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      Stratification of unresponsive patients by an independently validated index of brain complexity

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          Abstract

          Objective

          Validating objective, brain‐based indices of consciousness in behaviorally unresponsive patients represents a challenge due to the impossibility of obtaining independent evidence through subjective reports. Here we address this problem by first validating a promising metric of consciousness—the Perturbational Complexity Index (PCI)—in a benchmark population who could confirm the presence or absence of consciousness through subjective reports, and then applying the same index to patients with disorders of consciousness (DOCs).

          Methods

          The benchmark population encompassed 150 healthy controls and communicative brain‐injured subjects in various states of conscious wakefulness, disconnected consciousness, and unconsciousness. Receiver operating characteristic curve analysis was performed to define an optimal cutoff for discriminating between the conscious and unconscious conditions. This cutoff was then applied to a cohort of noncommunicative DOC patients (38 in a minimally conscious state [MCS] and 43 in a vegetative state [VS]).

          Results

          We found an empirical cutoff that discriminated with 100% sensitivity and specificity between the conscious and the unconscious conditions in the benchmark population. This cutoff resulted in a sensitivity of 94.7% in detecting MCS and allowed the identification of a number of unresponsive VS patients (9 of 43) with high values of PCI, overlapping with the distribution of the benchmark conscious condition.

          Interpretation

          Given its high sensitivity and specificity in the benchmark and MCS population, PCI offers a reliable, independently validated stratification of unresponsive patients that has important physiopathological and therapeutic implications. In particular, the high‐PCI subgroup of VS patients may retain a capacity for consciousness that is not expressed in behavior. Ann Neurol 2016;80:718–729

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          Most cited references39

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          Neural correlates of consciousness: progress and problems.

          There have been a number of advances in the search for the neural correlates of consciousness--the minimum neural mechanisms sufficient for any one specific conscious percept. In this Review, we describe recent findings showing that the anatomical neural correlates of consciousness are primarily localized to a posterior cortical hot zone that includes sensory areas, rather than to a fronto-parietal network involved in task monitoring and reporting. We also discuss some candidate neurophysiological markers of consciousness that have proved illusory, and measures of differentiation and integration of neural activity that offer more promising quantitative indices of consciousness.
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            The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility.

            To determine the measurement properties and diagnostic utility of the JFK Coma Recovery Scale-Revised (CRS-R). Analysis of interrater and test-retest reliability, internal consistency, concurrent validity, and diagnostic accuracy. Acute inpatient brain injury rehabilitation hospital. Convenience sample of 80 patients with severe acquired brain injury admitted to an inpatient Coma Intervention Program with a diagnosis of either vegetative state (VS) or minimally conscious state (MCS). Not applicable. The CRS-R, the JFK Coma Recovery Scale (CRS), and the Disability Rating Scale (DRS). Interrater and test-retest reliability were high for CRS-R total scores. Subscale analysis showed moderate to high interrater and test-retest agreement although systematic differences in scoring were noted on the visual and oromotor/verbal subscales. CRS-R total scores correlated significantly with total scores on the CRS and DRS indicating acceptable concurrent validity. The CRS-R was able to distinguish 10 patients in an MCS who were otherwise misclassified as in a VS by the DRS. The CRS-R can be administered reliably by trained examiners and repeated measurements yield stable estimates of patient status. CRS-R subscale scores demonstrated good agreement across raters and ratings but should be used cautiously because some scores were underrepresented in the current study. The CRS-R appears capable of differentiating patients in an MCS from those in a VS.
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              Willful modulation of brain activity in disorders of consciousness.

              The differential diagnosis of disorders of consciousness is challenging. The rate of misdiagnosis is approximately 40%, and new methods are required to complement bedside testing, particularly if the patient's capacity to show behavioral signs of awareness is diminished. At two major referral centers in Cambridge, United Kingdom, and Liege, Belgium, we performed a study involving 54 patients with disorders of consciousness. We used functional magnetic resonance imaging (MRI) to assess each patient's ability to generate willful, neuroanatomically specific, blood-oxygenation-level-dependent responses during two established mental-imagery tasks. A technique was then developed to determine whether such tasks could be used to communicate yes-or-no answers to simple questions. Of the 54 patients enrolled in the study, 5 were able to willfully modulate their brain activity. In three of these patients, additional bedside testing revealed some sign of awareness, but in the other two patients, no voluntary behavior could be detected by means of clinical assessment. One patient was able to use our technique to answer yes or no to questions during functional MRI; however, it remained impossible to establish any form of communication at the bedside. These results show that a small proportion of patients in a vegetative or minimally conscious state have brain activation reflecting some awareness and cognition. Careful clinical examination will result in reclassification of the state of consciousness in some of these patients. This technique may be useful in establishing basic communication with patients who appear to be unresponsive. 2010 Massachusetts Medical Society
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                Author and article information

                Contributors
                marcello.massimini@unimi.it
                Journal
                Ann Neurol
                Ann. Neurol
                10.1002/(ISSN)1531-8249
                ANA
                Annals of Neurology
                John Wiley and Sons Inc. (Hoboken )
                0364-5134
                1531-8249
                02 November 2016
                November 2016
                : 80
                : 5 ( doiID: 10.1002/ana.v80.5 )
                : 718-729
                Affiliations
                [ 1 ] Department of Biomedical and Clinical Sciences “L. Sacco”University of Milan MilanItaly
                [ 2 ]Fondazione Europea per la Ricerca Biomedica MilanItaly
                [ 3 ] Department of Health Science, School of Medicine and SurgeryUniversity of Milan‐Bicocca MonzaItaly
                [ 4 ] Institute of Science and TechnologyFederal University of São Paulo São José dos CamposBrazil
                [ 5 ]Istituto di Ricovero e Cura a Carattere Scientifico, Fondazione Don Gnocchi Onlus MilanItaly
                [ 6 ] Department of PsychiatryUniversity of Wisconsin Madison WI, USA
                [ 7 ] Department of NeurologyUniversity of Wisconsin Madison WI, USA
                [ 8 ] Coma Science Group, GIGAUniversity of Liège LiègeBelgium
                [ 9 ] Department of NeurologyUniversity of Liège and University Hospital of Liège LiègeBelgium
                [ 10 ]Neurocritical Care Unit, Department of Neuroscience, Azienda Socio‐Sanitaria Territoriale, Grande Ospedale Metropolitano Niguarda Cà Granda MilanItaly
                Author notes
                [*] [* ]Address correspondence to Dr Massimini, Department of Biomedical and Clinical Sciences “L. Sacco,” University of Milan, via GB Grassi 74, 20157 Milan, Italy. E‐mail: marcello.massimini@ 123456unimi.it
                Author information
                http://orcid.org/0000-0002-7548-7664
                Article
                ANA24779
                10.1002/ana.24779
                5132045
                27717082
                48a455f3-e72c-4d23-8ab9-811a6c9a6e36
                © 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 05 April 2016
                : 12 September 2016
                : 13 September 2016
                Page count
                Figures: 4, Tables: 1, Pages: 12, Words: 7212
                Funding
                Funded by: Prin 2010 “Connage”
                Funded by: European Union (EU)
                Award ID: FP7‐ICT‐2011‐9 n. 600806
                Funded by: James S. McDonnell Foundation
                Funded by: EU
                Award ID: H2020‐FETOPEN‐2014‐2015‐RIA
                Funded by: EU
                Award ID: H2020
                Funded by: Belgian National Fund for Scientific Research (O.G.)
                Funded by: Templeton World Charity Foundation
                Funded by: McDonnell Foundation
                Funded by: Distinguished Chair in Consciousness Science at the University of Wisconsin
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                ana24779
                November 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:01.12.2016

                Neurology
                Neurology

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