title: Neural correlates of consciousness in patients who have emerged from a minimally conscious state: a cross-sectional multimodal imaging study.
abstract: Between pathologically impaired consciousness and normal consciousness exists a scarcely researched transition zone, referred to as emergence from minimally conscious state, in which patients regain the capacity for functional communication, object use, or both. We investigated neural correlates of consciousness in these patients compared with patients with disorders of consciousness and healthy controls, by multimodal imaging.
  
  
  
  In this cross-sectional, multimodal imaging study, patients with unresponsive wakefulness syndrome, patients in a minimally conscious state, and patients who had emerged from a minimally conscious state, diagnosed with the Coma Recovery Scale-Revised, were recruited from the neurology department of the Centre Hospitalier Universitaire de Liège, Belgium. Key exclusion criteria were neuroimaging examination in an acute state, sedation or anaesthesia during scanning, large focal brain damage, motion parameters of more than 3 mm in translation and 3° in rotation, and suboptimal segmentation and normalisation. We acquired resting state functional and structural MRI data and (18)F-fluorodeoxyglucose (FDG) PET data; we used seed-based functional MRI (fMRI) analysis to investigate positive default mode network connectivity (within-network correlations) and negative default mode network connectivity (between-network anticorrelations). We correlated FDG-PET brain metabolism with fMRI connectivity. We used voxel-based morphometry to test the effect of anatomical deformations on functional connectivity.
  
  
  
  We recruited a convenience sample of 58 patients (21 [36%] with unresponsive wakefulness syndrome, 24 [41%] in a minimally conscious state, and 13 [22%] who had emerged from a minimally conscious state) and 35 healthy controls between Oct 1, 2009, and Oct 31, 2014. We detected consciousness-level-dependent increases (from unresponsive wakefulness syndrome, minimally conscious state, emergence from minimally conscious state, to healthy controls) for positive and negative default mode network connectivity, brain metabolism, and grey matter volume (p<0·05 false discovery rate corrected for multiple comparisons). Positive default mode network connectivity differed between patients and controls but not among patient groups (F test p<0·0001). Negative default mode network connectivity was only detected in healthy controls and in those who had emerged from a minimally conscious state; patients with unresponsive wakefulness syndrome or in a minimally conscious state showed pathological between-network positive connectivity (hyperconnectivity; F test p<0·0001). Brain metabolism correlated with positive default mode network connectivity (Spearman's r=0·50 [95% CI 0·26 to 0·61]; p<0·0001) and negative default mode network connectivity (Spearman's r=-0·52 [-0·35 to -0·67); p<0·0001). Grey matter volume did not differ between the studied groups (F test p=0·06).
  
  
  
  Partial preservation of between-network anticorrelations, which are seemingly of neuronal origin and cannot be solely explained by morphological deformations, characterise patients who have emerged from a minimally conscious state. Conversely, patients with disorders of consciousness show pathological between-network correlations. Apart from a deeper understanding of the neural correlates of consciousness, these findings have clinical implications and might be particularly relevant for outcome prediction and could inspire new therapeutic options.
  
  
  
  Belgian National Funds for Scientific Research (FNRS), European Commission, Natural Sciences and Engineering Research Council of Canada, James McDonnell Foundation, European Space Agency, Mind Science Foundation, French Speaking Community Concerted Research Action, Fondazione Europea di Ricerca Biomedica, University and University Hospital of Liège (Liège, Belgium), and University of Western Ontario (London, ON, Canada).
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium. Electronic address: diperric@gmail.com.
authors.forename: Carol
authors.initials: C
authors.lastname: Di Perri
authors.affiliation: GIGA-Cyclotron Research Centre: In Vivo Imaging, Université de Liège, Liège, Belgium.
authors.forename: Mohamed Ali
authors.initials: MA
authors.lastname: Bahri
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Amico
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Aurore
authors.initials: A
authors.lastname: Thibaut
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Lizette
authors.initials: L
authors.lastname: Heine
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Georgios
authors.initials: G
authors.lastname: Antonopoulos
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Charland-Verville
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wannez
authors.affiliation: Department of Mathematics, Universidad Nacional de Colombia sede Bogotá, Bogotá, Colombia.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gomez
authors.affiliation: Nuclear Medicine Department, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Roland
authors.initials: R
authors.lastname: Hustinx
authors.affiliation: Department of Neuroradiology, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Luaba
authors.initials: L
authors.lastname: Tshibanda
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium; Institut du Cerveau et de la Moelle épinière-ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Athena
authors.initials: A
authors.lastname: Demertzi
authors.affiliation: Brain and Mind Institute, Department of Physics and Astronomy, University of Western Ontario, London, ON, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Soddu
authors.affiliation: Coma Science Group, GIGA Research, Université et Centre Hospitalier Universitaire de Liège, Liège, Belgium. Electronic address: steven.laureys@ulg.ac.be.
authors.forename: Steven
authors.initials: S
authors.lastname: Laureys
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001931:Brain Mapping; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D003243:Consciousness / Q000502:physiology*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D016239:MEDLINE / Q000706:statistics & numerical data; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016571:Neural Networks, Computer; D010100:Oxygen / Q000097:blood; D018458:Persistent Vegetative State / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D049268:Positron-Emission Tomography; D055815:Young Adult
chemical_list: D019788:Fluorodeoxyglucose F18; D010100:Oxygen