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1.  Measuring consciousness in coma and related states 
World Journal of Radiology  2014;6(8):589-597.
Consciousness is a prismatic and ambiguous concept that still eludes any universal definition. Severe acquired brain injuries resulting in a disorder of consciousness (DOC) provide a model from which insights into consciousness can be drawn. A number of recent studies highlight the difficulty in making a diagnosis in patients with DOC based only on behavioral assessments. Here we aim to provide an overview of how neuroimaging techniques can help assess patients with DOC. Such techniques are expected to facilitate a more accurate understanding of brain function in states of unconsciousness and to improve the evaluation of the patient’s cognitive abilities by providing both diagnostic and prognostic indicators.
doi:10.4329/wjr.v6.i8.589
PMCID: PMC4147439  PMID: 25170396
Disorders of consciousness; Neuroimaging; Magnetic resonance imaging; Transcranial magnetic stimulation/electroencephalography; Minimally conscious state; Vegetative state/unresponsive wakefulness syndrome
2.  Assessment of visual fixation in vegetative and minimally conscious states 
BMC Neurology  2014;14:147.
Background
Visual fixation plays a key role in the differentiation between vegetative state/unresponsive wakefulness (VS/UWS) syndrome and minimally conscious state (MCS). However, the use of different stimuli changes the frequency of visual fixation occured in patients, thereby possibly affecting the accuracy of the diagnosis. In order to establish a standardized assessment of visual fixation in patients in disorders of consciousness (DOC), we compared the frequency of visual fixation elicited by mirror,a ball and a light.
Method
Visual fixation was assessed in eighty-one post-comatose patients diagnosed with a MCS or VS/UWS. Occurrence of fixation to different stimuli was analysis used Chi-square testing.
Result
40 (49%) out of the 81 patients showed fixation to visual stimuli. Among those, significantly more patients (39, 48%) had visual fixation elicited by mirror compared to a ball (23, 28%) and mirror compared to a light (20, 25%).
Conclusion
The use of a mirror during the assessment of visual fixation showed higher positive response rate, compared to other stimuli in eliciting a visual fixating response. Therefore, fixation elicited by a mirror can be a very sensitive and accurate test to differentiate the two disorders of consciousness.
doi:10.1186/1471-2377-14-147
PMCID: PMC4112970  PMID: 25027769
Disorders of consciousness; Vegetative state; Unresponsive wakefulness syndrome; Minimally conscious state; Visual fixation
3.  Posterior Cingulate Cortex-Related Co-Activation Patterns: A Resting State fMRI Study in Propofol-Induced Loss of Consciousness 
PLoS ONE  2014;9(6):e100012.
Background
Recent studies have been shown that functional connectivity of cerebral areas is not a static phenomenon, but exhibits spontaneous fluctuations over time. There is evidence that fluctuating connectivity is an intrinsic phenomenon of brain dynamics that persists during anesthesia. Lately, point process analysis applied on functional data has revealed that much of the information regarding brain connectivity is contained in a fraction of critical time points of a resting state dataset. In the present study we want to extend this methodology for the investigation of resting state fMRI spatial pattern changes during propofol-induced modulation of consciousness, with the aim of extracting new insights on brain networks consciousness-dependent fluctuations.
Methods
Resting-state fMRI volumes on 18 healthy subjects were acquired in four clinical states during propofol injection: wakefulness, sedation, unconsciousness, and recovery. The dataset was reduced to a spatio-temporal point process by selecting time points in the Posterior Cingulate Cortex (PCC) at which the signal is higher than a given threshold (i.e., BOLD intensity above 1 standard deviation). Spatial clustering on the PCC time frames extracted was then performed (number of clusters = 8), to obtain 8 different PCC co-activation patterns (CAPs) for each level of consciousness.
Results
The current analysis shows that the core of the PCC-CAPs throughout consciousness modulation seems to be preserved. Nonetheless, this methodology enables to differentiate region-specific propofol-induced reductions in PCC-CAPs, some of them already present in the functional connectivity literature (e.g., disconnections of the prefrontal cortex, thalamus, auditory cortex), some others new (e.g., reduced co-activation in motor cortex and visual area).
Conclusion
In conclusion, our results indicate that the employed methodology can help in improving and refining the characterization of local functional changes in the brain associated to propofol-induced modulation of consciousness.
doi:10.1371/journal.pone.0100012
PMCID: PMC4076184  PMID: 24979748
4.  Biased binomial assessment of cross-validated estimation of classification accuracies illustrated in diagnosis predictions 
NeuroImage : Clinical  2014;4:687-694.
Multivariate classification is used in neuroimaging studies to infer brain activation or in medical applications to infer diagnosis. Their results are often assessed through either a binomial or a permutation test. Here, we simulated classification results of generated random data to assess the influence of the cross-validation scheme on the significance of results. Distributions built from classification of random data with cross-validation did not follow the binomial distribution. The binomial test is therefore not adapted. On the contrary, the permutation test was unaffected by the cross-validation scheme. The influence of the cross-validation was further illustrated on real-data from a brain–computer interface experiment in patients with disorders of consciousness and from an fMRI study on patients with Parkinson disease. Three out of 16 patients with disorders of consciousness had significant accuracy on binomial testing, but only one showed significant accuracy using permutation testing. In the fMRI experiment, the mental imagery of gait could discriminate significantly between idiopathic Parkinson's disease patients and healthy subjects according to the permutation test but not according to the binomial test. Hence, binomial testing could lead to biased estimation of significance and false positive or negative results. In our view, permutation testing is thus recommended for clinical application of classification with cross-validation.
Highlights
•We assess the influence of cross-validation on significance of classification results.•Classification of random data did not follow binomial distribution.•The permutation test was unaffected by the cross-validation scheme.•Results are illustrated on real-data from BCI and fMRI studies.
doi:10.1016/j.nicl.2014.04.004
PMCID: PMC4053638  PMID: 24936420
classification; cross-validation; binomial; permutation test
5.  Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study 
Functional Neurology  2014;28(4):259-264.
Summary
Zolpidem has been reported as an “awakening drug” in some patients with disorders of consciousness (DOC). We here present the results of a prospective open-label study in chronic DOC patients. Sixty patients (35±15 years; 18 females; mean time since insult ± SD: 4±5.5 years; 31 with traumatic etiology) with a diagnosis of vegetative state/unresponsive wakefulness syndrome (n=28) or minimally conscious state (n=32) were behaviorally assessed using the Coma Recovery Scale-Revised (CRS-R) before and one hour after administration of 10 mg of zolpidem. At the group level, the diagnosis did not change after intake of zolpidem (p=0.10) and CRS-R total scores decreased (p=0.01). Twelve patients (20%) showed improved behaviors and/or CRS-R total scores after zolpidem administration but in only one patient was the diagnosis after zolpidem intake found to show a significant improvement (functional object use), which suggested a change of diagnosis. However, in this patient, a double-blind placebo-controlled trial was performed in order to better specify the effects of zolpidem, but the patient, on this trial, failed to show any clinical improvements.
The present open-label study therefore failed to show any clinically significant improvement (i.e., change of diagnosis) in any of the 60 studied chronic DOC patients.
PMCID: PMC3951253  PMID: 24598393
disorders of consciousness; minimally conscious state; treatment; vegetative state; zolpidem
6.  Near-death experiences in non-life-threatening events and coma of different etiologies 
Background: Near death experiences (NDEs) are increasingly being reported as a clearly identifiable physiological and psychological reality of clinical significance. However, the definition and causes of the phenomenon as well as the identification of NDE experiencers is still a matter of debate. To date, the most widely used standardized tool to identify and characterize NDEs in research is the Greyson NDE scale. Using this scale, retrospective and prospective studies have been trying to estimate their incidence in various populations but few studies have attempted to associate the experiences' intensity and content to etiology.
Methods: This retrospective investigation assessed the intensity and the most frequently recounted features of self-reported NDEs after a non-life-threatening event (i.e., “NDE-like” experience) or after a pathological coma (i.e., “real NDE”) and according to the etiology of the acute brain insult. We also compared our retrospectively acquired data in anoxic coma with historical data from the published literature on prospective post-anoxic studies using the Greyson NDE scale.
Results: From our 190 reports who met the criteria for NDE (i.e., Greyson NDE scale total score >7/32), intensity (i.e., Greyson NDE scale total score) and content (i.e., Greyson NDE scale features) did not differ between “NDE-like” (n = 50) and “real NDE” (n = 140) groups, nor within the “real NDE” group depending on the cause of coma (anoxic/traumatic/other). The most frequently reported feature was peacefulness (89–93%). Only 2 patients (1%) recounted a negative experience. The overall NDE core features' frequencies were higher in our retrospective anoxic cohort when compared to historical published prospective data.
Conclusions: It appears that “real NDEs” after coma of different etiologies are similar to “NDE-like” experiences occurring after non-life threatening events. Subjects reporting NDEs retrospectively tend to have experienced a different content compared to the prospective experiencers.
doi:10.3389/fnhum.2014.00203
PMCID: PMC4034153  PMID: 24904345
Near-death experiences; Greyson NDE scale; coma; cardiac arrest; traumatic brain injury; memory; non-life threatening events
7.  Changes in cerebral metabolism in patients with a minimally conscious state responding to zolpidem 
Background: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS).
Methods: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8).
Results: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration.
Conclusion: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS.
doi:10.3389/fnhum.2014.00917
PMCID: PMC4251320  PMID: 25520636
minimally conscious state; zolpidem; brain metabolism; positron emission tomography; prefrontal cortex; mesocircuit hypothesis
8.  Detection of response to command using voluntary control of breathing in disorders of consciousness 
Background: Detecting signs of consciousness in patients in a vegetative state/unresponsive wakefulness syndrome (UWS/VS) or minimally conscious state (MCS) is known to be very challenging. Plotkin et al. (2010) recently showed the possibility of using a breathing-controlled communication device in patients with locked in syndrome. We here aim to test a breathing-based “sniff controller” that could be used as an alternative diagnostic tool to evaluate response to command in severely brain damaged patients with chronic disorders of consciousness (DOC).
Methods: Twenty-five DOC patients were included. Patients’ resting breathing-amplitude was measured during a 5 min resting condition. Next, they were instructed to end the presentation of a music sequence by sniffing vigorously. An automated detection of changes in breathing amplitude (i.e., >1.5 SD of resting) ended the music and hence provided positive feedback to the patient.
Results: None of the 11 UWS/VS patients showed a sniff-based response to command. One out of 14 patients with MCS was able to willfully modulate his breathing pattern to answer the command on 16/19 trials (accuracy 84%). Interestingly, this patient failed to show any other motor response to command.
Discussion: We here illustrate the possible interest of using breathing-dependent response to command in the detection of residual cognition in patients with DOC after severe brain injury.
doi:10.3389/fnhum.2014.01020
PMCID: PMC4274966  PMID: 25566035
disorders of consciousness; breathing; sniffing; vegetative state; unresponsive wakefulness syndrome; minimally conscious state; diagnosis; brain-computer interface
9.  Altered network properties of the fronto-parietal network and the thalamus in impaired consciousness☆ 
NeuroImage : Clinical  2013;4:240-248.
Recovery of consciousness has been associated with connectivity in the frontal cortex and parietal regions modulated by the thalamus. To examine this model and to relate alterations to deficits in cognitive functioning and conscious processing, we investigated topological network properties in patients with chronic disorders of consciousness recovered from coma.
Resting state fMRI data of 34 patients with unresponsive wakefulness syndrome and 25 in minimally conscious state were compared to 28 healthy controls. We investigated global and local network characteristics. Additionally, behavioral measures were correlated with the local metrics of 28 regions within the fronto-parietal network and the thalamus.
In chronic disorders of consciousness, modularity at the global level was reduced suggesting a disturbance in the optimal balance between segregation and integration. Moreover, network properties were altered in several regions which are associated with conscious processing (particularly, in medial parietal, and frontal regions, as well as in the thalamus). Between minimally conscious and unconscious patients the local efficiency of medial parietal regions differed. Alterations in the thalamus were particularly evident in non-conscious patients. Most of the regions affected in patients with impaired consciousness belong to the so-called ‘rich club’ of highly interconnected central nodes. Disturbances in their topological characteristics have severe impact on information integration and are reflected in deficits in cognitive functioning probably leading to a total breakdown of consciousness.
Highlights
•We investigated network properties in patients with a disorder of consciousness.•Patients showed reduced global modularity.•Alterations in regions of the rich club were related to impaired consciousness.•These alterations have severe impact on information integration and segregation.•Disturbances in overall integration may lead to breakdown of consciousness.
doi:10.1016/j.nicl.2013.12.005
PMCID: PMC3895618  PMID: 24455474
DOC, disorders of consciousness; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; MCS, minimally conscious state; VS/UWS, vegetative state/unresponsive wakefulness syndrome; Consciousness; Vegetative state; Network; Graph theory; Connectivity; Small world
10.  Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury 
eLife  2013;2:e01157.
Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6–10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7–0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6–10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors.
DOI: http://dx.doi.org/10.7554/eLife.01157.001
eLife digest
Some individuals who experience severe brain damage are left with disorders of consciousness. While they can appear to be awake, these individuals lack awareness of their surroundings and cannot respond to events going on around them. Few treatments are available, but a minority of patients show striking improvements in speech, alertness and movement in response to the sleeping pill zolpidem.
Although the idea of a sleeping pill increasing consciousness is paradoxical, it is possible that in patients with impaired consciousness, zolpidem reduces the activity of an area of the brain that would otherwise inhibit activity in other regions of the brain. However, the precise mechanisms by which zolpidem increases consciousness in these patients, and the reasons why only a minority of individuals respond, are unknown.
Now, Williams et al. have used electrodes attached to the scalp to measure changes in brain activity in three patients known to respond to zolpidem. These measurements showed that before the drug was taken, there were two important differences between the brain activity of the patients and that of healthy subjects: first, the patients showed brain waves of a lower frequency than any seen in healthy subjects; second, these brain waves were much more synchronized than brain activity in healthy individuals. After taking zolpidem, this synchronicity was reduced and all of the patients also showed an increase in higher frequency brain waves.
Based on the effects of zolpidem on electrical activity throughout the brain, Williams et al. propose a new model to explain the therapeutic action of the drug in some minimally conscious patients. If the correlation between brain waves and zolpidem response holds up in future studies, this relation could be used to predict which patients might benefit from the drug. A better understanding of these processes should also help us to understand, diagnose and develop new treatments for disorders of consciousness.
DOI: http://dx.doi.org/10.7554/eLife.01157.002
doi:10.7554/eLife.01157
PMCID: PMC3833342  PMID: 24252875
Consciousness; central thalamus; striatum; GABA-A; arousal; anesthesia; Human
11.  Consciousness in humans and non-human animals: recent advances and future directions 
This joint article reflects the authors' personal views regarding noteworthy advances in the neuroscience of consciousness in the last 10 years, and suggests what we feel may be promising future directions. It is based on a small conference at the Samoset Resort in Rockport, Maine, USA, in July of 2012, organized by the Mind Science Foundation of San Antonio, Texas. Here, we summarize recent advances in our understanding of subjectivity in humans and other animals, including empirical, applied, technical, and conceptual insights. These include the evidence for the importance of fronto-parietal connectivity and of “top-down” processes, both of which enable information to travel across distant cortical areas effectively, as well as numerous dissociations between consciousness and cognitive functions, such as attention, in humans. In addition, we describe the development of mental imagery paradigms, which made it possible to identify covert awareness in non-responsive subjects. Non-human animal consciousness research has also witnessed substantial advances on the specific role of cortical areas and higher order thalamus for consciousness, thanks to important technological enhancements. In addition, much progress has been made in the understanding of non-vertebrate cognition relevant to possible conscious states. Finally, major advances have been made in theories of consciousness, and also in their comparison with the available evidence. Along with reviewing these findings, each author suggests future avenues for research in their field of investigation.
doi:10.3389/fpsyg.2013.00625
PMCID: PMC3814086  PMID: 24198791
consciousness; animals; human cognition; theoretical neuroscience; biotechnology; neuroimaging
12.  Electroencephalographic profiles for differentiation of disorders of consciousness 
Background
Electroencephalography (EEG) is best suited for long-term monitoring of brain functions in patients with disorders of consciousness (DOC). Mathematical tools are needed to facilitate efficient interpretation of long-duration sleep-wake EEG recordings.
Methods
Starting with matching pursuit (MP) decomposition, we automatically detect and parametrize sleep spindles, slow wave activity, K-complexes and alpha, beta and theta waves present in EEG recordings, and automatically construct profiles of their time evolution, relevant to the assessment of residual brain function in patients with DOC.
Results
Above proposed EEG profiles were computed for 32 patients diagnosed as minimally conscious state (MCS, 20 patients), vegetative state/unresponsive wakefulness syndrome (VS/UWS, 11 patients) and Locked-in Syndrome (LiS, 1 patient). Their interpretation revealed significant correlations between patients’ behavioral diagnosis and: (a) occurrence of sleep EEG patterns including sleep spindles, slow wave activity and light/deep sleep cycles, (b) appearance and variability across time of alpha, beta, and theta rhythms. Discrimination between MCS and VS/UWS based upon prominent features of these profiles classified correctly 87% of cases.
Conclusions
Proposed EEG profiles offer user-independent, repeatable, comprehensive and continuous representation of relevant EEG characteristics, intended as an aid in differentiation between VS/UWS and MCS states and diagnostic prognosis. To enable further development of this methodology into clinically usable tests, we share user-friendly software for MP decomposition of EEG (http://braintech.pl/svarog) and scripts used for creation of the presented profiles (attached to this article).
doi:10.1186/1475-925X-12-109
PMCID: PMC3819687  PMID: 24143892
Electroencephalography; Matching Pursuit; Disorders of consciousness; Minimally conscious state; Vegetative state; Locked-in syndrome
13.  Dynamic Change of Global and Local Information Processing in Propofol-Induced Loss and Recovery of Consciousness 
PLoS Computational Biology  2013;9(10):e1003271.
Whether unique to humans or not, consciousness is a central aspect of our experience of the world. The neural fingerprint of this experience, however, remains one of the least understood aspects of the human brain. In this paper we employ graph-theoretic measures and support vector machine classification to assess, in 12 healthy volunteers, the dynamic reconfiguration of functional connectivity during wakefulness, propofol-induced sedation and loss of consciousness, and the recovery of wakefulness. Our main findings, based on resting-state fMRI, are three-fold. First, we find that propofol-induced anesthesia does not bear differently on long-range versus short-range connections. Second, our multi-stage design dissociated an initial phase of thalamo-cortical and cortico-cortical hyperconnectivity, present during sedation, from a phase of cortico-cortical hypoconnectivity, apparent during loss of consciousness. Finally, we show that while clustering is increased during loss of consciousness, as recently suggested, it also remains significantly elevated during wakefulness recovery. Conversely, the characteristic path length of brain networks (i.e., the average functional distance between any two regions of the brain) appears significantly increased only during loss of consciousness, marking a decrease of global information-processing efficiency uniquely associated with unconsciousness. These findings suggest that propofol-induced loss of consciousness is mainly tied to cortico-cortical and not thalamo-cortical mechanisms, and that decreased efficiency of information flow is the main feature differentiating the conscious from the unconscious brain.
Author Summary
One of the most elusive aspects of the human brain is the neural fingerprint of the subjective feeling of consciousness. While a growing body of experimental evidence is starting to address this issue, to date we are still hard pressed to answer even basic questions concerning the nature of consciousness in humans as well as other species. In the present study we follow a recent theoretical construct according to which the crucial factor underlying consciousness is the modality with which information is exchanged across different parts of the brain. In particular, we represent the brain as a network of regions exchanging information (as is typically done in a comparatively young branch of mathematics referred to as graph theory), and assess how different levels of consciousness induced by anesthetic agent affect the quality of information exchange across regions of the network. Overall, our findings show that what makes the state of propofol-induced loss of consciousness different from all other conditions (namely, wakefulness, light sedation, and consciousness recovery) is the fact that all regions of the brain appear to be functionally further apart, reducing the efficiency with which information can be exchanged across different parts of the network.
doi:10.1371/journal.pcbi.1003271
PMCID: PMC3798283  PMID: 24146606
14.  A Comparison of Two Spelling Brain-Computer Interfaces Based on Visual P3 and SSVEP in Locked-In Syndrome 
PLoS ONE  2013;8(9):e73691.
Objectives
We study the applicability of a visual P3-based and a Steady State Visually Evoked Potentials (SSVEP)-based Brain-Computer Interfaces (BCIs) for mental text spelling on a cohort of patients with incomplete Locked-In Syndrome (LIS).
Methods
Seven patients performed repeated sessions with each BCI. We assessed BCI performance, mental workload and overall satisfaction for both systems. We also investigated the effect of the quality of life and level of motor impairment on the performance.
Results
All seven patients were able to achieve an accuracy of 70% or more with the SSVEP-based BCI, compared to 3 patients with the P3-based BCI, showing a better performance with the SSVEP BCI than with the P3 BCI in the studied cohort. Moreover, the better performance of the SSVEP-based BCI was accompanied by a lower mental workload and a higher overall satisfaction. No relationship was found between BCI performance and level of motor impairment or quality of life.
Conclusion
Our results show a better usability of the SSVEP-based BCI than the P3-based one for the sessions performed by the tested population of locked-in patients with respect to all the criteria considered. The study shows the advantage of developing alternative BCIs with respect to the traditional matrix-based P3 speller using different designs and signal modalities such as SSVEPs to build a faster, more accurate, less mentally demanding and more satisfying BCI by testing both types of BCIs on a convenience sample of LIS patients.
doi:10.1371/journal.pone.0073691
PMCID: PMC3783473  PMID: 24086289
15.  Changes in Effective Connectivity by Propofol Sedation 
PLoS ONE  2013;8(8):e71370.
Mechanisms of propofol-induced loss of consciousness remain poorly understood. Recent fMRI studies have shown decreases in functional connectivity during unconsciousness induced by this anesthetic agent. Functional connectivity does not provide information of directional changes in the dynamics observed during unconsciousness. The aim of the present study was to investigate, in healthy humans during an auditory task, the changes in effective connectivity resulting from propofol induced loss of consciousness. We used Dynamic Causal Modeling for fMRI (fMRI-DCM) to assess how causal connectivity is influenced by the anesthetic agent in the auditory system. Our results suggest that the dynamic observed in the auditory system during unconsciousness induced by propofol, can result in a mixture of two effects: a local inhibitory connectivity increase and a decrease in the effective connectivity in sensory cortices.
doi:10.1371/journal.pone.0071370
PMCID: PMC3747149  PMID: 23977030
17.  Unresponsiveness ≠ Unconsciousness 
Anesthesiology  2012;116(4):946-959.
Consciousness is subjective experience. During both sleep and anesthesia consciousness is common, evidenced by dreaming. A defining feature of dreaming is that, while conscious, we do not experience our environment – we are disconnected. Besides inducing behavioral unresponsiveness, a key goal of anesthesia is to prevent the experience of surgery (connected consciousness), by inducing either unconsciousness or disconnection of consciousness from the environment. Review of the isolated forearm technique demonstrates that consciousness, connectedness and responsiveness uncouple during anesthesia; in clinical conditions, a median 37% of patients demonstrate connected consciousness. We describe potential neurobiological constructs that can explain this phenomenon: during light anesthesia the subcortical mechanisms subserving spontaneous behavioral responsiveness are disabled but information integration within the corticothalamic network continues to produce consciousness, and unperturbed norepinephrinergic signaling maintains connectedness. These concepts emphasize the need for developing anesthetic regimens and depth of anesthesia monitors that specifically target mechanisms of consciousness, connectedness and responsiveness.
doi:10.1097/ALN.0b013e318249d0a7
PMCID: PMC3311716  PMID: 22314293
18.  Characteristics of Near-Death Experiences Memories as Compared to Real and Imagined Events Memories 
PLoS ONE  2013;8(3):e57620.
Since the dawn of time, Near-Death Experiences (NDEs) have intrigued and, nowadays, are still not fully explained. Since reports of NDEs are proposed to be imagined events, and since memories of imagined events have, on average, fewer phenomenological characteristics than real events memories, we here compared phenomenological characteristics of NDEs reports with memories of imagined and real events. We included three groups of coma survivors (8 patients with NDE as defined by the Greyson NDE scale, 6 patients without NDE but with memories of their coma, 7 patients without memories of their coma) and a group of 18 age-matched healthy volunteers. Five types of memories were assessed using Memory Characteristics Questionnaire (MCQ – Johnson et al., 1988): target memories (NDE for NDE memory group, coma memory for coma memory group, and first childhood memory for no memory and control groups), old and recent real event memories and old and recent imagined event memories. Since NDEs are known to have high emotional content, participants were requested to choose the most emotionally salient memories for both real and imagined recent and old event memories. Results showed that, in NDE memories group, NDE memories have more characteristics than memories of imagined and real events (p<0.02). NDE memories contain more self-referential and emotional information and have better clarity than memories of coma (all ps<0.02). The present study showed that NDE memories contained more characteristics than real event memories and coma memories. Thus, this suggests that they cannot be considered as imagined event memories. On the contrary, their physiological origins could lead them to be really perceived although not lived in the reality. Further work is needed to better understand this phenomenon.
doi:10.1371/journal.pone.0057620
PMCID: PMC3609762  PMID: 23544039
19.  Assessment of localisation to auditory stimulation in post-comatose states: use the patient’s own name 
BMC Neurology  2013;13:27.
Background
At present, there is no consensus on how to clinically assess localisation to sound in patients recovering from coma. We here studied auditory localisation using the patient’s own name as compared to a meaningless sound (i.e., ringing bell).
Methods
Eighty-six post-comatose patients diagnosed with a vegetative state/unresponsive wakefulness syndrome or a minimally conscious state were prospectively included. Localisation of auditory stimulation (i.e., head or eyes orientation toward the sound) was assessed using the patient’s own name as compared to a ringing bell. Statistical analyses used binomial testing with bonferroni correction for multiple comparisons.
Results
37 (43%) out of the 86 studied patients showed localisation to auditory stimulation. More patients (n=34, 40%) oriented the head or eyes to their own name as compared to sound (n=20, 23%; p<0.001).
Conclusions
When assessing auditory function in disorders of consciousness, using the patient’s own name is here shown to be more suitable to elicit a response as compared to neutral sound.
doi:10.1186/1471-2377-13-27
PMCID: PMC3606124  PMID: 23506054
Localisation to sound; Auditory localisation; Vegetative state; Unresponsive wakefulness syndrome; Minimally conscious state; Own name; Disorders of consciousness
20.  Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States 
BMC Medicine  2013;11:18.
Background
The Vegetative and Minimally Conscious States (VS; MCS) are characterized by absent or highly disordered signs of awareness alongside preserved sleep-wake cycles. According to international diagnostic guidelines, sleep-wake cycles are assessed by means of observations of variable periods of eye-opening and eye-closure. However, there is little empirical evidence for true circadian sleep-wake cycling in these patients, and there have been no large-scale investigations of the validity of this diagnostic criterion.
Methods
We measured the circadian sleep-wake rhythms of 55 VS and MCS patients by means of wrist actigraphy, an indirect method that is highly correlated with polysomnographic estimates of sleeping/waking.
Results
Contrary to the diagnostic guidelines, a significant proportion of patients did not exhibit statistically reliable sleep-wake cycles. The circadian rhythms of VS patients were significantly more impaired than those of MCS patients, as were the circadian rhythms of patients with non-traumatic injuries relative to those with traumatic injuries. The reliability of the circadian rhythms were significantly predicted by the patients' levels of visual and motor functioning, consistent with the putative biological generators of these rhythms.
Conclusions
The high variability across diagnoses and etiologies highlights the need for improved guidelines for the assessment of sleep-wake cycles in VS and MCS, and advocates the use of actigraphy as an inexpensive and non-invasive alternative.
doi:10.1186/1741-7015-11-18
PMCID: PMC3606428  PMID: 23347467
Vegetative State; Minimally Conscious State; circadian rhythms; sleep; actigraphy
21.  Looking for the Self in Pathological Unconsciousness 
There is an intimate relationship between consciousness and the notion of self. By studying patients with disorders of consciousness, we are offered with a unique lesion approach to tackle the neural correlates of self in the absence of subjective reports. Studies employing neuroimaging techniques point to the critical involvement of midline anterior and posterior cortices in response to the passive presentation of self-referential stimuli, such as the patient’s own name and own face. Also, resting state studies show that these midline regions are severely impaired as a function of the level of consciousness. Theoretical frameworks combining all this progress surpass the functional localization of self-related cognition and suggest a dynamic system-level approach to the phenomenological complexity of subjectivity. Importantly for non-communicating patients suffering from disorders of consciousness, the clinical translation of these technologies will allow medical professionals and families to better comprehend these disorders and plan efficient medical management for these patients.
doi:10.3389/fnhum.2013.00538
PMCID: PMC3759827  PMID: 24027519
consciousness; self; neuroimaging; disorders of consciousness; default mode network; external awareness
22.  Connectivity changes underlying spectral EEG changes during propofol-induced loss of consciousness 
The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (delta to alpha) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in cortico-thalamic interactions. Compared to wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward cortico-cortical connectivity from frontal to parietal cortices, while thalamo-cortical connectivity remained unchanged. These results emphasize the importance of recurrent cortico-cortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.
doi:10.1523/JNEUROSCI.3769-11.2012
PMCID: PMC3366913  PMID: 22593076
23.  Connectivity changes underlying spectral EEG changes during propofol-induced loss of consciousness 
The Journal of Neuroscience  2012;32(20):7082-7090.
The mechanisms underlying anesthesia-induced loss of consciousness remain a matter of debate. Recent electrophysiological reports suggest that while initial propofol infusion provokes an increase in fast rhythms (from beta to gamma range), slow activity (delta to alpha) rises selectively during loss of consciousness. Dynamic causal modeling was used to investigate the neural mechanisms mediating these changes in spectral power in humans. We analyzed source-reconstructed data from frontal and parietal cortices during normal wakefulness, propofol-induced mild sedation and loss of consciousness. Bayesian model selection revealed that the best model for explaining spectral changes across the three states involved changes in cortico-thalamic interactions. Compared to wakefulness, mild sedation was accounted for by an increase in thalamic excitability, which did not further increase during loss of consciousness. In contrast, loss of consciousness per se was accompanied by a decrease in backward cortico-cortical connectivity from frontal to parietal cortices, while thalamo-cortical connectivity remained unchanged. These results emphasize the importance of recurrent cortico-cortical communication in the maintenance of consciousness and suggest a direct effect of propofol on cortical dynamics.
doi:10.1523/JNEUROSCI.3769-11.2012
PMCID: PMC3366913  PMID: 22593076
24.  Resting State Networks and Consciousness 
In order to better understand the functional contribution of resting state activity to conscious cognition, we aimed to review increases and decreases in functional magnetic resonance imaging (fMRI) functional connectivity under physiological (sleep), pharmacological (anesthesia), and pathological altered states of consciousness, such as brain death, coma, vegetative state/unresponsive wakefulness syndrome, and minimally conscious state. The reviewed resting state networks were the DMN, left and right executive control, salience, sensorimotor, auditory, and visual networks. We highlight some methodological issues concerning resting state analyses in severely injured brains mainly in terms of hypothesis-driven seed-based correlation analysis and data-driven independent components analysis approaches. Finally, we attempt to contextualize our discussion within theoretical frameworks of conscious processes. We think that this “lesion” approach allows us to better determine the necessary conditions under which normal conscious cognition takes place. At the clinical level, we acknowledge the technical merits of the resting state paradigm. Indeed, fast and easy acquisitions are preferable to activation paradigms in clinical populations. Finally, we emphasize the need to validate the diagnostic and prognostic value of fMRI resting state measurements in non-communicating brain damaged patients.
doi:10.3389/fpsyg.2012.00295
PMCID: PMC3427917  PMID: 22969735
default mode network; resting state networks; consciousness; sleep; anesthesia; coma; hypnosis
25.  Electrophysiological correlates of behavioural changes in vigilance in vegetative state and minimally conscious state 
Brain  2011;134(8):2222-2232.
The existence of normal sleep in patients in a vegetative state is still a matter of debate. Previous electrophysiological sleep studies in patients with disorders of consciousness did not differentiate patients in a vegetative state from patients in a minimally conscious state. Using high-density electroencephalographic sleep recordings, 11 patients with disorders of consciousness (six in a minimally conscious state, five in a vegetative state) were studied to correlate the electrophysiological changes associated with sleep to behavioural changes in vigilance (sustained eye closure and muscle inactivity). All minimally conscious patients showed clear electroencephalographic changes associated with decreases in behavioural vigilance. In the five minimally conscious patients showing sustained behavioural sleep periods, we identified several electrophysiological characteristics typical of normal sleep. In particular, all minimally conscious patients showed an alternating non-rapid eye movement/rapid eye movement sleep pattern and a homoeostatic decline of electroencephalographic slow wave activity through the night. In contrast, for most patients in a vegetative state, while preserved behavioural sleep was observed, the electroencephalographic patterns remained virtually unchanged during periods with the eyes closed compared to periods of behavioural wakefulness (eyes open and muscle activity). No slow wave sleep or rapid eye movement sleep stages could be identified and no homoeostatic regulation of sleep-related slow wave activity was observed over the night-time period. In conclusion, we observed behavioural, but no electrophysiological, sleep wake patterns in patients in a vegetative state, while there were near-to-normal patterns of sleep in patients in a minimally conscious state. These results shed light on the relationship between sleep electrophysiology and the level of consciousness in severely brain-damaged patients. We suggest that the study of sleep and homoeostatic regulation of slow wave activity may provide a complementary tool for the assessment of brain function in minimally conscious state and vegetative state patients.
doi:10.1093/brain/awr152
PMCID: PMC3155704  PMID: 21841201
sleep; vegetative state; minimally conscious state; consciousness; EEG

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