Consciousness has two main components: wakefulness and awareness. The vegetative state is characterized by wakefulness without awareness. Recent functional neuroimaging results have shown that some ...parts of the cortex are still functioning in ‘vegetative’ patients. External stimulation, such as a painful stimulus, still activates ‘primary’ sensory cortices in these patients but these areas are functionally disconnected from ‘higher order’ associative areas needed for awareness. Such studies are disentangling the neural correlates of the vegetative state from the minimally conscious state, and have major clinical consequences in addition to empirical importance for the understanding of consciousness.
Summary Background Bedside clinical examinations can have high rates of misdiagnosis of unresponsive wakefulness syndrome (vegetative state) or minimally conscious state. The diagnostic and ...prognostic usefulness of neuroimaging-based approaches has not been established in a clinical setting. We did a validation study of two neuroimaging-based diagnostic methods: PET imaging and functional MRI (fMRI). Methods For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale–Revised (CRS–R), cerebral18 F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS–R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale–Extended. Findings We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute).18 F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85–98) and high congruence (85%, 77–90) with behavioural CRS–R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30–61) and had lower overall congruence with behavioural scores (63%, 51–73) than PET imaging.18 F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64–81), and fMRI in 36 of 65 patients (56%, 43–67). 13 of 41 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS–R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness. Interpretation Cerebral18 F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate. Funding The Belgian National Funds for Scientific Research (FNRS), Fonds Léon Fredericq, the European Commission, the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action, the University of Copenhagen, and the University of Liège.
Summary Background 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. Methods 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 and18 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. Findings 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). Interpretation 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. Funding 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).
The concept of consciousness continues to defy definition and elude the grasp of philosophical and scientific efforts to formulate a testable construct that maps to human experience. Severe acquired ...brain injury results in the dissolution of consciousness, providing a natural model from which key insights about consciousness may be drawn. In the clinical setting, neurologists and neurorehabilitation specialists are called on to discern the level of consciousness in patients who are unable to communicate through word or gesture, and to project outcomes and recommend approaches to treatment. Standards of care are not available to guide clinical decision-making for this population, often leading to inconsistent, inaccurate and inappropriate care. In this Review, we describe the state of the science with regard to clinical management of patients with prolonged disorders of consciousness. We review consciousness-altering pathophysiological mechanisms, specific clinical syndromes, and novel diagnostic and prognostic applications of advanced neuroimaging and electrophysiological procedures. We conclude with a provocative discussion of bioethical and medicolegal issues that are unique to this population and have a profound impact on care, as well as raising questions of broad societal interest.
Significant advances have been made in the behavioral assessment and clinical management of disorders of consciousness (DOC). In addition, functional neuroimaging paradigms are now available to help ...assess consciousness levels in this challenging patient population. The success of these neuroimaging approaches as diagnostic markers is, however, intrinsically linked to understanding the relationships between consciousness and the brain. In this context, a combined theoretical approach to neuroimaging studies is needed. The promise of such theoretically based markers is illustrated by recent findings that used a perturbational approach to assess the levels of consciousness. Further research on the contents of consciousness in DOC is also needed.
Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions ...between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct 'flavours' of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia.
Previously published studies have reported that up to 43% of patients with disorders of consciousness are erroneously assigned a diagnosis of vegetative state (VS). However, no recent studies have ...investigated the accuracy of this grave clinical diagnosis. In this study, we compared consensus-based diagnoses of VS and MCS to those based on a well-established standardized neurobehavioral rating scale, the JFK Coma Recovery Scale-Revised (CRS-R).
We prospectively followed 103 patients (55 +/- 19 years) with mixed etiologies and compared the clinical consensus diagnosis provided by the physician on the basis of the medical staff's daily observations to diagnoses derived from CRS-R assessments performed by research staff. All patients were assigned a diagnosis of 'VS', 'MCS' or 'uncertain diagnosis.'
Of the 44 patients diagnosed with VS based on the clinical consensus of the medical team, 18 (41%) were found to be in MCS following standardized assessment with the CRS-R. In the 41 patients with a consensus diagnosis of MCS, 4 (10%) had emerged from MCS, according to the CRS-R. We also found that the majority of patients assigned an uncertain diagnosis by clinical consensus (89%) were in MCS based on CRS-R findings.
Despite the importance of diagnostic accuracy, the rate of misdiagnosis of VS has not substantially changed in the past 15 years. Standardized neurobehavioral assessment is a more sensitive means of establishing differential diagnosis in patients with disorders of consciousness when compared to diagnoses determined by clinical consensus.
Despite the absence of responsiveness during anesthesia, conscious experience may persist. However, reliable, easily acquirable and interpretable neurophysiological markers of the presence of ...consciousness in unresponsive states are still missing. A promising marker is based on the decay-rate of the power spectral density (PSD) of the resting EEG.
We acquired resting electroencephalogram (EEG) in three groups of healthy participants (n = 5 each), before and during anesthesia induced by either xenon, propofol or ketamine. Dosage of each anesthetic agent was tailored to yield unresponsiveness (Ramsay score = 6). Delayed subjective reports assessed whether conscious experience was present (‘Conscious report’) or absent/inaccessible to recall (‘No Report’). We estimated the decay of the PSD of the resting EEG—after removing oscillatory peaks—via the spectral exponent β, for a broad band (1–40 Hz) and narrower sub-bands (1–20 Hz, 20–40 Hz). Within-subject anesthetic changes in β were assessed. Furthermore, based on β, ‘Conscious report’ states were discriminated against ‘no report’ states. Finally, we evaluated the correlation of the resting spectral exponent with a recently proposed index of consciousness, the Perturbational Complexity Index (PCI), derived from a previous TMS-EEG study.
The spectral exponent of the resting EEG discriminated states in which consciousness was present (wakefulness, ketamine) from states where consciousness was reduced or abolished (xenon, propofol). Loss of consciousness substantially decreased the (negative) broad-band spectral exponent in each subject undergoing xenon or propofol anesthesia—indexing an overall steeper PSD decay. Conversely, ketamine displayed an overall PSD decay similar to that of wakefulness—consistent with the preservation of consciousness—yet it showed a flattening of the decay in the high-frequencies (20–40 Hz)—consistent with its specific mechanism of action. The spectral exponent was highly correlated to PCI, corroborating its interpretation as a marker of the presence of consciousness. A steeper PSD of the resting EEG reliably indexed unconsciousness in anesthesia, beyond sheer unresponsiveness.
•Unconsciousness does not imply unresponsiveness.•Consciousness is abolished during xenon and propofol, yet preserved during ketamine.•EEG Spectral exponent indexes the 1/f-like decay of non-oscillatory PSD background.•Xenon and propofol steepen broad-band decay; ketamine flattens high-frequency decay.•Spectral exponent separates un/consciousness in anesthesia-induced unresponsiveness.
One challenging aspect of the clinical assessment of brain-injured, unresponsive patients is the lack of an objective measure of consciousness that is independent of the subject's ability to interact ...with the external environment. Theoretical considerations suggest that consciousness depends on the brain's ability to support complex activity patterns that are, at once, distributed among interacting cortical areas (integrated) and differentiated in space and time (information-rich). We introduce and test a theory-driven index of the level of consciousness called the perturbational complexity index (PCI). PCI is calculated by (i) perturbing the cortex with transcranial magnetic stimulation (TMS) to engage distributed interactions in the brain (integration) and (ii) compressing the spatiotemporal pattern of these electrocortical responses to measure their algorithmic complexity (information). We test PCI on a large data set of TMS-evoked potentials recorded in healthy subjects during wakefulness, dreaming, nonrapid eye movement sleep, and different levels of sedation induced by anesthetic agents (midazolam, xenon, and propofol), as well as in patients who had emerged from coma (vegetative state, minimally conscious state, and locked-in syndrome). PCI reliably discriminated the level of consciousness in single individuals during wakefulness, sleep, and anesthesia, as well as in patients who had emerged from coma and recovered a minimal level of consciousness. PCI can potentially be used for objective determination of the level of consciousness at the bedside.
A common endpoint of general anesthetics is behavioral unresponsiveness 1, which is commonly associated with loss of consciousness. However, subjects can become disconnected from the environment ...while still having conscious experiences, as demonstrated by sleep states associated with dreaming 2. Among anesthetics, ketamine is remarkable 3 in that it induces profound unresponsiveness, but subjects often report “ketamine dreams” upon emergence from anesthesia 4–9. Here, we aimed at assessing consciousness during anesthesia with propofol, xenon, and ketamine, independent of behavioral responsiveness. To do so, in 18 healthy volunteers, we measured the complexity of the cortical response to transcranial magnetic stimulation (TMS)—an approach that has proven helpful in assessing objectively the level of consciousness irrespective of sensory processing and motor responses 10. In addition, upon emergence from anesthesia, we collected reports about conscious experiences during unresponsiveness. Both frontal and parietal TMS elicited a low-amplitude electroencephalographic (EEG) slow wave corresponding to a local pattern of cortical activation with low complexity during propofol anesthesia, a high-amplitude EEG slow wave corresponding to a global, stereotypical pattern of cortical activation with low complexity during xenon anesthesia, and a wakefulness-like, complex spatiotemporal activation pattern during ketamine anesthesia. Crucially, participants reported no conscious experience after emergence from propofol and xenon anesthesia, whereas after ketamine they reported long, vivid dreams unrelated to the external environment. These results are relevant because they suggest that brain complexity may be sensitive to the presence of disconnected consciousness in subjects who are considered unconscious based on behavioral responses.
•The perturbational complexity index (PCI) in propofol and xenon anesthesia is low•Both these anesthetics are associated with the lack of post-anesthesia reports•Ketamine is associated with high PCI and by vivid post-anesthesia dream reports•PCI may index the presence of disconnected consciousness during unresponsiveness
Sarasso, Boly, et al. show that the complexity of the cortical response to TMS is low during propofol and xenon anesthesia but high during ketamine. Crucially, no reports are obtained upon awakening from both propofol and xenon while after ketamine, all subjects report long, vivid dreams, possibly indicating a state of disconnected consciousness.
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