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Language assessment in post-comatose patients is difficult due to their limited behavioral repertoire; yet associated language deficits might lead to an underestimation of consciousness levels in unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS; -/+) diagnoses. We present a systematic review of studies from 2002 assessing residual language abilities with neuroimaging, electrophysiological or behavioral measures in patients with severe brain injury. Eighty-five articles including a total of 2278 patients were assessed for quality. The median percentages of patients showing residual implicit language abilities (i.e., cortical responses to specific words/sentences) were 33 % for UWS, 50 % for MCS- and 78 % for MCS + patients, whereas explicit language abilities (i.e., command-following using brain-computer interfaces) were reported in 20 % of UWS, 33 % of MCS- and 50 % of MCS + patients. Cortical responses to verbal stimuli increased along with consciousness levels and the progressive recovery of consciousness after a coma was paralleled by the reappearance of both implicit and explicit language processing. This review highlights the importance of language assessment in patients with disorders of consciousness.

The Nociception Coma Scale-Revised (NCS-R) was developed to help assess pain in patients with disorders of consciousness (DOC). Several studies have shown its sensitivity in assessing response to acute noxious stimuli. However, they failed to determine a reliable cut-off score that could be used to infer pain processing in these patients. This retrospective cross-sectional study aimed to determine a NCS-R cut-off score supporting preserved neural basis for pain experience, based on brain metabolism preservation as measured by fluorodeoxyglucose positron emission tomography (FDG-PET). We included patients in unresponsive wakefulness syndrome (UWS) confirmed by the FDG-PET and examined the NCS-R total scores. As the highest score was 4, we defined the cut-off to be 5 and compared the brain metabolism of these patients to matched patients with DOC and a NCS-R cut-off score ≥5 (ie, potential pain), as well as healthy subjects. We found a higher global cerebral metabolism in healthy subjects compared to both patient groups and also in patients with potential pain compared with FDG-PET confirmed UWS. We observed a preserved metabolism in the left insula in patients with potential pain compared with FDG-PET confirmed UWS. PERSPECTIVES: Our data suggest that using the cut-off score of 5 could be helpful to improve pain management in patients with DOC. Future studies should focus on patients showing scores below this cut-off to better characterize their profile and improve care.

Background. The minimally conscious state (MCS) is subcategorized into MCS− and MCS+, depending on the absence or presence, respectively, of high-level behavioral responses such as command-following. Objective. We aim to investigate the functional and structural neuroanatomy underlying the presence of these responses in MCS− and MCS+ patients. Methods. In this cross-sectional retrospective study, chronic MCS patients were diagnosed using repeated Coma Recovery Scale–Revised assessments. Fluorodeoxyglucose-positron emission tomography data were acquired on 57 patients (16 MCS−; 41 MCS+) and magnetic resonance imaging with voxel-based morphometry analysis was performed on 66 patients (17 MCS−; 49 MCS+). Brain glucose metabolism and gray matter integrity were compared between patient groups and control groups. A metabolic functional connectivity analysis testing the hypothesis of preserved language network in MCS+ compared with MCS− was also done. Results. Patients in MCS+ presented higher metabolism mainly in the left middle temporal cortex, known to be important for semantic processing, compared with the MCS− group. The left angular gyrus was also functionally disconnected from the left prefrontal cortex in MCS− compared with MCS+ group. No significant differences were found in gray matter volume between patient groups. Conclusions. The clinical subcategorization of MCS is supported by differences in brain metabolism but not in gray matter structure, suggesting that brain function in the language network is the main support for recovery of command-following, intelligible verbalization and/or intentional communication in the MCS. Better characterizing the neural correlates of residual cognitive abilities of MCS patients contributes to reduce their misdiagnosis and to adapt therapeutic approaches.

Behavioral examinations may fail to detect language function in patients with severe traumatic brain injury (TBI) due to confounds such as having an endotracheal tube. We investigated whether resting and stimulus-evoked electroencephalography (EEG) methods detect the presence of language function in patients with severe TBI. Four EEG measures were assessed: (1) resting background (applying Forgacs’ criteria), (2) reactivity to speech, (3) background and reactivity (applying Synek’s criteria); and (4) an automated support vector machine (classifier for speech versus rest). Cohen’s kappa measured agreement between the four EEG measures and evidence of language function on a behavioral coma recovery scale-revised (CRS-R) and composite (CRS-R or functional MRI) reference standard. Sensitivity and specificity of each EEG measure were calculated against the reference standards. We enrolled 17 adult patients with severe TBI (mean ± SD age 27.0 ± 7.0 years; median [range] 11.5 [2–1173] days post-injury) and 16 healthy subjects (age 28.5 ± 7.8 years). The classifier, followed by Forgacs’ criteria for resting background, demonstrated the highest agreement with the behavioral reference standard. Only Synek’s criteria for background and reactivity showed significant agreement with the composite reference standard. The classifier and resting background showed balanced sensitivity and specificity for behavioral (sensitivity = 84.6% and 80.8%; specificity = 57.1% for both) and composite reference standards (sensitivity = 79.3% and 75.9%, specificity = 50% for both). Methods applying an automated classifier, resting background, or resting background with reactivity may identify severe TBI patients with preserved language function. Automated classifier methods may enable unbiased and efficient assessment of larger populations or serial timepoints, while qualitative visual methods may be practical in community settings.

Background Spasticity management in severely brain-injured patients with disorders of consciousness (DOC) is a major challenge because it leads to complications and severe pain that can seriously affect quality of life. Objectives We aimed to determine the feasibility of a single session of transcranial direct current stimulations (tDCS) to reduce spasticity in chronic patients with DOC. Methods We enrolled 14 patients in this double-blind, sham-controlled randomized crossover pilot study. Two cathodes were placed over the left and right primary motor cortex and 2 anodes over the left and right prefrontal cortex. Hypertonia of the upper limbs and level of consciousness were assessed by the Modified Ashworth Scale (MAS) and the Coma Recovery Scale-Revised (CRS-R). Resting state electroencephalography was also performed. Results At the group level, spasticity was reduced in only finger flexors. Four responders (29%) showed reduced hypertonicity in at least 2 joints after active but not sham stimulation. We found no behavioural changes by the CRS-R total score. At the group level, connectivity values in beta2 were higher with active versus sham stimulation. Relative power in the theta band and connectivity in the beta band were higher for responders than non-responders after the active stimulation. Conclusion This pilot study highlights the potential benefit of using tDCS for reducing upper-limb hypertonia in patients with chronic DOC. Large-sample clinical trials are needed to optimize and validate the technique.

Background and purpose. Patients with prolonged disorders of consciousness (pDoC) have a high mortality rate due to medical complications. Since an accurate prognosis is essential for decision-making on patients’ management, we analysed data from an international multicentre prospective cohort study to evaluate two-year mortality rate and bedside predictors of mortality. Methods. We enrolled adult patients in prolonged vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) after traumatic and non-traumatic brain injury within 3 months post-injury. At enrolment we collected demographic (age; sex), anamnestic (etiology; time post-injury), clinical (Coma Recovery Scale Revised, CRS-R; Disability Rating Scale; Nociception Coma Scale-Revised) and neurophysiologic (EEG; somatosensory evoked and event-related potentials) data. Patients were followed-up to gather data on mortality up to 24 months post- injury. Results. Among 143 traumatic (n=55) and non-traumatic (n=88) patients (VS/UWS=68, 19 females; MCS=75, 22 females), 41 (28.7%) died within 24 months post-injury. Mortality rate was higher in VS/UWS (42.6%) than in MCS (16%; p Conclusions. This study demonstrated that a feasible multimodal assessment in the post-acute phase can help clinicians to identify patients with pDoC at higher risk of mortality within 24 months after brain injury. This evidence can help clinicians and patients’ families to navigate the complex clinical decision-making process and promote an international standardization of prognostic procedures for patients with pDoC.

Disorders of consciousness (DOC) are a common consequence of severe brain injuries, and clinical evaluation is critical to provide a correct diagnosis and prognosis. The revised Motor Behavior Tool (MBT-r) is a clinical complementary tool aiming to identify subtle motor behaviors that might reflect residual cognition in DOC. In this prospective study including 30 DOC patients in the early stage after brain injury, we show that the revised MBT-r has an excellent inter-rater agreement and has the ability to identify a subgroup of patients, underestimated by the Coma Recovery Scale-Revised, showing residual cognition and a subsequent recovery of consciousness. ANN NEUROL 2019;85:443-447.

PRIMARY OBJECTIVE: The assessment of language in patients post-comatose patients is limited by their reduced behavioral repertoire. We developed the Brief Evaluation of Receptive Aphasia (BERA) tool for assessing phonological, semantic and morphosyntactic abilities in patients with severe brain injury based on visual fixation responses. RESEARCH DESIGN: Prospective cross-sectional study and case reports. METHODS AND PROCEDURE: The BERA and Language Screening Test were first administered to 52 conscious patients with aphasia on two consecutive days in order to determine the validity and reliability of the BERA. Four post-comatose patients were further examined with the BERA, the Coma Recovery Scale-Revised (CRS-R), positron emission tomography and structural magnetic resonance imaging. MAIN OUTCOME AND RESULTS: The BERA showed satisfactory intra- and inter-rater reliability, as well as internal and concurrent validity in patients with aphasia. The BERA scores indicated selective receptive difficulties for phonological, semantic and particularly morphosyntactic abilities in post-comatose patients. These results were in line with the cortical distribution of brain lesions. CONCLUSIONS: The BERA may complement the widely used CRS-R for assessing and diagnosing patients with disorders of consciousness by providing a systematic and detailed characterization of residual language abilities.

Neuro-orthopedic disorders are common in patients with disorders of consciousness (DOC) and can lead to potential pain. However, the patients' inability to communicate makes pain detection and management very challenging for clinicians. In this crossover randomized double-blind placebo-controlled study, we investigated the effects of an analgesic treatment on the presence of nociception-related behaviors. At baseline, the Nociception Coma Scale-Revised (NCS-R) was performed in 3 conditions: a non-noxious stimulation, a noxious stimulation, and during a physiotherapy session. Patients with a NCS-R total score during physiotherapy equal or above the score observed after the noxious stimulation could participate to the clinical trial, as well as patients with a score above 5. They received an analgesic treatment and a placebo on 2 consecutive days in a randomized order followed by an assessment with the NCS-R. Of the 18 patients, 15 displayed signs of potential pain during physiotherapy. Patients showed higher NCS-R scores during physiotherapy compared with the other conditions, suggesting that mobilizations were potentially painful. Of these 15 patients, 10 met the criteria to participate in the placebo-controlled trial. We did not find any effect of analgesic treatment on the NCS-R scores. This study highlights that physiotherapy may be potentially painful for patients with DOC, while analgesic treatments did not reduced NCS-R scores. Therefore, careful monitoring with appropriate assessment and treatment before and during mobilization should become a priority in clinical settings. Future studies should focus on the development of assessment tools sensitive to analgesic dosage to manage pain in DOC.

The evaluation of the level of consciousness in patients with disorders of consciousness (DOC) is primarily based on behavioural assessments. Patients with unresponsive wakefulness syndrome (UWS) do not show any sign of awareness of their environment, while minimally conscious state (MCS) patients show reproducible but fluctuating signs of awareness. Some patients, although with remaining cognitive abilities, are not able to exhibit overt voluntary responses at the bedside and may be misdiagnosed as UWS. Several studies investigated functional neuroimaging and neurophysiology as an additional tool to evaluate the level of consciousness and to detect covert command following in DOC. Most of these studies are based on auditory stimulation, neglecting patients suffering from decreased or absent hearing abilities. In the present study, we aim to assess the response to a P3-based paradigm in 40 patients with DOC and 12 healthy participants using auditory (AEP) and vibrotactile (VTP) stimulation. To this end, an EEG-based brain-computer interface was used at DOC patient’s bedside. We compared the significance of the P3 performance (i.e., the interpretation of significance of the evoked P3 response) as obtained by ‘direct processing’ (i.e., theoretical-based significance threshold) and ‘offline processing’ (i.e., permutation-based single subject level threshold). We evaluated whether the P3 performances were dependent on clinical variables such as diagnosis (UWS and MCS), aetiology and time since injury. Last we tested the dependency of AEP and VTP performances at the single subject level. Direct processing tends to overestimate P3 performance. We did not find any difference in the presence of a P3 performance according to the level of consciousness (UWS vs. MCS) or the aetiology (traumatic vs. non-traumatic brain injury). The performance achieved at the AEP paradigm was independent from what was achieved at the VTP paradigm, indicating that some patients performed better on the AEP task while others performed better on the VTP task. Our results support the importance of using multimodal approaches in the assessment of DOC patients in order to optimise the evaluation of patient’s abilities.

Objective: The aim of the study was to check on the reliability and validity of the translated version of Nociception Coma Scale–Revised. Design: Prospective psychometric study. Setting: Rehabilitation and neurology unit in hospital. Subjects: Patients with prolonged disorders of consciousness. Interventions: None. Main measures: The original English version of the Nociception Coma Scale–Revised was translated into Chinese. The reliability and validity were undertaken by trained raters. Intraclass correlation coefficients were used to assess inter-rater reliability and test–retest reliability. Cronbach’s alpha test was used to investigate internal consistency. Spearman’s correlation was used to calculate concurrent validity. The Coma Recovery Scale–revised was used to assess the consciousness of patients. Results: Eighty-four patients were enrolled in the study. Inter-rater reliability of the Chinese version of Nociception Coma Scale–Revised was high for total scores and motor and verbal subscores and good for facial subscores. Test–retest reliability was high for total score and for all subscores. Analysis revealed a moderate internal consistency for subscores. For the concurrent validity, a strong correlation was found between the Nociception Coma Scale–Revised and the Face, Legs, Activity, Cry, and Consolability behavioral scale for all patients. A moderate correlation was found between the Nociception Coma Scale–Revised and the Coma Recovery Scale–revised scores for all patients. Conclusion: The Chinese version of Nociception Coma Scale–Revised has good reliability and validity data for assessing responses to pain in patients with prolonged disorders of consciousness.

The Coma Recovery Scale-Revised (CRS-R) is the gold standard to assess severely brain-injured patients with prolonged disorders of consciousness (DoC). However, the amount of time needed to complete this examination may limit its use in clinical settings.We aimed to validate a new faster tool to assess consciousness in individuals with DoC.This prospective validation study introduces the Simplified Evaluation of CONsciousness Disorders (SECONDs), a tool composed of 8 items: arousal, localization to pain, visual fixation, visual pursuit, oriented behaviors, command-following, and communication (both intentional and functional). A total of 57 individuals with DoC were assessed on 2 consecutive days by 3 blinded examiners: one CRS-R and one SECONDs were performed on 1 day, whereas 2 SECONDs were performed on the other day. A Mann-Whitney U test was used to compare the duration of administration of the SECONDs versus the CRS-R, and weighted Fleiss' kappa coefficients were used to assess inter-/intra-rater reliability as well as concurrent validity.In the 57 participants, the SECONDs was about 2.5 times faster to administer than the CRS-R. The comparison of the CRS-R versus the SECONDs on the same day or the best of the 3 SECONDs led to "substantial" or "almost perfect" agreement (kappa coefficients ranging from 0.78 to 0.85). Intra-/inter-rater reliability also showed almost perfect agreement (kappa coefficients from 0.85 to 0.91 and 0.82 to 0.85, respectively).The SECONDs appears to be a fast, reliable and easy-to-use scale to diagnose DoC and may be a good alternative to other scales in clinical settings where time constraints preclude a more thorough assessment.

WOS: 000515065900001, PubMed: 32090418, 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.

Background: A significant proportion of brain-injured patients who are unresponsive at the bedside (i.e., unresponsive wakefulness syndrome – UWS) may present brain activity similar to patients in minimally conscious state (MCS). This peculiar condition has been termed “non-behavioural MCS” or “MCS*”. Methods: Brain 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was acquired on 135 brain-injured patients diagnosed in prolonged UWS (n=48) or MCS (n=87). Clinical diagnosis was based on repeated Coma Recovery Scale-Revised assessments. Relative metabolic preservation in the fronto-parietal network (measured with standardized uptake value) was evaluated by 3 experts blinded to the clinical diagnosis. Patients with hypometabolism of the fronto-parietal network were labelled UWS, while preservation either confirmed the behavioural diagnosis of MCS or, in absence of behavioural signs of consciousness, suggested a diagnosis of MCS*. The clinical outcome at 1-year follow-up, the functional connectivity (measured with electroencephalography), the grey matter atrophy (assessed with magnetic resonance imaging), and the regional brain metabolic patterns were investigated in the three groups (UWS, MCS* and MCS). Findings: Out of the 48 behavioural UWS patients, 32 (67%) presented a partial preservation of brain metabolism (i.e., MCS*). Compared to the hypometabolic UWS patients, MCS* patients demonstrated a better outcome, higher global functional connectivity in the alpha and theta bands, as well as greater grey matter preservation in the frontal and temporal regions, the fusiform gyrus, and the insula. MCS* patients presented lower brain metabolism mostly in the posterior regions compared to MCS patients. Interpretation: MCS* is a frequent phenomenon that is also associated with a better outcome than the diagnosis of UWS. Complementary exams should be provided to all unresponsive patients before taking medical decisions. Funding Statement: Belgian National Funds for Scientific Research, Human Brain Project SGA3 (No. 945539), DOCMA project (EU-H2020-MSCA–RISE–778234), Belgian Federal Science Policy Office (PRODEX), Bial Foundation, fund Generet, King Baudouin Foundation, AstraZeneca Foundation. Declaration of Interests: The authors declare that there is no conflict of interest regarding the publication of this paper. Ethics Approval Statement: The study was approved by the Ethics Committee of the Faculty of Medicine of the University of Liege. Written informed consent was obtained from healthy controls and patients' legal representatives.

Auditory localization (i.e. turning the head and/or the eyes towards an auditory stimulus) is often part of the clinical evaluation of patients recovering from coma. The objective of this study is to determine whether auditory localization could be considered as a new sign of minimally conscious state, using a multimodal approach. The presence of auditory localization and the clinical outcome at 2 years of follow-up were evaluated in 186 patients with severe brain injury, including 64 with unresponsive wakefulness syndrome, 28 in minimally conscious state minus, 71 in minimally conscious state plus and 23 who emerged from the minimally conscious state. Brain metabolism, functional connectivity and graph theory measures were investigated by means of 18F-fluorodeoxyglucose positron emission tomography, functional MRI and high-density electroencephalography in two subgroups of unresponsive patients, with and without auditory localization. These two subgroups were also compared to a subgroup of patients in minimally conscious state minus. Auditory localization was observed in 13% of unresponsive patients, 46% of patients in minimally conscious state minus, 62% of patients in minimally conscious state plus and 78% of patients who emerged from the minimally conscious state. The probability to observe an auditory localization increased along with the level of consciousness, and the presence of auditory localization could predict the level of consciousness. Patients with auditory localization had higher survival rates (at 2-year follow-up) than those without localization. Differences in brain function were found between unresponsive patients with and without auditory localization. Higher connectivity in unresponsive patients with auditory localization was measured between the fronto-parietal network and secondary visual areas, and in the alpha band electroencephalography network. Moreover, patients in minimally conscious state minus significantly differed from unresponsive patients without auditory localization in terms of brain metabolism and alpha network centrality, whereas no difference was found with unresponsive patients who presented auditory localization. Our multimodal findings suggest differences in brain function between unresponsive patients with and without auditory localization, which support our hypothesis that auditory localization should be considered as a new sign of minimally conscious state. Unresponsive patients showing auditory localization should therefore no longer be considered unresponsive but minimally conscious. This would have crucial consequences on these patients’ lives as it would directly impact the therapeutic orientation or end-of-life decisions usually taken based on the diagnosis., This study provides evidence that auditory localization should be considered as a new sign of minimally conscious state. The prevalence of auditory localization increases with the level of consciousness, and patients with unresponsive wakefulness syndrome and auditory localization have higher brain functioning and better outcome than unresponsive patients who do not show auditory localization., Graphical Abstract Graphical Abstract

[EN] Covert cognition in patients with disorders of consciousness represents a real diagnostic conundrum for clinicians. In this meta-analysis, our main objective was to identify clinical and demographic variables that are more likely to be associated with responding to an active paradigm. Among 2018 citations found on PubMed, 60 observational studies were found relevant. Based on the QUADAS-2, 49 studies were considered. Data from 25 publications were extracted and included in the meta-analysis. Most of these studies used electrophysiology as well as counting tasks or mental imagery. According to our statistical analysis, patients clinically diagnosed as being in a vegetative state and in a minimally conscious state minus (MCS-) show similar likelihood in responding to active paradigm and responders are most likely suffering from a traumatic brain injury. In the future, multi-centric studies should be performed in order to increase sample size, with similar methodologies and include structural and functional neuroimaging in order to identify cerebral markers related to such a challenging diagnosis., C.S. would like to thank Felice Loverso, the Casa Colina Board of Directors, the Casa Colina Foundation and the International Brain Injury Association for supporting this research.

Objectives To investigate the relation between consciousness and nociceptive responsiveness (ie, Nociception Coma Scale–Revised [NCS-R]), to examine the suitability of the NCS-R for assessing nociception in participants with disorders of consciousness (DOC), and to replicate previous findings on psychometric properties of the scale. Design Specialized DOC program. Setting Specialized DOC program and university hospitals. Participants Participants (N=85) diagnosed with DOC. Interventions Not applicable. Main Outcome Measures We prospectively assessed consciousness with the Coma Recovery Scale–Revised (CRS-R). Responses during baseline, non-noxious, and noxious stimulations were scored with the NCS-R and CRS-R oromotor and motor subscales. Results CRS-R total scores correlated with NCS-R total scores and subscores. CRS-R motor subscores correlated with NCS-R total scores and motor subscores, and CRS-R oromotor subscores correlated with NCS-R total scores as well as verbal and facial expression subscores. There was a difference between unresponsive wakefulness syndrome and minimally conscious state in the proportion of grimacing and/or crying participants during noxious conditions. We replicated previous findings on psychometric properties of the scale but found a different score as the best threshold for nociception. Conclusions We report a strong relation between the responsiveness to nociception and the level of consciousness. The NCS-R seems to be a valuable tool for assessing nociception in an efficient manner, but additional studies are needed to allow recommendations for clinical assessment of subjective pain experience.

BackgroundClinical assessment of patients with disorders of consciousness (DOC) relies on the clinician’s ability to detect a behavioral response to an instruction (e.g., “squeeze my hand”). However, recent studies have shown that some of these patients can produce volitional brain responses to command while no behavioral response is present. This highlights the importance of developing motor-independent diagnostic tool for this population, complementing standardized behavioral evaluation. We here evaluate the ability of a novel gaze-independent attention-based EEG paradigm to detect volitional attentional processes in patients with disorders of consciousness.MethodsThirty patients with DOC were included in the study: 12 with an unresponsive wakefulness syndrome, 16 in a minimally conscious state (MCS), two who emerged from a MCS. Patients were randomly instructed to either concentrate on a task or rest while brain activity was recorded using EEG during a gaze-independent paradigm.ResultsOne of two EMCS, one of 16 MCS and one of 12 UWS patients showed a response to command using the attention task. Interestingly, this method could detect a brain-based response to command in one MCS patient who did not present a behavioral response to command at the bedside the day of the assessment.ConclusionThis study show that task-related variation of attention during an active task could help to objectively detect response to command in patients with DOC.

Electroencephalography (EEG) has been proposed as a supplemental tool for reducing clinical misdiagnosis in severely brain-injured populations helping to distinguish conscious from unconscious patients. We studied the use of spectral entropy as a measure of focal attention in order to develop a motor-independent, portable, and objective diagnostic tool for patients with locked-in syndrome (LIS), answering the issues of accuracy and training requirement. Data from 20 healthy volunteers, 6 LIS patients, and 10 patients with a vegetative state/unresponsive wakefulness syndrome (VS/UWS) were included. Spectral entropy was computed during a gaze-independent 2-class (attention vs rest) paradigm, and compared with EEG rhythms (delta, theta, alpha, and beta) classification. Spectral entropy classification during the attention-rest paradigm showed 93% and 91% accuracy in healthy volunteers and LIS patients respectively. VS/UWS patients were at chance level. EEG rhythms classification reached a lower accuracy than spectral entropy. Resting-state EEG spectral entropy could not distinguish individual VS/UWS patients from LIS patients. The present study provides evidence that an EEG-based measure of attention could detect command-following in patients with severe motor disabilities. The entropy system could detect a response to command in all healthy subjects and LIS patients, while none of the VS/UWS patients showed a response to command using this system.

Transcranial direct current stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) has induced promising behavioral improvement, both in acute and chronic minimally conscious state (MCS - [ 1 ]) patients [ 2 , 3 ]. We previously defined a tDCS-responder as a patient who demonstrates a new sign of consciousness following stimulation, which was neither present beforehand, nor before or after the sham stimulation [ 2 ]. In a study investigating the metabolic and structural differences between DLPFC-tDCS-responders and non-responders, we have identified that tDCS-responders presented a preservation of brain metabolism and grey matter integrity under the stimulated area, but also in the thalamus and the precuneus, areas involved in consciousness recovery [ 4 ]. Even if these results provided relevant insights into potential biomarkers of responsiveness, the access to such neuroimaging techniques (positron emission tomography - PET - and magnetic resonance imaging - MRI) remains limited. Recently, it has been demonstrated that high-density electroencephalography (hdEEG) network metrics in the alpha band correlates with the level of consciousness [ 5 ]. In addition, a strong correlation between brain metabolism and hdEEG network metrics was reported, making this bedside assessment a robust way to evaluate patients’ brain function.

Severe brain injury may cause disruption of neural networks that sustain arousal and awareness, the two essential components of consciousness. Despite the potentially devastating immediate and long-term consequences, disorders of consciousness (DoC) are poorly understood in terms of their underlying neurobiology, the relationship between pathophysiology and recovery, and the predictors of treatment efficacy. Recent advances in neuroimaging techniques have enabled the study of network connectivity, providing great potential to improve the clinical care of patients with DoC. Initial discoveries in this field were made using positron emission tomography (PET). More recently, functional magnetic resonance (fMRI) techniques have added to our understanding of functional network dynamics in this population. Both methods have shown that whether at rest or performing a goal-oriented task, functional networks essential for processing intrinsic thoughts and extrinsic stimuli are disrupted in patients with DoC compared with healthy subjects. Atypical connectivity has been well established in the default mode network as well as in other cortical and subcortical networks that may be required for consciousness. Moreover, the degree of altered connectivity may be related to the severity of impaired consciousness, and recovery of consciousness has been shown to be associated with restoration of connectivity. In this review, we discuss PET and fMRI studies of functional and effective connectivity in patients with DoC and suggest how this field can move toward clinical application of functional network mapping in the future.

Objectives: To assess the effects of repeated transcranial direct current stimulation (tDCS) sessions on the level of consciousness in chronic patients in minimally conscious state (MCS). Methods: In this randomized double-blind sham-controlled crossover study, we enrolled 16 patients in chronic MCS. For 5 consecutive days, each patient received active or sham tDCS over the left prefrontal cortex (2 mA during 20 min). Consciousness was assessed with the Coma Recovery Scale-Revised (CRS-R) before the first stimulation (baseline), after each stimulation (day 1–day 5) and 1 week after the end of each session (day 12). Results: A treatment effect (p = 0.013; effect size = 0.43) was observed at the end of the active tDCS session (day 5) as well as 1 week after the end of the active tDCS session (day 12; p = 0.002; effect size = 0.57). A longitudinal increase of the CRS-R total scores was identified for the active tDCS session (p < 0.001), while no change was found for the sham session (p = 0.64). Nine patients were identified as responders (56%). Conclusion: Our results suggest that repeated (5 days) left prefrontal tDCS improves the recovery of consciousness in some chronic patients in MCS, up to 1 week after the end of the stimulations.

OBJECTIVE: To propose a new methodology based on single-trial analysis for detecting residual response to command with EMG in patients with disorders of consciousness (DOC), overcoming the issue of trial dependency and decreasing the influence of a patient's fluctuation of vigilance or arousal over time on diagnostic accuracy.METHODS: Forty-five patients with DOC (18 with vegetative/unresponsive wakefulness syndrome [VS/UWS], 22 in a minimally conscious state [MCS], 3 who emerged from MCS [EMCS], and 2 with locked-in syndrome [LIS]) and 20 healthy controls were included in the study. Patients were randomly instructed to either move their left or right hand or listen to a control command ("It is a sunny day") while EMG activity was recorded on both arms.RESULTS: Differential EMG activity was detected in all MCS cases displaying reproducible response to command at bedside on multiple assessments, even though only 6 of the 14 individuals presented a behavioral response to command on the day of the EMG assessment. An EMG response was also detected in all EMCS and LIS patients, and 2 MCS patients showing nonreflexive movements without command following at the bedside. None of the VS/UWS presented a response to command with this method.CONCLUSIONS: This method allowed us to reliably distinguish between different levels of consciousness and could potentially help decrease diagnostic errors in patients with motor impairment but presenting residual motor activity.

The present report shows the case of a patient who came with the diagnosis of UWS and who was then diagnosed as being in MCS minus following repeated standardized behavioral assessments. Neuroimaging data further suggested that the patient presented preservation of brain activity closer to what is usually observed in healthy subjects.The presence of a minimal sign of consciousness (i.e., localization to noxious stimuli) was only observed once out of seven behavioral assessments, and active tasks using fMRI and EEG suggested the presence of covert command-following. During this week of assessments, overt response to command was never observed at the patient's bedside. This behavior was solely seen following the experimental procedure of tDCS, after which the patient could reproducibly answer a simple behavioral command. Based on these findings, we hypothesize that tDCS may facilitate motor execution of the command when cognitive functions are preserved in patients with cognitive-motor dissociation.

Objective To investigate the influence of the presence of a tracheostomy tube to assess pain with the Nociception Coma Scale-Revised (NCS-R) in patients with disorders of consciousness (DOC). Design A cohort study in which patients were evaluated at a single time point. Setting Patients were evaluated in a tertiary care hospital. Participants Patients (N=125) (unresponsive wakefulness syndrome [UWS]: 46 patients, minimally conscious state [MCS]: 74 patients, emerging from MCS [eMCS]: 5 patients, mean age: 46±16y, time since injury: 817±1280d) in a convenience sample were evaluated with the NCS-R after noxious stimulation. Interventions Not applicable. Main Outcome Measures We compared the NCS-R scores of patients with and without tracheostomy with a Mann-Whitney U test. A secondary outcome was to evaluate the influence of the presence of a tracheostomy on the previously described cutoff score of 2. Results The presence of a tracheostomy was associated with lower verbal subscores (P=.002) as well as total scores (P=.039). The cutoff score of 2 remained valid for the group of patients with tracheostomy with a high sensitivity (71.43%) and specificity (89.29%), as well as when we excluded the verbal subscore of the NCS-R (sensitivity=83.2% and specificity=92.4%). Conclusion Our study confirms the validity of the NCS-R in DOC patients with a tracheostomy. However, the presence of a nonspeaking tracheostomy should be clearly mentioned when applying the NCS-R, because it significantly lowers the verbal subscore.

Graph signal processing (GSP) is a novel approach to analyse multi-dimensional neuroimaging data, constraining functional measures by structural characteristics in a single framework (i.e. graph signals). In this approach, functional time series are assigned to the vertices of the underlying weighted graph and GSP analysis is performed in each time point of the signal. Here we used GSP to study local brain connectivity changes in patients with disorders of consciousness based on resting state high density electroencephalography (hdEEG) recordings. Total variation of the graph signals is a measure of signal smoothness over the underlying graph. In this study, we constructed the underlying graph based on the geometrical distances between each electrode pairs in such a way that local smoothness of the signal can be studied. Total variation analysis in α-band showed that in the pathological states of altered consciousness, local short range communication of brain regions in this frequency band is stronger than in healthy states which shows that information is segregated in local regions in patients with disorders of consciousness.

Objective: To obtain a CRS-R index suitable for diagnosis of patients with disorders of consciousness (DOC) and compare it to other CRS-R based scores to evaluate its potential for clinics and research. Design: We evaluated the diagnostic accuracy of several CRS-R-based scores in 124 patients with DOC. ROC analysis of the CRS-R total score, the Rasch-based CRS-R score, CRS-R-MS and the CRS-R index evaluated the diagnostic accuracy for patients with the Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS). Correlations were computed between the CRS-R-MS, CRS-R index, the Rasch-based score and the CRS-R total score. Results: Both the CRS-R-MS and CRS-R index ranged from 0 to 100, with a cut-off of 8.315 that perfectly distinguishes between patients with UWS and MCS. The CRS-R total score and Rasch-based score did not provide a cut-off score for patients with UWS and MCS. The proposed CRS-R index correlated with the CRS-R total score, Rasch-based score and the CRS-R-MS. Conclusion: The CRS-R index is reliable to diagnose patients with UWS and MCS and can be used in compliance with the CRS-R scoring guidelines. The obtained index offers the opportunity to improve the interpretation of clinical assessment and can be used in (longitudinal) research protocols. Abbreviations: CRS-R: Coma Recovery Scale-Revised; CRS-R-MS: Coma Recovery Scale-Revised Modified Score; DOC: Disorders of Consciousness; MCS: Minimally Conscious State; UWS: Unresponsive Wakefulness Syndrome; ROC: Receiver Operating Characteristic; AUC: Area Under the Curve; IRT: Item Response Theory.

Increasing evidence links disorders of consciousness (DOC) with disruptions in functional connectivity between distant brain areas. However, to which extent the balance of brain network segregation and integration is modified in DOC patients remains unclear. Using high-density electroencephalography (EEG), the objective of our study was to characterize the local and global topological changes of DOC patients' functional brain networks.Resting state high-density-EEG data were collected and analyzed from 82 participants: 61 DOC patients recovering from coma with various levels of consciousness (EMCS (n = 6), MCS+ (n = 29), MCS- (n = 17) and UWS (n = 9)), and 21 healthy subjects (i.e., controls). Functional brain networks in five different EEG frequency bands and the broadband signal were estimated using an EEG connectivity approach at the source level. Graph theory-based analyses were used to evaluate their relationship with decreasing levels of consciousness as well as group differences between healthy volunteers and DOC patient groups.Results showed that networks in DOC patients are characterized by impaired global information processing (network integration) and increased local information processing (network segregation) as compared to controls. The large-scale functional brain networks had integration decreasing with lower level of consciousness. Keywords: Disorders of consciousness, High-density electroencephalography, Functional brain networks, Unresponsive wakefulness syndrome, Minimally conscious state