[en] Patients surviving severe brain injury may regain consciousness without recovering their ability to understand, move and communicate. Recently, electrophysiological and neuroimaging approaches, employing simple sensory stimulations or verbal commands, have proven useful in detecting higher order processing and, in some cases, in establishing some degree of communication in brain-injured subjects with severe impairment of motor function. To complement these approaches, it would be useful to develop methods to detect recovery of consciousness in ways that do not depend on the integrity of sensory pathways or on the subject's ability to comprehend or carry out instructions. As suggested by theoretical and experimental work, a key requirement for consciousness is that multiple, specialized cortical areas can engage in rapid causal interactions (effective connectivity). Here, we employ transcranial magnetic stimulation together with high-density electroencephalography to evaluate effective connectivity at the bedside of severely brain injured, non-communicating subjects. In patients in a vegetative state, who were open-eyed, behaviourally awake but unresponsive, transcranial magnetic stimulation triggered a simple, local response indicating a breakdown of effective connectivity, similar to the one previously observed in unconscious sleeping or anaesthetized subjects. In contrast, in minimally conscious patients, who showed fluctuating signs of non-reflexive behaviour, transcranial magnetic stimulation invariably triggered complex activations that sequentially involved distant cortical areas ipsi- and contralateral to the site of stimulation, similar to activations we recorded in locked-in, conscious patients. Longitudinal measurements performed in patients who gradually recovered consciousness revealed that this clear-cut change in effective connectivity could occur at an early stage, before reliable communication was established with the subject and before the spontaneous electroencephalogram showed significant modifications. Measurements of effective connectivity by means of transcranial magnetic stimulation combined with electroencephalography can be performed at the bedside while by-passing subcortical afferent and efferent pathways, and without requiring active participation of subjects or language comprehension; hence, they offer an effective way to detect and track recovery of consciousness in brain-injured patients who are unable to exchange information with the external environment.
Disciplines :
Neurology Anesthesia & intensive care
Author, co-author :
Rosanova, Mario ✱
Gosseries, Olivia ✱; Université de Liège - ULiège > Centre de recherches du cyclotron
Casarotto, Silvia
Boly, Mélanie ; Coma Science Group, Centre de Recherches du Cyclotron, Université de Liège & Département de Neurologie, CHU Sart Tilman
Casali, Adenauer G.
Bruno, Marie-Aurélie ; Coma Science Group, Centre de Recherches du Cyclotron, Université de Liège & Département de Neurologie, CHU Sart Tilman
Mariotti, Maurizio
BOVEROUX, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > Anesthésie et réanimation
Tononi, Giulio
Laureys, Steven ; Coma Science Group, Centre de Recherches du Cyclotron, Université de Liège & Département de Neurologie, CHU Sart Tilman
Massimini, Marcello
✱ These authors have contributed equally to this work.
Language :
English
Title :
Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients.
Adams JH, Graham DI, Jennett B. The neuropathology of the vegetative state after an acute brain insult. Brain 2000; 123: 1327-38. (Pubitemid 30420934)
Akaishi R, Morishima Y, Rajeswaren VP, Aoki S, Sakai K. Stimulation of the frontal eye field reveals persistent effective connectivity after controlled behavior. J Neurosci 2010; 30: 4295-305.
Alkire MT, Hudetz AG, Tononi G. Consciousness and anesthesia. Science 2008; 322: 876-80.
Babiloni F, Babiloni C, Locche L, Cincotti F, Rossini PM, Carducci F. High-resolution electro-encephalogram: source estimates of Laplacian-transformed somatosensory-evoked potentials using a realistic subject head model constructed from magnetic resonance images. Med Biol Eng Comput 2000; 38: 512-9.
Bardin JC, Fins JJ, Katz DI, Hersh J, Heier LA, Tabelow K, et al. Dissociations between behavioural and functional magnetic resonance imaging-based evaluations of cognitive function after brain injury. Brain 2011; 134: 769-82.
Bekinschtein TA, Dehaene S, Rohaut B, Tadel F, Cohen L, Naccache L. Neural signature of the conscious processing of auditory regularities. Proc Natl Acad Sci USA 2009; 106: 1672-7.
Berg P, Scherg M. A fast method for forward computation of multipleshell spherical head models. Electroencephalogr Clin Neurophysiol 1994; 90: 58-64. (Pubitemid 24057709)
Boly M, Garrido MI, Gosseries O, Bruno MA, Boveroux P, Schnakers C, et al. Preserved feedforward but impaired top-down processes in the vegetative state. Science 2011; 332: 858-62.
Bonato C, Miniussi C, Rossini PM. Transcranial magnetic stimulation and cortical evoked potentials: a TMS/EEG co-registration study. Clin Neurophysiol 2006; 117: 1699-707. (Pubitemid 44160504)
Brefel-Courbon C, Payoux P, Ory F, Sommet A, Slaoui T, Raboyeau G, et al. Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy. Ann Neurol 2007; 62: 102-5. (Pubitemid 47240911)
Casali AG, Casarotto S, Rosanova M, Mariotti M, Massimini M. General indices to characterize the electrical response of the cerebral cortex to TMS. Neuroimage 2010; 49: 1459-68.
Casarotto S, Romero Lauro LJ, Bellina V, Casali AG, Rosanova M, Pigorini A, et al. EEG responses to TMS are sensitive to changes in the perturbation parameters and repeatable over time. PLoS One 2010; 5: e10281.
Daltrozzo J, Wioland N, Mutschler V, Kotchoubey B. Predicting coma and other low responsive patients outcome using event-related brain potentials: a meta-analysis. Clin Neurophysiol 2007; 118: 606-14. (Pubitemid 46205430)
Dehaene S, Changeux JP, Naccache L, Sackur J, Sergent C. Conscious, preconscious, and subliminal processing: a testable taxonomy. Trends Cogn Sci 2006; 10: 204-11. (Pubitemid 43674496)
Del Cul A, Baillet S, Dehaene S. Brain dynamics underlying the nonlinear threshold for access to consciousness. PLoS Biol 2007; 5: e260.
Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods 2004; 134: 9-21. (Pubitemid 38224183)
Duncan CC, Summers AC, Perla EJ, Coburn KL, Mirsky AF. Evaluation of traumatic brain injury: brain potentials in diagnosis, function, and prognosis. Int J Psychophysiol 2011; 82: 24-40.
Englot DJ, Yang L, Hamid H, Danielson N, Bai X, Marfeo A, et al. Impaired consciousness in temporal lobe seizures: role of cortical slow activity. Brain 2010; 133: 3764-77.
Faugeras F, Rohaut B, Weiss N, Bekinschtein TA, Galanaud D, Puybasset L, et al. Probing consciousness with event-related potentials in the vegetative state. Neurology 2011; 77: 264-8.
Fellinger R, Klimesch W, Schnakers C, Perrin F, Freunberger R, Gruber W, et al. Cognitive processes in disorders of consciousness as revealed by EEG time-frequency analyses. Clin Neurophysiol 2011; 122: 2177-84.
Fernandez-Espejo D, Bekinschtein T, Monti MM, Pickard JD, Junque C, Coleman MR, et al. Diffusion weighted imaging distinguishes the vegetative state from the minimally conscious state. Neuroimage 2011; 54: 103-12.
Ferrarelli F, Massimini M, Peterson MJ, Riedner BA, Lazar M, Murphy MJ, et al. Reduced evoked gamma oscillations in the frontal cortex in schizophrenia patients: a TMS/EEG study. Am J Psychiatry 2008; 165: 996-1005.
Ferrarelli F, Massimini M, Sarasso S, Casali A, Riedner BA, Angelini G, et al. Breakdown in cortical effective connectivity during midazolaminduced loss of consciousness. Proc Natl Acad Sci USA 2010; 107: 2681-6.
Fischer C, Luaute J, Adeleine P, Morlet D. Predictive value of sensory and cognitive evoked potentials for awakening from coma. Neurology 2004; 63: 669-73. (Pubitemid 39100823)
Fischer C, Luaute J, Morlet D. Event-related potentials (MMN and novelty P3) in permanent vegetative or minimally conscious states. Clin Neurophysiol 2010; 121: 1032-42.
Friston K. Beyond phrenology: what can neuroimaging tell us about distributed circuitry? Annu Rev Neurosci 2002; 25: 221-50. (Pubitemid 34748017)
Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, et al. The minimally conscious state: definition and diagnostic criteria. Neurology 2002; 58: 349-53. (Pubitemid 34150906)
Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 2004; 85: 2020-9. (Pubitemid 39593531)
Giacino JT, Schnakers C, Rodriguez-Moreno D, Kalmar K, Schiff N, Hirsch J. Behavioral assessment in patients with disorders of consciousness: gold standard or fool's gold? Prog Brain Res 2009; 177: 33-48.
Hamalainen MS, Ilmoniemi RJ. Interpreting magnetic fields of the brain: minimum norm estimates. Med Biol Eng Comput 1994; 32: 35-42. (Pubitemid 24083542)
Hauk O. Keep it simple: a case for using classical minimum norm estimation in the analysis of EEG and MEG data. Neuroimage 2004; 21: 1612-21. (Pubitemid 38446585)
Hobson JA, Pace-Schott EF, Stickgold R. Dreaming and the brain: toward a cognitive neuroscience of conscious states. Behav Brain Sci 2000; 23: 793-842. (Pubitemid 32717339)
Holler Y, Bergmann J, Kronbichler M, Crone JS, Schmid EV, Golaszewski S, et al. Preserved oscillatory response but lack of mismatch negativity in patients with disorders of consciousness. Clin Neurophysiol 2011; 122: 1744-54.
Ilmoniemi RJ, Virtanen J, Ruohonen J, Karhu J, Aronen HJ, Naatanen R, et al. Neuronal responses to magnetic stimulation reveal cortical reactivity and connectivity. Neuroreport 1997; 8: 3537-40. (Pubitemid 27497479)
Jennett B, Plum F. Persistent vegetative state after brain damage. A syndrome in search of a name. Lancet 1972; 1: 734-7.
Kahkonen S, Komssi S, Wilenius J, Ilmoniemi RJ. Prefrontal TMS produces smaller EEG responses than motor-cortex TMS: implications for rTMS treatment in depression. Psychopharmacol 2005a; 181: 16-20. (Pubitemid 41440912)
Kinney HC, Samuels MA. Neuropathology of the persistent vegetative state. A review. J Neuropathol Exp Neurol 1994; 53: 548-58. (Pubitemid 24333014)
Komssi S, Huttunen J, Aronen HJ, Ilmoniemi RJ. EEG minimum-norm estimation compared with MEG dipole fitting in the localization of somatosensory sources at S1. Clin Neurophysiol 2004a; 115: 534-42. (Pubitemid 38230979)
Komssi S, Kahkonen S, Ilmoniemi RJ. The effect of stimulus intensity on brain responses evoked by transcranial magnetic stimulation. Hum Brain Mapp 2004b; 21: 154-64. (Pubitemid 38295899)
Komssi S, Savolainen P, Heiskala J, Kahkonen S. Excitation threshold of the motor cortex estimated with transcranial magnetic stimulation electroencephalography. Neuroreport 2007; 18: 13-6. (Pubitemid 46183382)
Kotchoubey B, Lang S, Mezger G, Schmalohr D, Schneck M, Semmler A, et al. Information processing in severe disorders of consciousness: vegetative state and minimally conscious state. Clin Neurophysiol 2005; 116: 2441-53. (Pubitemid 41265973)
Landsness E, Bruno MA, Noirhomme Q, Riedner B, Gosseries O, Schnakers C, et al. Electrophysiological correlates of behavioural changes in vigilance in vegetative state and minimally conscious state. Brain 2011; 134: 2222-32.
Laureys S. The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci 2005; 9: 556-9. (Pubitemid 41677486)
Laureys S, Owen AM, Schiff ND. Brain function in coma, vegetative state, and related disorders. Lancet Neurol 2004; 3: 537-46. (Pubitemid 39485860)
Lee L, Harrison LM, Mechelli A. A report of the functional connectivity workshop, Dusseldorf 2002. Neuroimage 2003; 19: 457-65.
Lehmann D, Skrandies W. Reference-free identification of components of checkerboard-evoked multichannel potential fields. Electroencephalogr Clin Neurophysiol 1980; 48: 609-21. (Pubitemid 10091391)
Litvak V, Komssi S, Scherg M, Hoechstetter K, Classen J, Zaaroor M, et al. Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex. Neuroimage 2007; 37: 56-70. (Pubitemid 47068999)
Luaute J, Maucort-Boulch D, Tell L, Quelard F, Sarraf T, Iwaz J, et al. Long-term outcomes of chronic minimally conscious and vegetative states. Neurology 2010; 75: 246-52.
Lv J, Simpson DM, Bell SL. Objective detection of evoked potentials using a bootstrap technique. Med Eng Phys 2007; 29: 191-8. (Pubitemid 44827825)
Maandag NJ, Coman D, Sanganahalli BG, Herman P, Smith AJ, Blumenfeld H, et al. Energetics of neuronal signaling and fMRI activity. Proc Natl Acad Sci USA 2007; 104: 20546-51.
Majerus S, Bruno MA, Schnakers C, Giacino JT, Laureys S. The problem of aphasia in the assessment of consciousness in brain-damaged patients. Prog Brain Res 2009; 177: 49-61.
Majerus S, Gill-Thwaites H, Andrews K, Laureys S. Behavioral evaluation of consciousness in severe brain damage. Prog Brain Res 2005; 150: 397-413. (Pubitemid 41381566)
Markowitsch HJ, Kessler J. Massive impairment in executive functions with partial preservation of other cognitive functions: the case of a young patient with severe degeneration of the prefrontal cortex. Exp Brain Res 2000; 133: 94-102. (Pubitemid 30411661)
Massimini M, Boly M, Casali A, Rosanova M, Tononi G. A perturbational approach for evaluating the brain's capacity for consciousness. Prog Brain Res 2009a; 177: 201-14.
Massimini M, Ferrarelli F, Esser SK, Riedner BA, Huber R, Murphy M, et al. Triggering sleep slow waves by transcranial magnetic stimulation. Proc Natl Acad Sci USA 2007; 104: 8496-501. (Pubitemid 47175516)
Massimini M, Ferrarelli F, Huber R, Esser SK, Singh H, Tononi G. Breakdown of cortical effective connectivity during sleep. Science 2005; 309: 2228-32. (Pubitemid 41396075)
Massimini M, Ferrarelli F, Murphy M, Huber R, Riedner B, Casarotto S, et al. Cortical reactivity and effective connectivity during REM sleep in humans. Cogn Neurosci 2010; 1: 176-83.
Massimini M, Tononi G, Huber R. Slow waves, synaptic plasticity and information processing: insights from transcranial magnetic stimulation and high-density EEG experiments. Eur J Neurosci 2009b; 29: 1761-70.
Mataro M, Jurado MA, Garcia-Sanchez C, Barraquer L, Costa-Jussa FR, Junque C. Long-term effects of bilateral frontal brain lesion: 60 years after injury with an iron bar. Arch Neurol 2001; 58: 1139-42. (Pubitemid 32660778)
McCubbin J, Yee T, Vrba J, Robinson SE, Murphy P, Eswaran H, et al. Bootstrap significance of low SNR evoked response. J Neurosci Methods 2008; 168: 265-72.
Monti MM, Laureys S, Owen AM. The vegetative state. BMJ 2010b; 341: c3765.
Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pickard JD, Tshibanda L, et al. Willful modulation of brain activity in disorders of consciousness. N Engl J Med 2010a; 362: 579-89.
Morishima Y, Akaishi R, Yamada Y, Okuda J, Toma K, Sakai K. Task-specific signal transmission from prefrontal cortex in visual selective attention. Nat Neurosci 2009; 12: 85-91.
Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness in the vegetative state. Science 2006; 313: 1402. (Pubitemid 44360261)
Paus T. Inferring causality in brain images: a perturbation approach. Philos Trans R Soc Lond B Biol Sci 2005; 360: 1109-14. (Pubitemid 41672868)
Rosanova M, Casali A, Bellina V, Resta F, Mariotti M, Massimini M. Natural frequencies of human corticothalamic circuits. J Neurosci 2009; 29: 7679-85.
Royal College of Physicians. Medical aspects of the persistent vegetative state (1). The Multi-Society Task Force on PVS. N Engl J Med 1994; 330: 1499-508.
Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends Neurosci 2010; 33: 1-9.
Schiff ND, Giacino JT, Kalmar K, Victor JD, Baker K, Gerber M, et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 2007; 448: 600-3. (Pubitemid 47206940)
Schiff ND, Ribary U, Moreno DR, Beattie B, Kronberg E, Blasberg R, et al. Residual cerebral activity and behavioural fragments can remain in the persistently vegetative brain. Brain 2002; 125: 1210-34. (Pubitemid 34587132)
Schnakers C, Perrin F, Schabus M, Hustinx R, Majerus S, Moonen G, et al. Detecting consciousness in a total locked-in syndrome: an active event-related paradigm. Neurocase 2009; 15: 271-7.
Schnakers C, Perrin F, Schabus M, Majerus S, Ledoux D, Damas P, et al. Voluntary brain processing in disorders of consciousness. Neurology 2008; 71: 1614-20.
Seth AK, Dienes Z, Cleeremans A, Overgaard M, Pessoa L. Measuring consciousness: relating behavioural and neurophysiological approaches. Trends Cogn Sci 2008; 12: 314-21.
Shah SA, Schiff ND. Central thalamic deep brain stimulation for cognitive neuromodulation-a review of proposed mechanisms and investigational studies. Eur J Neurosci 2010; 32: 1135-44.
Shulman RG, Hyder F, Rothman DL. Baseline brain energy supports the state of consciousness. Proc Natl Acad Sci USA 2009; 106: 11096-101.
Silva C, Maltez JC, Trindade E, Arriaga A, Ducla-Soares E. Evaluation of L1 and L2 minimum norm performances on EEG localizations. Clin Neurophysiol 2004; 115: 1657-68. (Pubitemid 38760312)
Tononi G. An information integration theory of consciousness. BMC Neurosci 2004; 5: 42.
Tononi G, Koch C. The neural correlates of consciousness: an update. Ann N Y Acad Sci 2008; 1124: 239-61. (Pubitemid 351506781)
Virtanen J, Ruohonen J, Naatanen R, Ilmoniemi RJ. Instrumentation for the measurement of electric brain responses to transcranial magnetic stimulation. Med Biol Eng Comput 1999; 37: 322-6. (Pubitemid 29265294)
Wagner T, Valero-Cabre A, Pascual-Leone A. Noninvasive human brain stimulation. Annu Rev Biomed Eng 2007; 9: 527-65. (Pubitemid 350246667)
Wijnen VJ, van Boxtel GJ, Eilander HJ, de Gelder B. Mismatch negativity predicts recovery from the vegetative state. Clin Neurophysiol 2007; 118: 597-605. (Pubitemid 46210195)