresponsiveness not equal unconsciousness. Anesthesiology, 116(4), 946–959.

    Article  Google Scholar 

  • Sarasso, S., Boly, M., Napolitani, M., Gosseries, O., Charland-Verville, V., Casarotto, S., Rosanova, M., Casali, A. G., Brichant, J. F., Boveroux, P., Rex, S., Tononi, G., Laureys, S., & Massimini, M. (2015). Consciousness and complexity during unresponsiveness induced by Propofol, Xenon, and Ketamine. Current Biology, 25(23), 3099–3105.

    Article  CAS  Google Scholar 

  • Schrouff, J., Perlbarg, V., Boly, M., Marrelec, G., Boveroux, P., Vanhaudenhuyse, A., Bruno, M. A., Laureys, S., Phillips, C., Pélégrini-Issac, M., Maquet, P., & Benali, H. (2011). Brain functional integration decreases during propofol-induced loss of consciousness. NeuroImage, 57(1), 198–205.

    Article  CAS  Google Scholar 

  • Shafer, S. L. (1996). STANPUMP User's Manual. Stanford: Stanford University.

    Google Scholar 

  • Shanahan, M. (2010). Metastable chimera states in community-structured oscillator networks. Chaos, 20(1), 013108.

    Article  Google Scholar 

  • Sleigh, J. W., & Donovan, J. (1999). Comparison of bispectral index, 95% spectral edge frequency and approximate entropy of the EEG, with changes in heart rate variability during induction of general anaesthesia. British Journal of Anaesthesia, 82(5), 666–671.

    Article  CAS  Google Scholar 

  • Sporns, O., Honey, C. J., & Kotter, R. (2007). Identification and classification of hubs in brain networks. PLoS One, 2(10), e1049.

    Article  Google Scholar 

  • Steyn-Ross, M. L., Steyn-Ross, D. A., Sleigh, J. W., & Liley, D. T. (1999). Theoretical electroencephalogram stationary spectrum for a white-noise-driven cortex: Evidence for a general anesthetic-induced phase transition. Physical Review E: Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics, 60(6 Pt B), 7299–7311.

    Article  CAS  Google Scholar 

  • Steyn-Ross, D. A., Steyn-Ross, M. L., Wilcocks, L. C., & Sleigh, J. W. (2001). Toward a theory of the general-anesthetic-induced phase transition of the cerebral cortex. II. Numerical simulations, spectral entropy, and correlation times. Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics, 64(1 Pt 1), 011918.

    Article  CAS  Google Scholar 

  • Tagliazucchi, E., Carhart-Harris, R., Leech, R., Nutt, D., & Chialvo, D. R. (2014). Enhanced repertoire of brain dynamical states during the psychedelic experience. Human Brain Mapping, 35(11), 5442–5456.

    Article  Google Scholar 

  • Tagliazucchi, E., Chialvo, D. R., Siniatchkin, M., Amico, E., Brichant, J. F., Bonhomme, V., Noirhomme, Q., Laufs, H., & Laureys, S. (2016). Large-scale signatures of unconsciousness are consistent with a departure from critical dynamics. Journal of the Royal Society, Interface, 13(114), 20151027.

    Article  Google Scholar 

  • Tognoli, E., & Kelso, J. A. (2014). The metastable brain. Neuron, 81(1), 35–48.

    Article  CAS  Google Scholar 

  • Tononi, G. (2004). An information integration theory of consciousness. BMC Neuroscience, 5, 42.

    Article  Google Scholar 

  • Tononi, G. (2008). Consciousness as integrated information: A provisional manifesto. Biological Bulletin, 215(3), 216–242.

    Article  Google Scholar 

  • Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., & Joliot, M. (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage, 15(1), 273–289.

    Article  CAS  Google Scholar 

  • Uhrig, L., Dehaene, S., & Jarraya, B. (2014). Cerebral mechanisms of general anesthesia. Annales Françaises d'Anesthèsie et de Rèanimation, 33(2), 72–82.

    Article  CAS  Google Scholar 

  • Vakkuri, A., Yli-Hankala, A., Talja, P., Mustola, S., Tolvanen-Laakso, H., Sampson, T., & Viertio-Oja, H. (2004). Time-frequency balanced spectral entropy as a measure of anesthetic drug effect in central nervous system during sevoflurane, propofol, and thiopental anesthesia. Acta Anaesthesiologica Scandinavica, 48(2), 145–153.

    Article  CAS  Google Scholar 

  • Zhang, W., Wang, J., Fan, L., Zhang, Y., Fox, P. T., Eickhoff, S. B., Yu, C., & Jiang, T. (2016). Functional organization of the fusiform gyrus revealed with connectivity profiles. Human Brain Mapping, 37(8), 3003–3016.

    Article  Google Scholar 

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Acknowledgements

Research reported in this publication was supported by grants from the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers R01-GM103894 and T32-GM89586. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Ms. Lydia Washechek, BA, for editorial assistance.

Funding

This study was funded by grants from the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers R01 GM103894 and T32 GM89586. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Radiology, Center for Imaging Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    Xiaolin Liu

  2. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA

    Kathryn K. Lauer, Christopher J. Roberts, Suyan Liu, Suneeta Gollapudy & William Gross

  3. Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA

    B. Douglas Ward, Zhan Xu & Shi-Jiang Li

  4. Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA

    Robert Rohloff & Jeffrey R. Binder

  5. Cognitive and Mental Health Research Center, Beijing Institute of Basic Medical Sciences, Beijing, China

    Shanshan Chen, Lubin Wang & Zheng Yang

  6. Department of Anesthesiology and Center for Consciousness Science, University of Michigan, 1301 East Catherine Street, Ann Arbor, MI, 48109, USA

    Anthony G. Hudetz

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  1. Xiaolin Liu
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Liu, X., Lauer, K.K., Ward, B.D. et al. Regional entropy of functional imaging signals varies differently in sensory and cognitive systems during propofol-modulated loss and return of behavioral responsiveness. Brain Imaging and Behavior 13, 514–525 (2019). https://doi.org/10.1007/s11682-018-9886-0

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