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1.  Exploration of Functional Connectivity During Preferred Music Stimulation in Patients with Disorders of Consciousness 
Frontiers in Psychology  2015;6:1704.
Preferred music is a highly emotional and salient stimulus, which has previously been shown to increase the probability of auditory cognitive event-related responses in patients with disorders of consciousness (DOC). To further investigate whether and how music modifies the functional connectivity of the brain in DOC, five patients were assessed with both a classical functional connectivity scan (control condition), and a scan while they were exposed to their preferred music (music condition). Seed-based functional connectivity (left or right primary auditory cortex), and mean network connectivity of three networks linked to conscious sound perception were assessed. The auditory network showed stronger functional connectivity with the left precentral gyrus and the left dorsolateral prefrontal cortex during music as compared to the control condition. Furthermore, functional connectivity of the external network was enhanced during the music condition in the temporo-parietal junction. Although caution should be taken due to small sample size, these results suggest that preferred music exposure might have effects on patients auditory network (implied in rhythm and music perception) and on cerebral regions linked to autobiographical memory.
PMCID: PMC4637404  PMID: 26617542
music; disorders of consciousness; fMRI; functional connectivity; auditory network; external network
2.  Breakthrough in cardiac arrest: reports from the 4th Paris International Conference 
Jean-Luc Diehl The French Intensive Care Society organized on 5th and 6th June 2014 its 4th “Paris International Conference in Intensive Care”, whose principle is to bring together the best international experts on a hot topic in critical care medicine. The 2014 theme was “Breakthrough in cardiac arrest”, with many high-quality updates on epidemiology, public health data, pre-hospital and in-ICU cares. The present review includes short summaries of the major presentations, classified into six main chapters:Epidemiology of CAPre-hospital managementPost-resuscitation management: targeted temperature managementPost-resuscitation management: optimizing organ perfusion and metabolic parametersNeurological assessment of brain damagesPublic healthcare
PMCID: PMC4573754  PMID: 26380990
Cardiac arrest; Cardio-pulmonary resuscitation; Targeted temperature management; Therapeutic hypothermia; Persistent vegetative state; Minimally conscious state; Organ donation
3.  Complexity of Multi-Dimensional Spontaneous EEG Decreases during Propofol Induced General Anaesthesia 
PLoS ONE  2015;10(8):e0133532.
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.
PMCID: PMC4529106  PMID: 26252378
4.  Predicting outcome from subacute unresponsive wakefulness syndrome or vegetative state 
Critical Care  2014;18(2):132.
Predicting recovery of consciousness in patients who survive their coma but evolve to a vegetative state (recently coined unresponsive wakefulness syndrome) remains a challenge. Most previous prognostic studies have focused on the acute coma phase. A novel outcome scale (combining behavioural, aetiology, electroencephalographic, sleep electroencephalographic and somatosensory evoked potential data) has been proposed for patients in subacute unresponsive wakefulness syndrome. The scale’s clinical application awaits validation in a larger population.
PMCID: PMC4056757  PMID: 25029668
5.  Cerebral response to subject’s own name showed high prognostic value in traumatic vegetative state 
BMC Medicine  2015;13:83.
Previous studies have shown the prognostic value of stimulation elicited blood-oxygen-level-dependent (BOLD) signal in traumatic patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS). However, to the best of our knowledge, no studies have focused on the relevance of etiology and level of consciousness in patients with disorders of consciousness (DOC) when explaining the relationship between BOLD signal and both outcome and signal variability. We herein propose a study in a large sample of traumatic and non-traumatic DOC patients in order to ascertain the relevance of etiology and level of consciousness in the variability and prognostic value of a stimulation-elicited BOLD signal.
66 patients were included, and the response of each subject to his/her own name said by a familiar voice (SON-FV) was recorded using fMRI; 13 patients were scanned twice in the same day, respecting the exact same conditions in both cases. A behavioral follow-up program was carried out at 3, 6, and 12 months after scanning.
Of the 39 VS/UWS patients, 12 (75%) out of 16 patients with higher level activation patterns recovered to minimally conscious state (MCS) or emergence from MCS (EMCS) and 17 (74%) out of 23 patients with lower level activation patterns or no activation had a negative outcome. Taking etiology into account for VS/UWS patients, a higher positive predictive value was assigned to traumatic patients, i.e., up to 92% (12/13) patients with higher level activation pattern achieved good recovery whereas 11 out of 13 (85%) non-traumatic patients with lower level activation or without activation had a negative clinical outcome. The reported data from visual analysis of fMRI activation patterns were corroborated using ROC curve analysis, which supported the correlation between auditory cortex activation volume and VS/UWS patients’ recovery. The average brain activity overlap in primary and secondary auditory cortices in patients scanned twice was 52%.
The activation type and volume in auditory cortex elicited by SON-FV significantly correlated with VS/UWS patients’ prognosis, particularly in patients with traumatic etiology, however, this could not be established in MCS patients. Repeated use of this simple fMRI task might help obtain more reliable prognostic information.
PMCID: PMC4406334  PMID: 25880206
Functional MRI; Own name; Prognosis; Traumatic brain injury; Vegetative state/unresponsive wakefulness syndrome
6.  Prevalence of increases in functional connectivity in visual, somatosensory and language areas in congenital blindness 
There is ample evidence that congenitally blind individuals rely more strongly on non-visual information compared to sighted controls when interacting with the outside world. Although brain imaging studies indicate that congenitally blind individuals recruit occipital areas when performing various non-visual and cognitive tasks, it remains unclear through which pathways this is accomplished. To address this question, we compared resting state functional connectivity in a group of congenital blind and matched sighted control subjects. We used a seed-based analysis with a priori specified regions-of-interest (ROIs) within visual, somato-sensory, auditory and language areas. Between-group comparisons revealed increased functional connectivity within both the ventral and the dorsal visual streams in blind participants, whereas connectivity between the two streams was reduced. In addition, our data revealed stronger functional connectivity in blind participants between the visual ROIs and areas implicated in language and tactile (Braille) processing such as the inferior frontal gyrus (Broca's area), thalamus, supramarginal gyrus and cerebellum. The observed group differences underscore the extent of the cross-modal reorganization in the brain and the supra-modal function of the occipital cortex in congenitally blind individuals.
PMCID: PMC4486836  PMID: 26190978
congenitally blind; functional connectivity; seed-based analysis; vision
7.  Corrigendum: Prevalence of increases in functional connectivity in visual, somatosensory and language areas in congenital blindness 
PMCID: PMC4534798  PMID: 26321919
congenitally blind; functional connectivity; Seed-based analysis; Vision; Resting-state fMRI
8.  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.
PMCID: PMC4147439  PMID: 25170396
Disorders of consciousness; Neuroimaging; Magnetic resonance imaging; Transcranial magnetic stimulation/electroencephalography; Minimally conscious state; Vegetative state/unresponsive wakefulness syndrome
9.  Assessment of visual fixation in vegetative and minimally conscious states 
BMC Neurology  2014;14:147.
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.
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.
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%).
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.
PMCID: PMC4112970  PMID: 25027769
Disorders of consciousness; Vegetative state; Unresponsive wakefulness syndrome; Minimally conscious state; Visual fixation
10.  Posterior Cingulate Cortex-Related Co-Activation Patterns: A Resting State fMRI Study in Propofol-Induced Loss of Consciousness 
PLoS ONE  2014;9(6):e100012.
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.
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.
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).
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.
PMCID: PMC4076184  PMID: 24979748
11.  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.
•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.
PMCID: PMC4053638  PMID: 24936420
classification; cross-validation; binomial; permutation test
12.  Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study 
Functional Neurology  2014;28(4):259-264.
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
13.  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.
PMCID: PMC4034153  PMID: 24904345
Near-death experiences; Greyson NDE scale; coma; cardiac arrest; traumatic brain injury; memory; non-life threatening events
14.  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.
PMCID: PMC4251320  PMID: 25520636
minimally conscious state; zolpidem; brain metabolism; positron emission tomography; prefrontal cortex; mesocircuit hypothesis
15.  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.
PMCID: PMC4274966  PMID: 25566035
disorders of consciousness; breathing; sniffing; vegetative state; unresponsive wakefulness syndrome; minimally conscious state; diagnosis; brain-computer interface
16.  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.
•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.
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
17.  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.
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.
PMCID: PMC3833342  PMID: 24252875
Consciousness; central thalamus; striatum; GABA-A; arousal; anesthesia; Human
18.  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.
PMCID: PMC3814086  PMID: 24198791
consciousness; animals; human cognition; theoretical neuroscience; biotechnology; neuroimaging
19.  Electroencephalographic profiles for differentiation of disorders of consciousness 
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.
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.
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.
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 ( and scripts used for creation of the presented profiles (attached to this article).
PMCID: PMC3819687  PMID: 24143892
Electroencephalography; Matching Pursuit; Disorders of consciousness; Minimally conscious state; Vegetative state; Locked-in syndrome
20.  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.
PMCID: PMC3798283  PMID: 24146606
21.  A Comparison of Two Spelling Brain-Computer Interfaces Based on Visual P3 and SSVEP in Locked-In Syndrome 
PLoS ONE  2013;8(9):e73691.
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).
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.
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.
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.
PMCID: PMC3783473  PMID: 24086289
22.  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.
PMCID: PMC3747149  PMID: 23977030
24.  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.
PMCID: PMC3311716  PMID: 22314293
25.  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.
PMCID: PMC3609762  PMID: 23544039

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