Top-down mechanisms of anesthetic-induced unconsciousness

George A Mashour, George A Mashour

Abstract

The question of how structurally and pharmacologically diverse general anesthetics disrupt consciousness has persisted since the nineteenth century. There has traditionally been a significant focus on "bottom-up" mechanisms of anesthetic action, in terms of sensory processing, arousal systems, and structural scales. However, recent evidence suggests that the neural mechanisms of anesthetic-induced unconsciousness may involve a "top-down" process, which parallels current perspectives on the neurobiology of conscious experience itself. This article considers various arguments for top-down mechanisms of anesthetic-induced unconsciousness, with a focus on sensory processing and sleep-wake networks. Furthermore, recent theoretical work is discussed to highlight the possibility that top-down explanations may be causally sufficient, even assuming critical bottom-up events.

Keywords: anesthesia; anesthetic mechanisms; consciousness; ketamine; propofol; sleep.

Figures

Figure 1
Figure 1
Consciousness is not correlated with activation of primary sensory cortex. This example of contrastive analysis demonstrates activation of primary auditory cortex even in the absence of conscious perception. By contrast, detection of the auditory stimulus is correlated with activation of a widespread network prominently involving frontal-parietal networks. Reproduced from Dehaene and Changeux (2011), Neuron, with permission.
Figure 2
Figure 2
Anesthetic-induced unconsciousness is not correlated with inactivation of primary sensory cortex. Transverse and sagittal sections of primary visual (A,C) and auditory (B,D) cortices during wakefulness (A,B) and propofol-induced unconsciousness (C,D); note the relative preservation across states. Reproduced from Boveroux et al. (2010), Anesthesiology, with permission.
Figure 3
Figure 3
Consciousness is not correlated with early event-related potentials. This electrophysiological study of visual processing concluded that early event-related potentials (reflecting more primary sensory processing) are not correlated with conscious perception. Top-down processing from prefrontal cortex was more closely associated with consciousness. Reproduced from Del Cul et al. (2007), PLoS Biology, with permission.
Figure 4
Figure 4
Anesthetic-induced unconsciousness is not correlated with effects on early evoked potentials. This study of visual evoked potentials in rats demonstrates a clear dose-dependent effect of the inhaled anesthetic desflurane on long-latency potentials, with sparing of early potentials reflecting processing in primary visual cortex. Reproduced from Hudetz et al. (2009), Anesthesiology, with permission.
Figure 5
Figure 5
Ventrolateral preoptic nucleus is not necessary for anesthetic-induced unconsciousness. Lesions of the ventrolateral preoptic nucleus reveal an acute effect of resistance but a chronic effect of hypersensitivity to the inhaled anesthetic isoflurane. Reproduced from Moore et al. (2012), Current Biology, with permission. *p < 0.05; ***p < 0.001.
Figure 6
Figure 6
Inhibition of top-down connectivity is a common correlate of anesthetic-induced unconsciousness across three distinct classes of general anesthetics. This figure depicts frontal-to-parietal (feedback) and parietal-to-frontal (feedforward) connectivity before, during and after anesthetic-induced unconsciousness in surgical patients (A–C). Lower panels (D–F) show asymmetry of directional connectivity, with positive values representing feedback dominance and negative values representing feedforward dominance. Connectivity was measured using electroencephalography and symbolic transfer entropy, which is rooted in information theory. Blue shaded area represents induction of anesthesia; the period before induction is baseline consciousness and the period after is anesthetic-induced unconsciousness. Each state is separated into three substates of Baseline (B1–B3) and Anesthetized (A1–A3) conditions; the timescale is different because patients receiving ketamine were studied using a different protocol than patients receiving propofol and sevoflurane. FB, Feedback; FF, Feedforward. Reproduced from Lee et al. (2013), Anesthesiology, with permission.

References

    1. Alkire M. T., Haier R. J., Barker S. J., Shah N. K., Wu J. C., Kao Y. J. (1995). Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography. Anesthesiology 82, 393–403 10.1097/00000542-199502000-00010
    1. Alkire M. T., Haier R. J., Fallon J. H. (2000). Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious. Cogn. 9, 370–386 10.1006/ccog.1999.0423
    1. Antkowiak B. (1999). Different actions of general anesthetics on the firing patterns of neocortical neurons mediated by the GABA(A) receptor. Anesthesiology 91, 500–511
    1. Antognini J. F., Schwartz K. (1993). Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 79, 1244–1249 10.1097/00000542-199312000-00015
    1. Banoub M., Tetzlaff J. E., Schubert A. (2003). Pharmacologic and physiologic influences affecting sensory evoked potentials: implications for perioperative monitoring. Anesthesiology 99, 716–737 10.1097/00000542-200309000-00029
    1. Boly M., Garrido M. I., Gosseries O., Bruno M. A., Boveroux P., Schnakers C., et al. (2011). Preserved feedforward but impaired top-down processes in the vegetative state. Science 332, 858–862 10.1126/science.1202043
    1. 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). Arch. Ital. Biol. 150, 155–163 10.4449/aib.v150i2.1242
    1. Boveroux P., Vanhaudenhuyse A., Bruno M. A., Noirhomme Q., Lauwick S., Luxen A., et al. (2010). Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness. Anesthesiology 113, 1038–1053 10.1097/ALN.0b013e3181f697f5
    1. Brecht M., Schneider M., Sakmann B., Margrie T. W. (2004). Whisker movements evoked by stimulation of single pyramidal cells in rat motor cortex. Nature 427, 704–710 10.1038/nature02266
    1. Casali A. G., Gosseries O., Rosanova M., Boly M., Sarasso S., Casali K. R., et al. (2013). A theoretically based index of consciousness independent of sensory processing and behavior. Sci. Transl. Med. 5, 198ra105 10.1126/scitranslmed.3006294
    1. Clark A. (2013). Whatever next? Predictive brains, situated agents, and the future of cognitive science. Behav. Brain Sci. 36, 181–204 10.1017/S0140525X12000477
    1. Crick F., Koch C. (1995). Are we aware of neural activity in primary visual cortex? Nature 375, 121–123 10.1038/375121a0
    1. Crowder C. M. (2008). Does natural selection explain the universal response of metazoans to volatile anesthetics? Anesth. Analg. 107, 862–863 10.1213/ane.0b013e31817d866a
    1. Dehaene S., Changeux J. P. (2011). Experimental and theoretical approaches to conscious processing. Neuron 70, 200–227 10.1016/j.neuron.2011.03.018
    1. Del Cul A., Baillet S., Dehaene S. (2007). Brain dynamics underlying the nonlinear threshold for access to consciousness. PLoS Biol. 5:e260 10.1371/journal.pbio.0050260
    1. Eikermann M., Vetrivelan R., Grosse-Sundrup M., Henry M. E., Hoffmann U., Yokota S., et al. (2011). The ventrolateral preoptic nucleus is not required for isoflurane general anesthesia. Brain Res. 1426, 30–37 10.1016/j.brainres.2011.10.018
    1. Ferrarelli F., Massimini M., Sarasso S., Casali A., Riedner B. A., Angelini G., et al. (2010). Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proc. Natl. Acad. Sci. U.S.A. 107, 2681–2686 10.1073/pnas.0913008107
    1. Franks N. P., Lieb W. R. (1984). Do general anaesthetics act by competitive binding to specific receptors? Nature 310, 599–601
    1. Friedman E. B., Sun Y., Moore J. T., Hung H. T., Meng Q. C., Perera P., et al. (2010). A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia. PLoS ONE 5:e11903 10.1371/journal.pone.0011903
    1. Hoel E. P., Albantakis L., Tononi G. (2013). Quantifying causal emergence shows that macro can beat micro. Proc. Natl. Acad. Sci. U.S.A. 110, 19790–19795 10.1073/pnas.1314922110
    1. Houweling A. R., Brecht M. (2008). Behavioural report of single neuron stimulation in somatosensory cortex. Nature 451, 65–68 10.1038/nature06447
    1. Hu F. Y., Hanna G. M., Han W., Mardini F., Thomas S. A., Wyner A. J., et al. (2012). Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine beta-hydroxylase knockout mice. Anesthesiology 117, 1006–1017 10.1097/ALN.0b013e3182700ab9
    1. Hudetz A. G., Vizuete J. A., Imas O. A. (2009). Desflurane selectively suppresses long-latency cortical neuronal response to flash in the rat. Anesthesiology 111, 231–239 10.1097/ALN.0b013e3181ab671e
    1. Imas O. A., Ropella K. M., Ward B. D., Wood J. D., Hudetz A. G. (2005). Volatile anesthetics disrupt frontal-posterior recurrent information transfer at gamma frequencies in rat. Neurosci. Lett. 387, 145–150 10.1016/j.neulet.2005.06.018
    1. Jevtovic-Todorovic V., Todorovic S. M., Mennerick S., Powell S., Dikranian K., Benshoff N., et al. (1998). Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat. Med. 4, 460–463 10.1038/nm0498-460
    1. Joiner W. J., Friedman E. B., Hung H. T., Koh K., Sowcik M., Sehgal A., et al. (2013). Genetic and anatomical basis of the barrier separating wakefulness and anesthetic-induced unresponsiveness. PLoS Genet. 9:e1003605 10.1371/journal.pgen.1003605
    1. Jordan D., Ilg R., Riedl V., Schorer A., Grimberg S., Neufang S., et al. (2013). Simultaneous electroencephalographic and functional magnetic resonance imaging indicate impaired cortical top-down processing in association with anesthetic-induced unconsciousness. Anesthesiology 119, 1031–1042 10.1097/ALN.0b013e3182a7ca92
    1. Kelz M. B., Sun Y., Chen J., Cheng Meng Q., Moore J. T., Veasey S. C., et al. (2008). An essential role for orexins in emergence from general anesthesia. Proc. Natl. Acad. Sci. U.S.A. 105, 1309–1314 10.1073/pnas.0707146105
    1. Ku S. W., Lee U., Noh G. J., Jun I. G., Mashour G. A. (2011). Preferential inhibition of frontal-to-parietal feedback connectivity is a neurophysiologic correlate of general anesthesia in surgical patients. PLoS ONE 6:e25155 10.1371/journal.pone.0025155
    1. Kushikata T., Yoshida H., Kudo M., Kudo T., Kudo T., Hirota K. (2011). Role of coerulean noradrenergic neurones in general anaesthesia in rats. Br. J. Anaesth. 107, 924–929 10.1093/bja/aer303
    1. Langsjo J. W., Maksimow A., Salmi E., Kaista K., Aalto S., Oikonen V., et al. (2005). S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans. Anesthesiology 103, 258–268 10.1097/00000542-200508000-00008
    1. Lau H., Rosenthal D. (2011). Empirical support for higher-order theories of conscious awareness. Trends Cogn. Sci. 15, 365–373 10.1016/j.tics.2011.05.009
    1. Laureys S. (2005). The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn. Sci. 9, 556–559 10.1016/j.tics.2005.10.010
    1. Lee U., Ku S., Noh G., Baek S., Choi B., Mashour G. A. (2013). Disruption of frontal-parietal communication by ketamine, propofol, and sevoflurane. Anesthesiology 118, 1264–1275 10.1097/ALN.0b013e31829103f5
    1. Li C. Y., Poo M. M., Dan Y. (2009). Burst spiking of a single cortical neuron modifies global brain state. Science 324, 643–646 10.1126/science.1169957
    1. 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, 59–69 10.1097/ALN.0b013e318277a801
    1. Lu J., Nelson L. E., Franks N., Maze M., Chamberlin N. L., Saper C. B. (2008). Role of endogenous sleep-wake and analgesic systems in anesthesia. J. Comp. Neurol. 508, 648–662 10.1002/cne.21685
    1. Luo T., Leung L. S. (2011). Involvement of tuberomamillary histaminergic neurons in isoflurane anesthesia. Anesthesiology 115, 36–43 10.1097/ALN.0b013e3182207655
    1. Lydic R., Biebuyck J. F. (1994). Sleep neurobiology: relevance for mechanistic studies of anaesthesia. Br. J. Anaesth. 72, 506–508 10.1093/bja/72.5.506
    1. Manninen P. H., Lam A. M., Nicholas J. F. (1985). The effects of isoflurane and isoflurane-nitrous oxide anesthesia on brainstem auditory evoked potentials in humans. Anesth. Analg. 64, 43–47 10.1213/00000539-198501000-00009
    1. Mashour G. A. (2013). Cognitive unbinding: a neuroscientific paradigm of general anesthesia and related states of unconsciousness. Neurosci. Biobehav. Rev. 37, 2751–2759 10.1016/j.neubiorev.2013.09.009
    1. Mihic S. J., Ye Q., Wick M. J., Koltchine V. V., Krasowski M. D., Finn S. E., et al. (1997). Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature 389, 385–389 10.1038/38738
    1. Moore J. T., Chen J., Han B., Meng Q. C., Veasey S. C., Beck S. G., et al. (2012). Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis. Curr. Biol. 22, 2008–2016 10.1016/j.cub.2012.08.042
    1. Moruzzi G., Magoun H. W. (1949). Brain stem reticular formation and activation of the EEG. Electroencephalogr. Clin. Neurophysiol. 1, 455–473 10.1016/0013-4694(49)90219-9
    1. Nelson L. E., Guo T. Z., Lu J., Saper C. B., Franks N. P., Maze M. (2002). The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat. Neurosci. 5, 979–984 10.1038/nn913
    1. Ni Mhuircheartaigh R., Warnaby C., Rogers R., Jbabdi S., Tracey I. (2013). Slow-wave activity saturation and thalamocortical isolation during propofol anesthesia in humans. Sci. Transl. Med. 5, 208ra148 10.1126/scitranslmed.3006007
    1. Perouansky M. (2012). The quest for a unified model of anesthetic action: a century in Claude Bernard's shadow. Anesthesiology 117, 465–474 10.1097/ALN.0b013e318264492e
    1. Rampil I. J. (1994). Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 80, 606–610 10.1097/00000542-199403000-00017
    1. Salmi E., Langsjo J. W., Aalto S., Nagren K., Metsahonkala L., Kaisti K. K., et al. (2005). Subanesthetic ketamine does not affect 11C-flumazenil binding in humans. Anesth. Analg. 101, 722–725 10.1213/01.ane.0000156951.83242.8d
    1. Sanders R. D., Tononi G., Laureys S., Sleigh J. W. (2012). Unresponsiveness not equal unconsciousness. Anesthesiology 116, 946–959 10.1097/ALN.0b013e318249d0a7
    1. Saper C. B., Scammell T. E., Lu J. (2005). Hypothalamic regulation of sleep and circadian rhythms. Nature 437, 1257–1263 10.1038/nature04284
    1. Tononi G. (2012). Integrated information theory of consciousness: an updated account. Arch. Ital. Biol. 150, 293–329
    1. van Swinderen B. (2006). A succession of anesthetic endpoints in the Drosophila brain. J. Neurobiol. 66, 1195–1211 10.1002/neu.20300
    1. van Swinderen B., Saifee O., Shebester L., Roberson R., Nonet M. L., Crowder C. M. (1999). A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 96, 2479–2484 10.1073/pnas.96.5.2479
    1. Zecharia A. Y., Yu X., Gotz T., Ye Z., Carr D. R., Wulff P., et al. (2012). GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness. J. Neurosci. 32, 13062–13075 10.1523/jneurosci.2931-12.2012
    1. Zhou C., Douglas J. E., Kumar N. N., Shu S., Bayliss D. A., Chen X. (2013). Forebrain HCN1 channels contribute to hypnotic actions of ketamine. Anesthesiology 118, 785–795 10.1097/ALN.0b013e318287b7c8

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever