Accurately measuring the neural correlates of consciousness is a grand challenge for neuroscience. Despite theoretical advances, developing reliable brain measures to track the loss of reportable consciousness during sedation is hampered by significant individual variability in susceptibility to anaesthetics. We addressed this challenge using high-density electroencephalography to characterise changes in brain networks during propofol sedation. Assessments of spectral connectivity networks before, during and after sedation were combined with measurements of behavioural responsiveness and drug concentrations in blood. Strikingly, we found that participants who had weaker alpha band networks at baseline were more likely to become unresponsive during sedation, despite registering similar levels of drug in blood. In contrast, phase-amplitude coupling between slow and alpha oscillations correlated with drug concentrations in blood. Our findings highlight novel markers that prognosticate individual differences in susceptibility to propofol and track drug exposure. These advances could inform accurate drug titration and brain state monitoring during anaesthesia.
References
[1]
Tononi G. An information integration theory of consciousness. BMC Neuroscience. 2004;5(1):42. doi: 10.1186/1471-2202-5-42
[2]
Alkire MT, Hudetz AG, Tononi G. Consciousness and anesthesia. Science. 2008;322(5903):876–80. doi: 10.1126/science.1149213. pmid:18988836
[3]
Lee U, Mashour GA, Kim S, Noh GJ, Choi BM. Propofol induction reduces the capacity for neural information integration: implications for the mechanism of consciousness and general anesthesia. Conscious Cogn. 2009;18(1):56–64. doi: 10.1016/j.concog.2008.10.005. pmid:19054696
[4]
Ferrarelli F, Massimini M, Sarasso S, Casali A, Riedner BA, Angelini G, et al. Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proc Natl Acad Sci U S A. 2010;107(6):2681–6. doi: 10.1073/pnas.0913008107. pmid:20133802
[5]
Brown EN, Lydic R, Schiff ND. General Anesthesia, Sleep, and Coma. New England Journal of Medicine. 2010;363(27):2638–50. doi: 10.1056/NEJMra0808281. pmid:21190458
[6]
Gibbs FA, Gibbs EL, Lennox WG. Effect on the electroencephalogram of certain drugs which influence nervous activity. Archives of Internal Medicine. 1937;60:154–69. doi: 10.1001/archinte.1937.00180010159012
[7]
Pandit JJ, Cook TM, Jonker WR, O'Sullivan E, Anaesthetists obottNAPotRCo, Britain tAoAoG, et al. A national survey of anaesthetists (NAP5 Baseline) to estimate an annual incidence of accidental awareness during general anaesthesia in the UK. Anaesthesia. 2013;68(4):343–53. doi: 10.1111/anae.12190. pmid:23488832
[8]
Vijayan S, Ching S, Purdon PL, Brown EN, Kopell NJ. Thalamocortical mechanisms for the anteriorization of alpha rhythms during propofol-induced unconsciousness. J Neurosci. 2013;33(27):11070–5. Epub 2013/07/05. doi: 10.1523/JNEUROSCI.5670-12.2013. pmid:23825412
[9]
Molaee-Ardekani B, Senhadji L, Sharnsollahi MB, Wodey E, Vosoughi-Vahdat B. Delta waves differently modulate high frequency components of EEG oscillations in various unconsciousness levels. P Ann Int Ieee Embs. 2007:1294–7. doi: 10.1109/iembs.2007.4352534
[10]
Monti MM, Lutkenhoff ES, Rubinov M, Boveroux P, Vanhaudenhuyse A, Gosseries O, et al. Dynamic change of global and local information processing in propofol-induced loss and recovery of consciousness. PLoS Comput Biol. 2013;9(10):e1003271. doi: 10.1371/journal.pcbi.1003271. pmid:24146606
[11]
Lewis LD, Weiner VS, Mukamel EA, Donoghue JA, Eskandar EN, Madsen JR, et al. Rapid fragmentation of neuronal networks at the onset of propofol-induced unconsciousness. Proc Natl Acad Sci U S A. 2012;109(49):E3377–86. Epub 2012/11/07. doi: 10.1073/pnas.1210907109. pmid:23129622
[12]
Breshears JD, Roland JL, Sharma M, Gaona CM, Freudenburg ZV, Tempelhoff R, et al. Stable and dynamic cortical electrophysiology of induction and emergence with propofol anesthesia. Proc Natl Acad Sci U S A. 2010;107(49):21170–5. doi: 10.1073/pnas.1011949107. pmid:21078987
[13]
Avidan MS, Jacobsohn E, Glick D, Burnside BA, Zhang L, Villafranca A, et al. Prevention of Intraoperative Awareness in a High-Risk Surgical Population. New England Journal of Medicine. 2011;365(7):591–600. doi: 10.1056/NEJMoa1100403. pmid:21848460
[14]
Doi M, Gajraj RJ, Mantzaridis H, Kenny GN. Relationship between calculated blood concentration of propofol and electrophysiological variables during emergence from anaesthesia: comparison of bispectral index, spectral edge frequency, median frequency and auditory evoked potential index. Br J Anaesth. 1997;78(2):180–4. pmid:9068338 doi: 10.1093/bja/78.2.180
[15]
Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology. 1997;86(4):836–47. pmid:9105228 doi: 10.1097/00000542-199704000-00014
[16]
Palanca BJ, Mashour GA, Avidan MS. Processed electroencephalogram in depth of anesthesia monitoring. Current opinion in anaesthesiology. 2009;22(5):553–9. doi: 10.1097/ACO.0b013e3283304032. pmid:19652597
[17]
Schneider G, Gelb AW, Schmeller B, Tschakert R, Kochs E. Detection of awareness in surgical patients with EEG-based indices—bispectral index and patient state index. Br J Anaesth. 2003;91(3):329–35. pmid:12925469 doi: 10.1093/bja/aeg188
[18]
Purdon PL, Pierce ET, Mukamel EA, Prerau MJ, Walsh JL, Wong KFK, et al. Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proc Natl Acad Sci U S A. 2013;110(12):1142–51. doi: 10.1073/pnas.1221180110
[19]
Cimenser A, Purdon PL, Pierce ET, Walsh JL, Salazar-Gomez AF, Harrell PG, et al. Tracking brain states under general anesthesia by using global coherence analysis. Proc Natl Acad Sci U S A. 2011;108(21):8832–7. doi: 10.1073/pnas.1017041108. pmid:21555565
[20]
Schrouff J, Perlbarg V, Boly M, Marrelec G, Boveroux P, Vanhaudenhuyse A, et al. Brain functional integration decreases during propofol-induced loss of consciousness. Neuroimage. 2011;57(1):198–205. doi: 10.1016/j.neuroimage.2011.04.020. pmid:21524704
[21]
Ní Mhuircheartaigh R, Warnaby C, Rogers R, Jbabdi S, Tracey I. Slow-Wave Activity Saturation and Thalamocortical Isolation During Propofol Anesthesia in Humans. Science Translational Medicine. 2013;5(208):208ra148. doi: 10.1126/scitranslmed.3006007. pmid:24154602
[22]
Vinck M, Oostenveld R, van Wingerden M, Battaglia F, Pennartz CM. An improved index of phase-synchronization for electrophysiological data in the presence of volume-conduction, noise and sample-size bias. Neuroimage. 2011;55(4):1548–65. doi: 10.1016/j.neuroimage.2011.01.055. pmid:21276857
[23]
Baker AP, Brookes MJ, Rezek IA, Smith SM, Behrens T, Probert Smith PJ, et al. Fast transient networks in spontaneous human brain activity. Culham JC, editor2014 2014-03-25 19:12:20.
[24]
Rosanova M, Casali A, Bellina V, Resta F, Mariotti M, Massimini M. Natural frequencies of human corticothalamic circuits. J Neurosci. 2009;29(24):7679–85. doi: 10.1523/JNEUROSCI.0445-09.2009. pmid:19535579
[25]
Achard S, Bullmore E. Efficiency and cost of economical brain functional networks. PLoS Comput Biol. 2007;3(2):e17. pmid:17274684 doi: 10.1371/journal.pcbi.0030017
Tinker JH, Sharbrough FW, Michenfelder JD. Anterior Shift of the Dominant EEG Rhythm during Anesthesia in the Java Monkey: Correlation with Anesthetic Potency. Anesthesiology. 1977;46(4):252–9. pmid:402870 doi: 10.1097/00000542-197704000-00005
[31]
Gugino LD, Chabot RJ, Prichep LS, John ER, Formanek V, Aglio LS. Quantitative EEG changes associated with loss and return of consciousness in healthy adult volunteers anaesthetized with propofol or sevoflurane. British Journal of Anaesthesia. 2001;87(3):421–8. pmid:11517126 doi: 10.1093/bja/87.3.421
[32]
Supp GG, Siegel M, Hipp JF, Engel AK. Cortical hypersynchrony predicts breakdown of sensory processing during loss of consciousness. Curr Bio. 2011;21(23):1988–93. doi: 10.1016/j.cub.2011.10.017
[33]
Barrett AB, Murphy M, Bruno MA, Noirhomme Q, Boly M, Laureys S, et al. Granger causality analysis of steady-state electroencephalographic signals during propofol-induced anaesthesia. PLoS One. 2012;7(1):e29072. doi: 10.1371/journal.pone.0029072. pmid:22242156
[34]
McCarthy MM, Brown EN, Kopell N. Potential network mechanisms mediating electroencephalographic beta rhythm changes during propofol-induced paradoxical excitation. J Neurosci. 2008;28(50):13488–504. doi: 10.1523/JNEUROSCI.3536-08.2008. pmid:19074022
[35]
Mukamel EA, Pirondini E, Babadi B, Wong KF, Pierce ET, Harrell PG, et al. A transition in brain state during propofol-induced unconsciousness. J Neurosci. 2014;34(3):839–45. doi: 10.1523/JNEUROSCI.5813-12.2014. pmid:24431442
Casali AG, Gosseries O, Rosanova M, Boly M, Sarasso S, Casali KR, et al. A theoretically based index of consciousness independent of sensory processing and behavior. Sci Transl Med. 2013;5(198):198ra05. Epub 2013/08/16. doi: 10.1126/scitranslmed.3006294
[38]
Ching S, Cimenser A, Purdon PL, Brown EN, Kopell NJ. Thalamocortical model for a propofol-induced alpha-rhythm associated with loss of consciousness. Proc Natl Acad Sci U S A. 2010;107(52):22665–70. Epub 2010/12/15. doi: 10.1073/pnas.1017069108. pmid:21149695
[39]
Boly M, Moran R, Murphy M, Boveroux P, Bruno MA, Noirhomme Q, et al. Connectivity changes underlying spectral EEG changes during propofol-induced loss of consciousness. J Neurosci. 2012;32(20):7082–90. Epub 2012/05/18. doi: 10.1523/JNEUROSCI.3769-11.2012. pmid:22593076
[40]
Lee U, Ku S, Noh G, Baek S, Choi B, Mashour GA. Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane. Anesthesiology. 2013;118(6):1264–75. doi: 10.1097/ALN.0b013e31829103f5. pmid:23695090
[41]
Blain-Moraes S, Lee U, Ku S, Noh G, Mashour GA. Electroencephalographic effects of ketamine on power, cross-frequency coupling, and connectivity in the alpha bandwidth. Front Syst Neurosci. 2014;8:114. doi: 10.3389/fnsys.2014.00114. pmid:25071473
[42]
Blain-Moraes S, Tarnal V, Vanini G, Alexander A, Rosen D, Shortal B, et al. Neurophysiological Correlates of Sevoflurane-induced Unconsciousness. Anesthesiology. 2015;122(2):307–16. doi: 10.1097/ALN.0000000000000482. pmid:25296108
[43]
Moon JY, Lee U, Blain-Moraes S, Mashour GA. General relationship of global topology, local dynamics, and directionality in large-scale brain networks. PLoS Comput Biol. 2015;11(4):e1004225. doi: 10.1371/journal.pcbi.1004225. pmid:25874700
[44]
Murphy M, Bruno M-A, Riedner BA, Boveroux P, Noirhomme Q, Landsness EC, et al. Propofol Anesthesia and Sleep: A High-Density EEG Study. Sleep. 2011;34(3):283–91. pmid:21358845
[45]
Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology. 1998;89(4):980–1002. pmid:9778016 doi: 10.1097/00000542-199810000-00023
[46]
Marsh B, White M, Morton N, Kenny GNC. Pharmacokinetic model driven infusion of propofol in children. British Journal of Anaesthesia. 1991;67(1):41–8. pmid:1859758 doi: 10.1093/bja/67.1.41
[47]
Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. Journal of Neuroscience Methods. 2004;134(1):9–21. pmid:15102499 doi: 10.1016/j.jneumeth.2003.10.009
[48]
Chennu S, Finoia P, Kamau E, Allanson J, Williams GB, Monti MM, et al. Spectral signatures of reorganised brain networks in disorders of consciousness. PLOS Computational Biology. 2014;10(10):e1003887. doi: 10.1371/journal.pcbi.1003887. pmid:25329398
[49]
Lee H, Mashour GA, Noh G- J, Kim S, Lee U. Reconfiguration of Network Hub Structure after Propofol-induced Unconsciousness. Anesthesiology. 2013;119(6). doi: 10.1097/aln.0b013e3182a8ec8c
[50]
Canolty RT, Knight RT. The functional role of cross-frequency coupling. Trends Cogn Sci. 2010;14(11):506–15. doi: 10.1016/j.tics.2010.09.001. pmid:20932795
[51]
Ozkurt TE, Schnitzler A. A critical note on the definition of phase-amplitude cross-frequency coupling. J Neurosci Methods. 2011;201(2):438–43. doi: 10.1016/j.jneumeth.2011.08.014. pmid:21871489
[52]
Tadel F, Baillet S, Mosher JC, Pantazis D, Leahy RM. Brainstorm: A User-Friendly Application for MEG/EEG Analysis. Computational Intelligence and Neuroscience. 2011;2011. doi: 10.1155/2011/879716
[53]
Achard S, Delon-Martin C, Vértes PE, Renard F, Schenck M, Schneider F, et al. Hubs of brain functional networks are radically reorganized in comatose patients. Proc Natl Acad Sci U S A. 2012;109(50):20608–13. doi: 10.1073/pnas.1208933109. pmid:23185007
[54]
Lynall ME, Bassett DS, Kerwin R, McKenna PJ, Kitzbichler M, Muller U, et al. Functional connectivity and brain networks in schizophrenia. J Neurosci. 2010;30(28):9477–87. doi: 10.1523/JNEUROSCI.0333-10.2010. pmid:20631176
[55]
Rubinov M, Sporns O. Complex network measures of brain connectivity: Uses and interpretations. NeuroImage. 2010;52(3):1059–69. doi: 10.1016/j.neuroimage.2009.10.003. pmid:19819337
[56]
Blondel VD, Guillaume J-L, Lambiotte R, Lefebvre E. Fast unfolding of communities in large networks. Journal of Statistical Mechanics: Theory and Experiment. 2008;2008(10):P10008. doi: 10.1088/1742-5468/2008/10/p10008
[57]
Achard S, Salvador R, Whitcher B, Suckling J, Bullmore E. A Resilient, Low-Frequency, Small-World Human Brain Functional Network with Highly Connected Association Cortical Hubs. The Journal of Neuroscience. 2006;26(1):63–72. pmid:16399673 doi: 10.1523/jneurosci.3874-05.2006
[58]
Pernet CR, Wilcox R, Rousselet GA. Robust correlation analyses: false positive and power validation using a new open source matlab toolbox. Front Psychol. 2012;3:606. doi: 10.3389/fpsyg.2012.00606. pmid:23335907
