Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness
Abstract
Whereas converging lines of evidence suggest that anesthetic-induced unconsciousness may result from disruption of functional interactions within neural networks involving the thalamus and cerebral cortex, the effects anesthetics have on human thalamocortical connectivity remain unexamined with current neuroimaging techniques. To address this issue we retrospectively analyzed positron emission tomography data from 11 volunteers scanned for regional cerebral glucose utilization (rCMRglu) when awake and again during isoflurane- (n = 6) or halothane- (n = 5) induced unconsciousness using statistical parametric mapping (SPM99) and structural equation modeling. A main effect analysis, contrasting awake and unconscious metabolic activity, localized a discrete region of the left va/vl thalamus whose relative rCMRglu activity was significantly suppressed (P < 0.05, corrected) during the unconscious state. To identify brain regions whose functional connectivity with this region of the thalamus was impaired during the unconscious state, a psychophysiological interaction analysis was performed. This analysis revealed effects predominantly in topographically related areas of the primary motor and supplementary motor association cortices. Structural equation modeling of a neuroanatomical network encompassing these empirically identified regions revealed significant state-related changes in effective connectivity (chi(2)diff (6)-15.88; P < 0.05) which primarily involved impairment of thalamocortical and corticocortical projections during the unconscious state. These findings support the hypothesis that a mechanistic component underlying general-anesthetic-induced unconsciousness involves disruption of functional interactions within thalamocortical neural networks.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PET studies during inhaled anesthetics in humans show disrupted thalamocortical functional connectivity associated with unconsciousness.
“Earlier studies using positron emission tomography during exposure to inhaled anesthetics in humans revealed a disruption of thalamocortical functional connectivity in association with unconsciousness [130].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [130]
Cites
Statistical parametric maps in functional imaging: A general linear approach
Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. ‐., Frith, C. D., & Frackowiak, R. S. J. (1994) · Human Brain Mapping · doi:10.1002/hbm.460020402 · Cited by 9,688 · see citing works
Talairach, J., Tournoux, P., & Rayport, M. (1988) · Thieme eBooks · Cited by 5,058 · see citing works
Psychophysiological and Modulatory Interactions in Neuroimaging
Friston, K. J., Buechel, C., Fink, G. R., Morris, J., Rolls, E., & Dolan, R. J. (1997) · NeuroImage · doi:10.1006/nimg.1997.0291 · Cited by 3,097 · see citing works
Functional and effective connectivity in neuroimaging: a synthesis
Friston, K. J. (1994) · Human Brain Mapping · doi:10.1002/hbm.460020107 · Cited by 2,452 · see citing works
Phelps, M. E., Huang, S. C., Hoffman, E. J., Selin, C. E., Sokoloff, L., & Kuhl, D. E. (1979) · Annals of Neurology · doi:10.1002/ana.410060502 · Cited by 2,417 · see citing works
Functional Connectivity: The Principal-Component Analysis of Large (PET) Data Sets
Friston, K. J., Frith, C., Liddle, P., & Frackowiak, R. (1993) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1038/jcbfm.1993.4 · Cited by 2,094 · see citing works
Tononi, G. (1998) · Science · doi:10.1126/science.282.5395.1846 · Cited by 1,561 · see citing works
Noninvasive determination of local cerebral metabolic rate of glucose in man
Huang, S. C., Phelps, M. E., Hoffman, E. J., Sideris, K., Selin, C. J., & Kuhl, D. E. (1980) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1980.238.1.e69 · Cited by 926 · see citing works
Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks
Buzsáki, G., & Chrobak, J. J. (1995) · Current Opinion in Neurobiology · doi:10.1016/0959-4388(95)80012-3 · Cited by 878 · see citing works
Structural equation modeling and its application to network analysis in functional brain imaging
McLntosh, A. R., & Gonzalez-Lima, F. (1994) · Human Brain Mapping · doi:10.1002/hbm.460020104 · Cited by 838 · see citing works
Corticothalamic resonance, states of vigilance and mentation
Steriade, M. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00353-5 · Cited by 817 · see citing works
Büchel, C. (1997) · Cerebral Cortex · doi:10.1093/cercor/7.8.768 · Cited by 791 · see citing works
Crick, F. H. C. (1996) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-199606000-00013 · Cited by 791 · see citing works
Neural Correlates of Perceptual Rivalry in the Human Brain
Lumer, E. D., Friston, K. J., & Rees, G. E. (1998) · Science · doi:10.1126/science.280.5371.1930 · Cited by 745 · see citing works
The neuronal basis for consciousness
The American Association for Research into Nervous and Mental Diseases, Llinás, R., Ribary, U., Contreras, D., & Pedroarena, C. M. (1998) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.1998.0336 · Cited by 710 · see citing works
Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin
Jevtović‐Todorović, V., Todorovć, S. M., Mennerick, S. J., Powell, S., Dikranian, K. T., Benshoff, N. D., Zorumski, C. F., & Olney, J. W. (1998) · Nature Medicine · doi:10.1038/nm0498-460 · Cited by 675 · see citing works
Llinás, R. R., & Paré, D. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90075-y · Cited by 641 · see citing works
The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway
Nelson, L. E., Guo, T. Z., Lu, J., Saper, C. B., Franks, N. P., & Maze, M. (2002) · Nature Neuroscience · doi:10.1038/nn913 · Cited by 568 · see citing works
Impact of Network Activities on Neuronal Properties in Corticothalamic Systems
Steriade, M. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.86.1.1 · Cited by 530 · see citing works
Fiset, P., Paus, T., Daloze, T., Plourde, G., Meuret, P., Bonhomme, V., Hajj-Ali, N., Backman, S. B., & Evans, A. C. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-13-05506.1999 · Cited by 475 · see citing works
Edelman, G. M. (2000) · Medical Entomology and Zoology · Cited by 437 · see citing works
Simulations of cortical pyramidal neurons synchronized by inhibitory interneurons
Lytton, W. W., & Sejnowski, T. J. (1991) · Journal of Neurophysiology · doi:10.1152/jn.1991.66.3.1059 · Cited by 432 · see citing works
Increased Synchronization of Neuromagnetic Responses during Conscious Perception
Srinivasan, R., Russell, D. P., Edelman, G. M., & Tononi, G. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-13-05435.1999 · Cited by 428 · see citing works
Restoration of thalamocortical connectivity after recovery from persistent vegetative state
Laureys, S., Faymonville, M., Luxen, A., Lamy, M., Franck, G., & Maquet, P. (2000) · The Lancet · doi:10.1016/s0140-6736(00)02271-6 · Cited by 398 · see citing works
Alkire, M. T., Haier, R. J., & Fallon, J. H. (2000) · Consciousness and Cognition · doi:10.1006/ccog.1999.0423 · Cited by 391 · see citing works
Self-citationImpaired Effective Cortical Connectivity in Vegetative State: Preliminary Investigation Using PET
Laureys, S., Goldman, S., Phillips, C. L. M., Bogaert, P. V., Aerts, J. J., Luxen, A., Franck, G., & Maquet, P. (1999) · NeuroImage · doi:10.1006/nimg.1998.0414 · Cited by 382 · see citing works
Mapping Cognition to the Brain Through Neural Interactions
McIntosh, A. R. (1999) · Memory · doi:10.1080/096582199387733 · Cited by 374 · see citing works
The neural basis of intermittent motor control in humans
Groß, J., Timmermann, L., Kujala, J., Dirks, M., Schmitz, F., Salmelin, R. H., & Schnitzler, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.032682099 · Cited by 374 · see citing works
Cerebral Metabolism during Propofol Anesthesia in Humans Studied with Positron Emission Tomography
Alkire, M. T., Haier, R. J., Barker, S. J., Shah, N. K., Wu, J. C., & Kao, J. Y. (1995) · Anesthesiology · doi:10.1097/00000542-199502000-00010 · Cited by 350 · see citing works
Self-citationGeneral Anesthetics Hyperpolarize Neurons in the Vertebrate Central Nervous System
Nicoll, R. A., & Madison, D. V. (1982) · Science · doi:10.1126/science.7112112 · Cited by 312 · see citing works
Kaisti, K. K., Metsähonkala, L., Teräs, M., Oikonen, V., Aalto, S., Jääskeläinen, S., Hinkka, S., & Scheinin, H. (2002) · Anesthesiology · doi:10.1097/00000542-200206000-00015 · Cited by 276 · see citing works
Invariant Reversible QEEG Effects of Anesthetics
John, E. R., Prichep, L. S., Kox, W., Valdés-Sosa, P., Bosch-Bayard, J., Aubert, E., Tom, M., diMichele, F., & Gugino, L. D. (2001) · Consciousness and Cognition · doi:10.1006/ccog.2001.0507 · Cited by 274 · see citing works
Llinás, R. R., Leznik, E., & Urbano, F. J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012604899 · Cited by 262 · see citing works
Contrasting Synaptic Actions of the Inhalational General Anesthetics Isoflurane and Xenon
de Sousa, S. L. M., Dickinson, R., Lieb, W. R., & Franks, N. P. (2000) · Anesthesiology · doi:10.1097/00000542-200004000-00024 · Cited by 244 · see citing works
Alkire, M. T. M., Haier, R. J. P., Shah, N. K. M., & Anderson, C. T. M. (1997) · Anesthesiology · doi:10.1097/00000542-199703000-00006 · Cited by 235 · see citing works
Self-citationAlkire, M. T., Pomfrett, C. J. D., Haier, R. J., Gianzero, M. V., Chan, C. M., Jacobsen, B. P., & Fallon, J. H. (1999) · Anesthesiology · doi:10.1097/00000542-199903000-00011 · Cited by 221 · see citing works
Self-citationA field theory of consciousness.
John, E. R. (2001) · Consciousness and Cognition · doi:10.1006/ccog.2001.0508 · Cited by 214 · see citing works
Edelman, S. (2008) · doi:10.1093/oso/9780195320671.003.0004 · Cited by 181 · see citing works
Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers
Alkire, M. T. (1998) · Anesthesiology · doi:10.1097/00000542-199808000-00007 · Cited by 177 · see citing works
Self-citationCENTRAL NEURONAL PATHWAYS AND THE PROCESS OF ANAESTHESIA
Angel, A. (1993) · British Journal of Anaesthesia · doi:10.1093/bja/71.1.148 · Cited by 167 · see citing works
(1993) · CogPrints (University of Southampton) · Cited by 161 · see citing works
Mechanism of Anesthesia Revealed by Shunting Actions of Isoflurane on Thalamocortical Neurons
Ries, C. R., & Puil, E. (1999) · Journal of Neurophysiology · doi:10.1152/jn.1999.81.4.1795 · Cited by 158 · see citing works
Laureys, S., Peigneux, P., Phillips, C. L. M., Fuchs, S., Degueldre, C., Aerts, J. J., Fiore, G. D., Petiau, C., Luxen, A., der Linden, M. V., et al. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00269-x · Cited by 155 · see citing works
COTTERILL, R. M. J. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00058-7 · Cited by 155 · see citing works
The Relevance of Sensory Input for the Cerebellar Control of Movements
Jueptner, M., Ottinger, S., Fellows, S. J., Adamschewski, J., Flerich, L., Müller, S. P., Diener, H., Thilmann, A. F., & Weiller, C. (1997) · NeuroImage · doi:10.1006/nimg.1996.0249 · Cited by 151 · see citing works
Co-Planar Stereotaxic Atlas of the Human Brain-3-Dimensional Proportional System
Talairach, J. (1988) · Medical Entomology and Zoology · Cited by 149 · see citing works
Midazolam Changes Cerebral Blood Flow in Discrete Brain Regions
Veselis, R. A., Reinsel, R. A., Beattie, B. J., Mawlawi, O. R., Feshchenko, V. A., DiResta, G. R., Larson, S. M., & Blasberg, R. G. (1997) · Anesthesiology · doi:10.1097/00000542-199711000-00015 · Cited by 141 · see citing works
Changes in Limbic and Prefrontal Functional Interactions in a Working Memory Task for Faces
McIntosh, A. R., Grady, C. L., Haxby, J. V., Ungerrleider, L. G., & Horwitz, B. (1996) · Cerebral Cortex · doi:10.1093/cercor/6.4.571 · Cited by 140 · see citing works
Ketamine-induced anesthesia involves the N-methyl-d-aspartate receptor-channel complex in mice
Irifune, M., Shimizu, T., Nomoto, M., & Fukuda, T. (1992) · Brain Research · doi:10.1016/0006-8993(92)91525-j · Cited by 137 · see citing works
Bonhomme, V. L., Fiset, P., Meuret, P., Backman, S. B., Plourde, G., Paus, T., Bushnell, M. C., & Evans, A. C. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.85.3.1299 · Cited by 121 · see citing works
Alkire, M. T., Haier, R. J., Fallon, J. H., & Cahill, L. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.24.14506 · Cited by 106 · see citing works
Self-citationVolatile anesthetics and glutamate activation of N-methyl-D-aspartate receptors
Martin, D. C., Plagenhoef, M. R., Abraham, J., Dennison, R. L., & Aronstam, R. S. (1995) · Biochemical Pharmacology · doi:10.1016/0006-2952(94)00519-r · Cited by 91 · see citing works
Thalamocortical Organization in the Cerebello-thalamo-cortical System
Shinoda, Y., Kakei, S., Futami, T., et al. (1993) · Cerebral Cortex · doi:10.1093/cercor/3.5.421 · Cited by 89 · see citing works
Depression of Thalamic Metabolism by Lorazepam Is Associated with Sleepiness
Volkow, N. D. (1995) · Neuropsychopharmacology · doi:10.1016/0893-133x(94)00068-b · Cited by 88 · see citing works
The G. L. Brown lecture. Adventures in anaesthesia
Angel, A. (1991) · Experimental Physiology · doi:10.1113/expphysiol.1991.sp003471 · Cited by 86 · see citing works
Nishikawa, K., Jenkins, A., Paraskevakis, I., & Harrison, N. L. (2002) · Neuropharmacology · doi:10.1016/s0028-3908(01)00189-7 · Cited by 79 · see citing works
Sleep oscillations and their blockage by activating systems.
Steriade, M. (1994) · PubMed Central · Cited by 73 · see citing works
Isoflurane hyperpolarizes neurones in rat and human cerebral cortex
Berg–Johnsen, J., & Langmoen, I. A. (1987) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1987.tb08192.x · Cited by 71 · see citing works
The human brain : in photographs and diagrams
Nolte, J., & Angevine, J. B. (2013) · Cited by 62 · see citing works
The Human Brain: in photographs and diagrams
Allen, C. H. (1995) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.59.3.345 · Cited by 55 · see citing works
The role of the NMDA synapse in general anesthesia
Flohr, H., Glade, U., & Motzko, D. (1998) · Toxicology Letters · doi:10.1016/s0378-4274(98)00161-1 · Cited by 49 · see citing works
Sugiyama, K., Muteki, T., & Shimoji, K. (1992) · Brain Research · doi:10.1016/0006-8993(92)90613-e · Cited by 46 · see citing works
Angel, A., & LeBeau, F. E. N. (1992) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(92)90273-m · Cited by 44 · see citing works
PET imaging of conscious and unconscious verbal memory
Alkire, M. T., Haier, R. J., Fallon, J. H., et al. (1996) · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Vanhaudenhuyse, A., Noirhomme, Q., Tshibanda, L. J.-F., Bruno, M.-A., Boveroux, P., Schnakers, C., Soddu, A., Perlbarg, V., Ledoux, D., Brichant, J.-F., et al. (2010) · Brain · doi:10.1093/brain/awp313 · Cited by 911 · see citing works
Boveroux, P., Vanhaudenhuyse, A., Bruno, M.-A., Noirhomme, Q., Lauwick, S., Luxen, A., Degueldre, C., Plenevaux, A., Schnakers, C., Phillips, C., et al. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181f697f5 · Cited by 630 · see citing works
Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness
Ferrarelli, F., Massimini, M., Sarasso, S., Casali, A., Riedner, B. A., Angelini, G., Tononi, G., & Pearce, R. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913008107 · Cited by 554 · see citing works
Williams, L. M., Das, P., Liddell, B. J., Kemp, A. H., Rennie, C. J., & Gordon, E. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1016-06.2006 · Cited by 232 · see citing works
“This method of assessing condition-dependent covariation has been used as an index of “functional connectivity” between these regions (White and Alkire, 2003).”
MethodNeurological phenotypes for Down syndrome across the life span
Lott, I. T. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-54299-1.00006-6 · Cited by 225 · see citing works
Slow-wave activity saturation and thalamocortical isolation during propofol anesthesia in humans
Ní Mhuircheartaigh, R., Warnaby, C., Rogers, R., Jbabdi, S., & Tracey, I. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006007 · Cited by 202 · see citing works
Imas, O. A., Ropella, K. M., Ward, B. D., Wood, J. D., & Hudetz, A. G. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.06.018 · Cited by 189 · see citing works
Akeju, O., Loggia, M. L., Catana, C., Pavone, K. J., Vazquez, R., Rhee, J., Contreras Ramirez, V., Chonde, D. B., Izquierdo-Garcia, D., Arabasz, G., et al. (2014) · eLife · doi:10.7554/elife.04499 · Cited by 168 · see citing works
Ranft, A., Golkowski, D., Kiel, T., Riedl, V., Kohl, P., Rohrer, G., Pientka, J., Berger, S., Thul, A., Maurer, M., et al. (2016) · Anesthesiology · doi:10.1097/aln.0000000000001322 · Cited by 142 · see citing works
The Biology of General Anesthesia from Paramecium to Primate
Kelz, M. B., & Mashour, G. A. (2019) · Current Biology · doi:10.1016/j.cub.2019.09.071 · Cited by 151 · see citing works
The Minimal Energetic Requirement of Sustained Awareness after Brain Injury
Stender, J., Mortensen, K. N., Thibaut, A., Darkner, S., Laureys, S., Gjedde, A., & Kupers, R. (2016) · Current Biology · doi:10.1016/j.cub.2016.04.024 · Cited by 131 · see citing works
Stender, J., Kupers, R., Rodell, A., Thibaut, A., Chatelle, C., Bruno, M.-A., Gejl, M., Bernard, C., Hustinx, R., Laureys, S., et al. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.169 · Cited by 133 · see citing works
Mashour, G. A., & Hudetz, A. G. (2017) · Frontiers in Neural Circuits · doi:10.3389/fncir.2017.00044 · Cited by 133 · see citing works
Anesthesia and the neurobiology of consciousness
Mashour, G. A. (2024) · Neuron · doi:10.1016/j.neuron.2024.03.002 · Cited by 127 · see citing works
The effects of anesthetics on brain activity and cognitive function
Heinke, W., & Koelsch, S. (2005) · Current Opinion in Anaesthesiology · doi:10.1097/01.aco.0000189879.67092.12 · Cited by 116 · see citing works
Mashour, G. A. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.09.009 · Cited by 92 · see citing works
Towards an integrative theory of consciousness: Part 1 (Neurobiological and cognitive models)
De Sousa, A. (2013) · Mens Sana Monographs · doi:10.4103/0973-1229.109335 · Cited by 33 · see citing works
- Authors
- White, N. S., & Alkire, M. T.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Alkire, Michael T
- ORCID
- White, Nathan S
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 19
- Issue
- 2
- Pages
- 402-411
- ISSN
- 1053-8119 (ISSN-L)
- OpenAlex
- W2017237202
- Cited by
- 223
- References
- 64
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 8 · 2023: 12 · 2022: 8 · 2021: 7 · 2020: 5 · 2019: 11 · 2018: 5 · 2017: 11 · 2016: 15 · 2015: 10 · 2014: 17 · 2013: 11 · 2012: 13
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- thalamocortical connections, thalamus, isoflurane, halothane, regional cerebral glucose utilization, psychophysiological interaction, effective connectivity, supplementary motor area, primary motor cortex, corticocortical connections, artificial neural networks
- MeSH terms
- Anesthesia, General, Blood Glucose, Brain Mapping, Cerebral Cortex, Computer Simulation, Dominance, Cerebral, Energy Metabolism, Halothane, Humans, Image Processing, Computer-Assisted, Isoflurane, Magnetic Resonance Imaging, Mathematical Computing, Nerve Net, Neural Pathways, Synaptic Transmission, Reference Values, Retrospective Studies, Thalamic Nuclei, Tomography, Emission-Computed, Unconsciousness, Wakefulness, Fluorodeoxyglucose F18
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
