European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness.

BACKGROUND AND PURPOSE: Patients with acquired brain injury and acute or prolonged disorders of consciousness (DoC) are challenging. Evidence to support diagnostic decisions on coma and other DoC is limited but accumulating. This guideline provides the state-of-the-art evidence regarding the diagnosis of DoC, summarizing data from bedside examination techniques, functional neuroimaging and electroencephalography (EEG). METHODS: Sixteen members of the European Academy of Neurology (EAN) Scientific Panel on Coma and Chronic Disorders of Consciousness, representing 10 European countries, reviewed the scientific evidence for the evaluation of coma and other DoC using standard bibliographic measures. Recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The guideline was endorsed by the EAN. RESULTS: Besides a comprehensive neurological examination, the following suggestions are made: probe for voluntary eye movements using a mirror; repeat clinical assessments in the subacute and chronic setting, using the Coma Recovery Scale - Revised; use the Full Outline of Unresponsiveness score instead of the Glasgow Coma Scale in the acute setting; obtain clinical standard EEG; search for sleep patterns on EEG, particularly rapid eye movement sleep and slow-wave sleep; and, whenever feasible, consider positron emission tomography, resting state functional magnetic resonance imaging (fMRI), active fMRI or EEG paradigms and quantitative analysis of high-density EEG to complement behavioral assessment in patients without command following at the bedside. CONCLUSIONS: Standardized clinical evaluation, EEG-based techniques and functional neuroimaging should be integrated for multimodal evaluation of patients with DoC. The state of consciousness should be classified according to the highest level revealed by any of these three approaches.

Correction to: Actigraphy assessments of circadian sleep-wake cycles in the Vegetative and Minimally Conscious States.

The original article [1] contains an error affecting the actigraphy time-stamps throughout the article, particularly in Table 1.

Propofol-induced unresponsiveness is associated with impaired feedforward connectivity in cortical hierarchy.

BACKGROUND: Impaired consciousness has been associated with impaired cortical signal propagation after transcranial magnetic stimulation (TMS). We hypothesised that the reduced current propagation under propofol-induced unresponsiveness is associated with changes in both feedforward and feedback connectivity across the cortical hierarchy. METHODS: Eight subjects underwent left occipital TMS coupled with high-density EEG recordings during wakefulness and propofol-induced unconsciousness. Spectral analysis was applied to responses recorded from sensors overlying six hierarchical cortical sources involved in visual processing. Dynamic causal modelling (DCM) of induced time-frequency responses and evoked response potentials were used to investigate propofol's effects on connectivity between regions. RESULTS: Sensor space analysis demonstrated that propofol reduced both induced and evoked power after TMS in occipital, parietal, and frontal electrodes. Bayesian model selection supported a DCM with hierarchical feedforward and feedback connections. DCM of induced EEG responses revealed that the primary effect of propofol was impaired feedforward responses in cross-frequency theta/alpha-gamma coupling and within frequency theta coupling (F contrast, family-wise error corrected P<0.05). An exploratory analysis (thresholded at uncorrected P<0.001) also suggested that propofol impaired feedforward and feedback beta band coupling. Post hoc analyses showed impairments in all feedforward connections and one feedback connection from parietal to occipital cortex. DCM of the evoked response potential showed impaired feedforward connectivity between left-sided occipital and parietal cortex (T contrast P=0.004, Bonferroni corrected). CONCLUSIONS: Propofol-induced loss of consciousness is associated with impaired hierarchical feedforward connectivity assessed by EEG after occipital TMS.

Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep.

BACKGROUND: We used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep. METHODS: Connectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye-movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets. RESULTS: In all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol. CONCLUSIONS: Thalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation. TRIAL REGISTRY NUMBER: Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

Effects of preference and sensory modality on behavioural reaction in patients with disorders of consciousness.

BACKGROUND: Reliable evaluation of patients with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS) remains a major challenge. It has been suggested that the expression of residual cerebral function could be improved by allowing patients to listen to their favourite music. However, the potential effect of music on behavioural responsiveness, as well as the effect of preferred stimuli in other sensory modalities (e.g. olfaction), remain poorly understood. OBJECTIVE: The aim of our study was to investigate the effect of sensory modality (auditory versus olfactory) and preference (preferred versus neutral) of the test stimuli on patients' subsequent performance on the Coma Recovery Scale-Revised (CRS-R). RESEARCH DESIGN: Within-subject design because of inter-individual differences between patients. METHODS AND PROCEDURES: We studied four items from the CRS-R (visual pursuit using a mirror, auditory localization of the own name and two movements to command) in 13 patients (7 MCS; 6 UWS). MAIN OUTCOMES AND RESULTS: Auditory stimuli triggered higher responsiveness compared to olfactory stimuli, and preferred stimuli were followed by higher scores than did neutral stimuli. CONCLUSIONS: Findings suggest that preferred auditory stimuli at the bedside contribute to the expression of residual function and could improve the diagnostic assessment.

Ising model with conserved magnetization on the human connectome: Implications on the relation structure-function in wakefulness and anesthesia.

Dynamical models implemented on the large scale architecture of the human brain may shed light on how a function arises from the underlying structure. This is the case notably for simple abstract models, such as the Ising model. We compare the spin correlations of the Ising model and the empirical functional brain correlations, both at the single link level and at the modular level, and show that their match increases at the modular level in anesthesia, in line with recent results and theories. Moreover, we show that at the peak of the specific heat (the critical state), the spin correlations are minimally shaped by the underlying structural network, explaining how the best match between the structure and function is obtained at the onset of criticality, as previously observed. These findings confirm that brain dynamics under anesthesia shows a departure from criticality and could open the way to novel perspectives when the conserved magnetization is interpreted in terms of a homeostatic principle imposed to neural activity.

Function-structure connectivity in patients with severe brain injury as measured by MRI-DWI and FDG-PET.

A vast body of literature exists showing functional and structural dysfunction within the brains of patients with disorders of consciousness. However, the function (fluorodeoxyglucose FDG-PET metabolism)-structure (MRI-diffusion-weighted images; DWI) relationship and how it is affected in severely brain injured patients remains ill-defined. FDG-PET and MRI-DWI in 25 severely brain injured patients (19 Disorders of Consciousness of which 7 unresponsive wakefulness syndrome, 12 minimally conscious; 6 emergence from minimally conscious state) and 25 healthy control subjects were acquired here. Default mode network (DMN) function-structure connectivity was assessed by fractional anisotropy (FA) and metabolic standardized uptake value (SUV). As expected, a profound decline in regional metabolism and white matter integrity was found in patients as compared with healthy subjects. Furthermore, a function-structure relationship was present in brain-damaged patients between functional metabolism of inferior-parietal, precuneus, and frontal regions and structural integrity of the frontal-inferiorparietal, precuneus-inferiorparietal, thalamo-inferioparietal, and thalamofrontal tracts. When focusing on patients, a stronger relationship between structural integrity of thalamo-inferiorparietal tracts and thalamic metabolism in patients who have emerged from the minimally conscious state as compared with patients with disorders of consciousness was found. The latter finding was in line with the mesocircuit hypothesis for the emergence of consciousness. The findings showed a positive function-structure relationship within most regions of the DMN. Hum Brain Mapp 37:3707-3720, 2016. © 2016 Wiley Periodicals, Inc.

The vegetative state/unresponsive wakefulness syndrome: a systematic review of prevalence studies.

One of the worst outcomes of acquired brain injury is the vegetative state, recently renamed 'unresponsive wakefulness syndrome' (VS/UWS). A patient in VS/UWS shows reflexive behaviour such as spontaneous eye opening and breathing, but no signs of awareness of the self or the environment. We performed a systematic review of VS/UWS prevalence studies and assessed their reliability. Medline, Embase, the Cochrane Library, CINAHL and PsycINFO were searched in April 2013 for cross-sectional point or period prevalence studies explicitly stating the prevalence of VS/UWS due to acute causes within the general population. We additionally checked bibliographies and consulted experts in the field to obtain 'grey data' like government reports. Relevant publications underwent quality assessment and data-extraction. We retrieved 1032 papers out of which 14 met the inclusion criteria. Prevalence figures varied from 0.2 to 6.1 VS/UWS patients per 100 000 members of the population. However, the publications' methodological quality differed substantially, in particular with regards to inclusion criteria and diagnosis verification. The reliability of VS/UWS prevalence figures is poor. Methodological flaws in available prevalence studies, the fact that 5/14 of the studies predate the identification of the minimally conscious state (MCS) as a distinct entity in 2002, and insufficient verification of included cases may lead to both overestimation and underestimation of the actual number of patients in VS/UWS.

[Swallowing in disorders of consciousness]. / Déglutition et états de conscience altérée.

INTRODUCTION: Interest in studying swallowing disorders in patients with altered consciousness has increased over the past decade. Swallowing deficit is frequently encountered in severe brain-injured patients. STATE OF ART: Results of studies have highlighted different factors such as the delay between the injury and the treatment and the level of consciousness of these patients, as well as the presence or not of tracheotomy, which will determine the feasibility of resuming oral feeding. Nowadays, very few valid and sensitive scales can be used to assess swallowing deficit in patients with disorders of consciousness. The Facial Oral Tract Therapy (FOTT) scale is an inter-professional multidisciplinary approach offering a structured way to evaluate and treat patients with swallowing disorders. In contrast with other scales, patients do not have to follow verbal instructions for the FOTT. PERSPECTIVES: This paper presents a review of existing literature on the assessment and management of swallowing disorders in patients with altered state of consciousness, and a description of the FOTT method. CONCLUSION: The FOTT seems to be an interesting assessment and rehabilitation tool for patients with disorders of consciousness. However, clinical studies are needed to confirm the validity and sensitivity of this technique.

[Transcranial direct current stimulation: a new tool for neurostimulation]. / La stimulation transcrânienne à courant continu: un nouvel outil de neurostimulation.

Transcranial direct current stimulation (tDCS) is a safe method to modulate cortical excitability. Anodal stimulation can improve the stimulated area's functions whereas cathodal stimulation reduces them. Currently, a lot of clinical trials have been conducted to study the effect of tDCS on post-stroke motor and language deficits, in depression, chronic pain, memory impairment and tinnitus in order to decrease symptoms. Results showed that, if an effect is observed with tDCS, it does not persist over time. Current studies suggest that direct current stimulation is a promising technique that helps to improve rehabilitation after stroke, to enhance cognitive deficiencies, to reduce depression and to relieve chronic pain. Moreover, it is a safe, simple and cheap device that could be easily integrated in a rehabilitation program.

Method for quantifying arousal and consciousness in healthy states and severe brain injury via EEG-based measures of corticothalamic physiology.

BACKGROUND: Characterization of normal arousal states has been achieved by fitting predictions of corticothalamic neural field theory (NFT) to electroencephalographic (EEG) spectra to yield relevant physiological parameters. NEW METHOD: A prior fitting method is extended to distinguish conscious and unconscious states in healthy and brain injured subjects by identifying additional parameters and clusters in parameter space. RESULTS: Fits of NFT predictions to EEG spectra are used to estimate neurophysiological parameters in healthy and brain injured subjects. Spectra are used from healthy subjects in wake and sleep and from patients with unresponsive wakefulness syndrome, in a minimally conscious state (MCS), and emerged from MCS. Subjects cluster into three groups in parameter space: conscious healthy (wake and REM), sleep, and brain injured. These are distinguished by the difference X-Y between corticocortical (X) and corticothalamic (Y) feedbacks, and by mean neural response rates α and ß to incoming spikes. X-Y tracks consciousness in healthy individuals, with smaller values in wake/REM than sleep, but cannot distinguish between brain injuries. Parameters α and ß differentiate deep sleep from wake/REM and brain injury. COMPARISON WITH EXISTING METHODS: Other methods typically rely on laborious clinical assessment, manual EEG scoring, or evaluation of measures like Φ from integrated information theory, for which no efficient method exists. In contrast, the present method can be automated on a personal computer. CONCLUSION: The method provides a means to quantify consciousness and arousal in healthy and brain injured subjects, but does not distinguish subtypes of brain injury.

Burnout in healthcare workers managing chronic patients with disorders of consciousness.

OBJECTIVES: The aim of this study was to assess the presence of burnout among professional caregivers managing patients with severe brain injury recovering from coma and working in neurorehabilitation centres or nursing homes. METHODS: The Maslach Burnout Inventory was sent to 40 centres involved in the Belgian federal network for the care of vegetative and minimally conscious patients. The following demographic data were also collected: age, gender, profession, expertise in the field, amount of time spent with patients and working place. RESULTS: Out of 1068 questionnaires sent, 568 were collected (53% response rate). Forty-five were excluded due to missing data. From the 523 healthcare workers, 18% (n = 93) presented a burnout, 33% (n = 171) showed emotional exhaustion and 36% (n = 186) had a depersonalization. Profession (i.e. nurse/nursing assistants), working place (i.e. nursing home) and the amount of time spent with patients were associated with burnout. The logistic regression showed that profession was nevertheless the strongest variable linked to burnout. CONCLUSIONS: According to this study, a significant percentage of professional caregivers and particularly nurses taking care of patients in a vegetative state and in a minimally conscious state suffered from burnout. Prevention of burnout symptoms among caregivers is crucial and is expected to promote more efficient medical care of these challenging patients.

Unresponsive wakefulness syndrome.

Recent studies providing evidence for preserved awareness in some behaviorally unresponsive patients stress the need to improve diagnosis in patients with disorders of consciousness - and stress the possible dissociation between responsiveness and preserved consciousness. Because active paradigms can only bring information in the few cases where they return positive, a major effort is needed to setup ancillary markers evaluating the brain's ability to generate consciousness without requiring the patients' collaboration - in this context, research on neural correlates of consciousness and coma science progress hand in hand.

A default mode of brain function in altered states of consciousness.

Using modern brain imaging techniques, new discoveries are being made concerning the spontaneous activity of the brain when it is devoid of attention-demanding tasks. Spatially separated patches of neuronal assemblies have been found to show synchronized oscillatory activity behavior and are said to be functionally connected. One of the most robust of these is the default mode network, which is associated with intrinsic processes like mind wandering and self-projection. Furthermore, activity in this network is anticorrelated with activity in a network that is linked to attention to external stimuli. The integrity of both networks is disturbed in altered states of consciousness, like sleep, general anesthesia and hypnosis. In coma and related disorders of consciousness, encompassing the vegetative state (unresponsive wakefulness syndrome) and minimally conscious state, default mode network integrity correlates with the level of remaining consciousness, offering the possibility of using this information for diagnostic and prognostic purposes. Functional brain imaging is currently being validated as a valuable addition to the standardized behavioral assessments that are already in use.

Neural correlates of consciousness during general anesthesia using functional magnetic resonance imaging (fMRI).

This paper reviews the current knowledge about the mechanisms of anesthesia-induced alteration of consciousness. It is now evident that hypnotic anesthetic agents have specific brain targets whose function is hierarchically altered in a dose-dependent manner. Higher order networks, thought to be involved in mental content generation, as well as sub-cortical networks involved in thalamic activity regulation seems to be affected first by increasing concentrations of hypnotic agents that enhance inhibitory neurotransmission. Lower order sensory networks are preserved, including thalamo-cortical connectivity into those networks, even at concentrations that suppress responsiveness, but cross-modal sensory interactions are inhibited. Thalamo-cortical connectivity into the consciousness networks decreases with increasing concentrations of those agents, and is transformed into an anti-correlated activity between the thalamus and the cortex for the deepest levels of sedation, when the subject is non responsive. Future will tell us whether these brain function alterations are also observed with hypnotic agents that mainly inhibit excitatory neurotransmission. The link between the observations made using fMRI and the identified biochemical targets of hypnotic anesthetic agents still remains to be identified.

Electrophysiological investigations of brain function in coma, vegetative and minimally conscious patients.

Electroencephalographic activity in the context of disorders of consciousness is a swiss knife like tool that can evaluate different aspects of cognitive residual function, detect consciousness and provide a mean to communicate with the outside world without using muscular channels. Standard recordings in the neurological department offer a first global view of the electrogenesis of a patient and can spot abnormal epileptiform activity and therefore guide treatment. Although visual patterns have a prognosis value, they are not sufficient to provide a diagnosis between vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS) patients. Quantitative electroencephalography (qEEG) processes the data and retrieves features, not visible on the raw traces, which can then be classified. Current results using qEEG show that MCS can be differentiated from VS/UWS patients at the group level. Event Related Potentials (ERP) are triggered by varying stimuli and reflect the time course of information processing related to the stimuli from low-level peripheral receptive structures to high-order associative cortices. It is hence possible to assess auditory, visual, or emotive pathways. Different stimuli elicit positive or negative components with different time signatures. The presence of these components when observed in passive paradigms is usually a sign of good prognosis but it cannot differentiate VS/UWS and MCS patients. Recently, researchers have developed active paradigms showing that the amplitude of the component is modulated when the subject's attention is focused on a task during stimulus presentation. Hence significant differences between ERPs of a patient in a passive compared to an active paradigm can be a proof of consciousness. An EEG-based brain-computer interface (BCI) can then be tested to provide the patient with a communication tool. BCIs have considerably improved the past two decades. However they are not easily adaptable to comatose patients as they can have visual or auditory impairments or different lesions affecting their EEG signal. Future progress will require large databases of resting state-EEG and ERPs experiment of patients of different etiologies. This will allow the identification of specific patterns related to the diagnostic of consciousness. Standardized procedures in the use of BCIs will also be needed to find the most suited technique for each individual patient.

Linking sleep and general anesthesia mechanisms: this is no walkover.

This review aims at defining the link between physiological sleep and general anesthesia. Despite common behavioral and electrophysiological characteristics between both states, current literature suggests that the transition process between waking and sleep or anesthesia-induced alteration of consciousness is not driven by the same sequence of events. On the one hand, sleep originates in sub-cortical structures with subsequent repercussions on thalamo-cortical interactions and cortical activity. On the other hand, anesthesia seems to primarily affect the cortex with subsequent repercussions on the activity of sub-cortical networks. This discrepancy has yet to be confirmed by further functional brain imaging and electrophysiological experiments. The relationship between the observed functional modifications of brain activity during anesthesia and the known biochemical targets of hypnotic anesthetic agents also remains to be determined.

[The Sensory Modality Assessment and Rehabilitation Technique (SMART): a behavioral assessment scale for disorders of consciousness]. / La Sensory Modality Assessment and Rehabilitation Technique (SMART) : une échelle comportementale d'évaluation et de revalidation pour des états altérés de conscience.

INTRODUCTION: Difficulties in detecting bedside signs of consciousness in non-communicative patients still lead to a high rate of misdiagnosis illustrating the need to employ standardized behavioral assessment scales. STATE OF ART: The Sensory Modality Assessment and Rehabilitation Technique (SMART) is a behavioral assessment scale of consciousness that assesses responses to multimodal sensory stimulation in disorders of consciousness. These stimulations can also be considered to have therapeutic value. PERSPECTIVES: We here review the different components and use of the SMART assessment and discuss its validity, reliability, and robustness in clinical practice. The scale has a high intra- and inter-observer reliability thanks to a detailed procedure description. However, in the absence of objective gold standards in the assessment of consciousness, it is currently difficult to make strong claims about its validity. A comparison between SMART and other standardized and validated coma-scales is proposed. CONCLUSION: In our view, SMART is an interesting tool for monitoring patients with altered states of consciousness subsequent to coma. Currently, we await studies on its concurrent validity as compared to other validated behavioral assessment scales and on the effect of SMART stimulations on patient outcome.

Clinical and advanced neurophysiology in the prognostic and diagnostic evaluation of disorders of consciousness: review of an IFCN-endorsed expert group.

The analysis of spontaneous EEG activity and evoked potentialsis a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). Thepast few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury,opening up the prospect that new concepts and tools may be available at the bedside. This paper provides a comprehensive, critical overview of bothconsolidated and investigational electrophysiological techniquesfor the prognostic and diagnostic assessment of DoC.We describe conventional clinical EEG approaches, then focus on evoked and event-related potentials, and finally we analyze the potential of novel research findings. In doing so, we (i) draw a distinction between acute, prolonged and chronic phases of DoC, (ii) attempt to relate both clinical and research findings to the underlying neuronal processes and (iii) discuss technical and conceptual caveats.The primary aim of this narrative review is to bridge the gap between standard and emerging electrophysiological measures for the detection and prediction of recovery of consciousness. The ultimate scope is to provide a reference and common ground for academic researchers active in the field of neurophysiology and clinicians engaged in intensive care unit and rehabilitation.

Pain and non-pain processing during hypnosis: a thulium-YAG event-related fMRI study.

The neural mechanisms underlying the antinociceptive effects of hypnosis still remain unclear. Using a parametric single-trial thulium-YAG laser fMRI paradigm, we assessed changes in brain activation and connectivity related to the hypnotic state as compared to normal wakefulness in 13 healthy volunteers. Behaviorally, a difference in subjective ratings was found between normal wakefulness and hypnotic state for both non-painful and painful intensity-matched stimuli applied to the left hand. In normal wakefulness, non-painful range stimuli activated brainstem, contralateral primary somatosensory (S1) and bilateral insular cortices. Painful stimuli activated additional areas encompassing thalamus, bilateral striatum, anterior cingulate (ACC), premotor and dorsolateral prefrontal cortices. In hypnosis, intensity-matched stimuli in both the non-painful and painful range failed to elicit any cerebral activation. The interaction analysis identified that contralateral thalamus, bilateral striatum and ACC activated more in normal wakefulness compared to hypnosis during painful versus non-painful stimulation. Finally, we demonstrated hypnosis-related increases in functional connectivity between S1 and distant anterior insular and prefrontal cortices, possibly reflecting top-down modulation.