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Background: Cortical excitability is higher in unconsciousness than in wakefulness, but it is unclear how this relates to anaesthesia. We investigated cortical excitability in response to dexmedetomidine, the effects of which are not fully known., Methods: We recorded transcranial magnetic stimulation (TMS) and EEG in frontal and parietal cortex of 20 healthy subjects undergoing dexmedetomidine sedation in four conditions (baseline, light sedation, deep sedation, recovery). We used the first component (0-30 ms) of the TMS-evoked potential (TEP) to measure cortical excitability (amplitude), slope, and positive and negative peak latencies (collectively, TEP indices). We used generalised linear mixed models to test the effect of condition, brain region, and responsiveness on TEP indices., Results: Compared with baseline, amplitude in the frontal cortex increased by 6.52 μV (P<0.001) in light sedation, 4.55 μV (P=0.003) in deep sedation, and 5.03 μV (P<0.001) in recovery. Amplitude did not change in the parietal cortex. Compared with baseline, slope increased in all conditions (P<0.02) in the frontal but not parietal cortex. The frontal cortex showed 5.73 μV higher amplitude (P<0.001), 0.63 μV ms -1 higher slope (P<0.001), and 2.2 ms shorter negative peak latency (P=0.001) than parietal areas. Interactions between dexmedetomidine and region had effects over amplitude (P=0.004) and slope (P=0.009), with both being higher in light sedation, deep sedation, and recovery compared with baseline., Conclusions: Transcranial magnetic stimulation-evoked potential amplitude changes non-linearly as a function of depth of sedation by dexmedetomidine, with a region-specific paradoxical increase. Future research should investigate other anaesthetics to elucidate the link between cortical excitability and depth of sedation., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: 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., Objective: We aimed to validate a new faster tool to assess consciousness in individuals with DoC., Methods: 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., Results: 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)., Conclusions: 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., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Brain-injured patients who are unresponsive at the bedside (ie, vegetative state/unresponsive wakefulness syndrome - VS/UWS) may present brain activity similar to patients in minimally conscious state (MCS). This peculiar condition has been termed "non-behavioural MCS" or "MCS*". In the present study we aimed to investigate the proportion and underlying brain characteristics of patients in MCS*., Methods: Brain 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was acquired on 135 brain-injured patients diagnosed in prolonged VS/UWS (n = 48) or MCS (n = 87). From an existing database, relative metabolic preservation in the fronto-parietal network (measured with standardized uptake value) was visually inspected by three experts. Patients with hypometabolism of the fronto-parietal network were labelled "VS/UWS", while its (partial) preservation either confirmed the behavioural diagnosis of "MCS" or, in absence of behavioural signs of consciousness, suggested a diagnosis of "MCS*". Clinical outcome at 1-year follow-up, functional connectivity, grey matter atrophy, and regional brain metabolic patterns were investigated in the three groups (VS/UWS, MCS* and MCS)., Results: 67% of behavioural VS/UWS presented a partial preservation of brain metabolism (ie, MCS*). Compared to VS/UWS patients, MCS* patients demonstrated a better outcome, global functional connectivity and grey matter preservation more compatible with the diagnosis of MCS. MCS* patients presented lower brain metabolism mostly in the posterior brain regions compared to MCS patients., Interpretation: MCS* is a frequent phenomenon that is associated with better outcome and better brain preservation than the diagnosis of VS/UWS. Complementary exams should be provided to all unresponsive patients before taking medical decisions. ANN NEUROL 2021;90:89-100., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Establishing an accurate diagnosis is crucial for patients with disorders of consciousness (DoC) following a severe brain injury. The Coma Recovery Scale-Revised (CRS-R) is the recommended behavioral scale for assessing the level of consciousness among these patients, but its long duration of administration is a major hurdle in clinical settings. The Simplified Evaluation of CONsciousness Disorders (SECONDs) is a shorter scale that was developed to tackle this issue. It consists of six mandatory items, observation, command-following, visual pursuit, visual fixation, oriented behaviors, and arousal, and two conditional items, communication and localization to pain. The score ranges between 0 and 8 and corresponds to a specific diagnosis (i.e., coma, unresponsive wakefulness syndrome, minimally conscious state minus/plus, or emergence from the minimally conscious state). A first validation study on patients with prolonged DoC showed high concurrent validity and intra- and inter-rater reliability. The SECONDs requires less training than the CRS-R and its administration lasts about 7 minutes (interquartile range: 5-9 minutes). An additional index score allows the more precise tracking of a patient's behavioral fluctuation or evolution over time. The SECONDs is therefore a fast and valid tool for assessing the level of consciousness in patients with severe brain injury. It can easily be used by healthcare staff and implemented in time-constrained clinical settings, such as intensive care units, to help decrease misdiagnosis rates and to optimize treatment decisions. These administration guidelines provide detailed instructions for administering the SECONDs in a standardized and reproducible manner, which is an essential requirement for achieving a reliable diagnosis.

Due to life-saving medical advances, the diagnosis and treatment of disorders of consciousness (DOC) has become a more commonly occurring clinical issue. One recently developed intervention option has been non-invasive transcranial direct current stimulation. This dichotomy of patient responders may be better understood by investigating the mechanism behind the transcranial direct current stimulation (tDCS) intervention. The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) has been an important diagnostic tool in DOC patients. We therefore examined the neural response using TMS-EEG both before and after tDCS in seven DOC patients (four diagnosed as in a minimally conscious state and three with unresponsive wakefulness syndrome). tDCS was applied over the dorsolateral prefrontal cortex, while TMS pulses were applied to the premotor cortex. None of the seven patients showed relevant behavioral change after tDCS. We did, however, find that the overall evoked slow activity was reduced following tDCS intervention. We also found a positive correlation between the strength of the slow activity and the amount of high-frequency suppression. However, there was no significant pre-post tDCS difference in high frequencies. In the resting-state EEG, we observed that both the incidence of slow waves and the positive slope of the wave were affected by tDCS. Taken together, these results suggest that the tDCS intervention can reduce the slow-wave activity component of bistability, but this may not directly affect high-frequency activity. We hypothesize that while reduced slow activity may be necessary for the recovery of neural function, especially consciousness, this alone is insufficient., (Copyright © 2020 Mensen, Bodart, Thibaut, Wannez, Annen, Laureys and Gosseries.)

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., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Charles Bonnet syndrome (CBS) is a rare condition characterized by visual impairment associated with complex visual hallucinations in elderly people. Although studies suggested that visual hallucinations may be caused by brain damage in the visual system in CBS patients, alterations in specific brain regions in the occipital cortex have not been studied. Functional connectivity during resting-state functional magnetic resonance imaging (rs-fMRI; without hallucinations) in CBS patients, has never been explored. We aimed to investigate brain structural and functional changes in a patient with CBS, as compared with late blind (LB) and normally sighted subjects. We employed voxel-based morphometry and cortical thickness analyses to investigate alterations in grey matter characteristics, and rs-fMRI to study changes in functional brain connectivity. Decreased grey matter volume was observed in the middle occipital gyrus and in the cuneus in the CBS patient, and in the middle occipital gyrus and in the lingual gyrus within LB subjects, compared to their respective control groups. Reductions in cortical thickness in associative and multimodal cortices were observed in the CBS patient when comparing with LB subjects. The precuneus exhibited increased functional connectivity with the secondary visual cortex in the CBS patient compared to the controls. In contrast, LB patients showed decreased functional connectivity compared to sighted controls between the DMN and the temporo-occipital fusiform gyrus, a region known to support hallucinations. Our findings suggest a reorganization of the functional connectivity between regions involved in self-awareness and in visual and salience processing in CBS that may contribute to the appearance of visual hallucinations., Competing Interests: The authors have declared that no competing interests exist.

The recovery of patients with disorders of consciousness is a real challenge, especially at the chronic stage. After a severe brain injury, patients can regain some slight signs of consciousness, while not being able to functionally communicate. This entity is called the minimally conscious state (MCS), which has been divided into MCS- and MCS+, respectively based on the absence or presence of language-related signs of consciousness. In this series of cases we aimed to describe retrospectively the longitudinal recovery of specific language-related behaviors using neuroimaging measurement in severely brain-injured patients. Among 209 chronic MCS patients admitted to our center from 2008 to 2018, 19 were assessed at two time points by means of behavioral and neuroimaging assessments. Three of them met our inclusion criteria and were diagnosed as MCS- during their first stay and had recovered command-following when they were reassessed (i.e., MCS+). As compared to their first assessments, when the three patients were in a MCS+, they showed less hypometabolism and/or higher gray matter volume in brain regions such as the precuneus and thalamus, as well as the left caudate and temporal/angular cortices known to be involved in various aspects of semantics. According to these preliminary results, the reappearance of language-related behaviors was concomitant with the recovery of metabolism and gray matter in neural regions that have been associated with self-consciousness and language processing. Prospective studies should be conducted to deepen our understanding of the neural correlates of the recovery of language-related behaviors in chronic MCS.

Different behavioural signs of consciousness can distinguish patients with an unresponsive wakefulness syndrome from patients in minimally conscious state (MCS). The Coma Recovery Scale-Revised (CRS-R) is the most sensitive scale to differentiate the different altered states of consciousness and eleven items detect the MCS. The aim of this study is to document the prevalence of these items. We analysed behavioural assessments of 282 patients diagnosed in MCS based on the CRS-R. Results showed that some items are particularly frequent among patients in MCS, namely fixation, visual pursuit, and reproducible movement to command, which were observed in more than 50% of patients. These responses were also the most probably observed items when the patients only showed one sign of consciousness. On the other hand, some items were rarely or never observed alone, e.g., object localisation (reaching), object manipulation, intelligible verbalisation, and object recognition. The results also showed that limiting the CRS-R assessment to the five most frequently observed items (i.e., fixation, visual pursuit, reproducible movement to command, automatic motor response and localisation to noxious stimulation) detected 99% of the patients in MCS. If clinicians have only limited time to assess patients with disorders of consciousness, we suggest to evaluate at least these five items of the CRS-R.

Background: Patients with chronic disorders of consciousness face a significant lack of treatment options., Objective: We aimed at investigating the feasibility and the behavioral effects of home-based transcranial direct current stimulation (tDCS), applied by relatives or caregivers, in chronic patients in minimally conscious state (MCS)., Methods: Each participant received, in a randomized order, 20 sessions of active and 20 sessions of sham tDCS applied over the prefrontal cortex for 4 weeks; separated by 8 weeks of washout. Level of consciousness was assessed using the Coma Recovery Scale-Revised before the first stimulation (baseline), at the end of the 20 tDCS sessions (direct effects) and 8 weeks after the end of each stimulation period (long-term effects). Reported adverse events and data relative to the adherence (i.e., amount of sessions effectively received) were collected as well., Results: Twenty-seven patients completed the study and 22 patients received at least 80% of the stimulation sessions. All patients tolerated tDCS well, no severe adverse events were noticed after real stimulation and the overall adherence (i.e., total duration of stimulation) was good. A moderate effect size (0.47 and 0.53, for modified intention to treat and per protocol analysis, respectively) was observed at the end of the 4 weeks of tDCS in favor of the active treatment., Conclusions: We demonstrated that home-based tDCS can be used adequately outside a research facility or hospital by patients' relatives or caregivers. In addition, 4 weeks of tDCS moderately improved the recovery of signs of consciousness in chronic MCS patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Patients with prolonged disorders of consciousness (DoC) after severe brain injury may present residual behavioral and cognitive functions. Yet the bedside assessment of these functions is compromised by patients' multiple impairments. Standardized behavioral scales such as the Coma Recovery Scale-Revised (CRS-R) have been developed to diagnose DoC, but there is also a need for neuropsychological measurement in these patients. The Cognitive Assessment by Visual Election (CAVE) was therefore recently created. In this study, we describe five patients in minimally conscious state (MCS) or emerging from the MCS (EMCS). Their cognitive profiles, derived from the CRS-R and CAVE, are presented alongside their neuroimaging results using structural magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Scores on the CAVE decreased along with the CRS-R total score, establishing a consistent behavioral/cognitive profile for each patient. Out of these five cases, the one with highest CRS-R and CAVE performance had the least extended cerebral hypometabolism. All patients showed structural and functional brain impairments that were consistent with their behavioral/cognitive profile as based on previous literature. For instance, the presence of visual and motor residual functions was respectively associated with a relative preservation of occipital and motor cortex/cerebellum metabolism. Moreover, residual language comprehension skills were found in the presence of preserved temporal and angular cortex metabolism. Some patients also presented structural impairment of hippocampus, suggesting the presence of memory impairments. Our results suggest that brain-behavior relationships might be observed even in severely brain-injured patients and they highlight the importance of developing new tools to assess residual cognition and language in MCS and EMCS patients. Indeed, a better characterization of their cognitive profile will be helpful in preparation of rehabilitation programs and daily routines.

Introduction: Resistance to eye opening (REO) is a commonly encountered phenomenon in clinical practice. We aim to investigate whether REO is a sign of consciousness or a reflex in severely brain-injured patients., Methods: We recorded REO in chronic patients with disorders of consciousness during a multimodal diagnostic assessment. REO evaluations were performed daily in each patient and clinical diagnosis of unresponsive wakefulness syndrome (UWS), minimally conscious state with (MCS+) or without (MCS-) preserved language processing was made using the Coma Recovery Scale-Revised (CRS-R)., Results: Out of 150 consecutive patients, 79 patients fit inclusion criteria. REO was seen in 19 patients (24.1%). At the group level, there was a significant relationship between the presence of REO and the level of consciousness. We also observed a difference in the repeatability of REO between patients in UWS, MCS- and MCS+. Out of 23 patients in UWS, six showed REO, in whom five showed atypical brain patterns activation., Conclusion: Our findings suggest a voluntary basis for REO and stress the need for multiple serial assessments of REO in these patients, especially since most patients show fluctuating levels of consciousness.

Objective: The aim of the study is to explore the possibility of oral feeding in unresponsive wakefulness syndrome/vegetative state (UWS/VS) patients., Method: We reviewed the clinical information of 68 UWS/VS patients (mean age 45 ± 11; range 16-79 years) searching for mention of oral feeding. UWS/VS diagnosis was made after repeated behavioural assessments using the Coma Recovery Scale-Revised. Patients also had complementary neuroimaging evaluations (positron emission tomography, functional magnetic resonance imaging and electroencephalography and diffusion tensor imaging)., Results: Out of the 68 UWS/VS patients, only two could resume oral feeding (3%). The first patient had oral feeding (only liquid and semi liquid) in addition to gastrostomy feeding and the second one could achieve full oral feeding (liquid and mixed solid food). Clinical assessments concluded that they fulfilled the criteria for a diagnosis of UWS/VS. Results from neuroimaging and neurophysiology were typical for the first patient with regard to the diagnosis of UWS/VS but atypical for the second patient., Conclusion: Oral feeding that implies a full and complex oral phase could probably be considered as a sign of consciousness. However, we actually do not know which components are necessary to consider the swallowing conscious as compared to reflex. We also discussed the importance of swallowing assessment and management in all patients with altered state of consciousness.

Background: Previous studies have separately reported impaired functional, structural, and effective connectivity in patients with disorders of consciousness (DOC). The perturbational complexity index (PCI) is a transcranial magnetic stimulation (TMS) derived marker of effective connectivity. The global fractional anisotropy (FA) is a marker of structural integrity. Little is known about how these parameters are related to each other., Objective: We aimed at testing the relationship between structural integrity and effective connectivity., Methods: We assessed 23 patients with severe brain injury more than 4 weeks post-onset, leading to DOC or locked-in syndrome, and 14 healthy subjects. We calculated PCI using repeated single pulse TMS coupled with high-density electroencephalography, and used it as a surrogate of effective connectivity. Structural integrity was measured using the global FA, derived from diffusion weighted imaging. We used linear regression modelling to test our hypothesis, and computed the correlation between PCI and FA in different groups., Results: Global FA could predict 74% of PCI variance in the whole sample and 56% in the patients' group. No other predictors (age, gender, time since onset, behavioural score) improved the models. FA and PCI were correlated in the whole population (r = 0.86, p < 0.0001), the patients, and the healthy subjects subgroups., Conclusion: We here demonstrated that effective connectivity correlates with structural integrity in brain-injured patients. Increased structural damage level decreases effective connectivity, which could prevent the emergence of consciousness., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent advances in functional neuroimaging have demonstrated novel potential for informing diagnosis and prognosis in the unresponsive wakeful syndrome and minimally conscious states. However, these technologies come with considerable expense and difficulty, limiting the possibility of wider clinical application in patients. Here, we show that high density electroencephalography, collected from 104 patients measured at rest, can provide valuable information about brain connectivity that correlates with behaviour and functional neuroimaging. Using graph theory, we visualize and quantify spectral connectivity estimated from electroencephalography as a dense brain network. Our findings demonstrate that key quantitative metrics of these networks correlate with the continuum of behavioural recovery in patients, ranging from those diagnosed as unresponsive, through those who have emerged from minimally conscious, to the fully conscious locked-in syndrome. In particular, a network metric indexing the presence of densely interconnected central hubs of connectivity discriminated behavioural consciousness with accuracy comparable to that achieved by expert assessment with positron emission tomography. We also show that this metric correlates strongly with brain metabolism. Further, with classification analysis, we predict the behavioural diagnosis, brain metabolism and 1-year clinical outcome of individual patients. Finally, we demonstrate that assessments of brain networks show robust connectivity in patients diagnosed as unresponsive by clinical consensus, but later rediagnosed as minimally conscious with the Coma Recovery Scale-Revised. Classification analysis of their brain network identified each of these misdiagnosed patients as minimally conscious, corroborating their behavioural diagnoses. If deployed at the bedside in the clinical context, such network measurements could complement systematic behavioural assessment and help reduce the high misdiagnosis rate reported in these patients. These metrics could also identify patients in whom further assessment is warranted using neuroimaging or conventional clinical evaluation. Finally, by providing objective characterization of states of consciousness, repeated assessments of network metrics could help track individual patients longitudinally, and also assess their neural responses to therapeutic and pharmacological interventions., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To determine whether repeated examinations using the Coma Recovery Scale-Revised (CRS-R) have an impact on diagnostic accuracy of patients with disorders of consciousness and to provide guidelines regarding the number of assessments required for obtaining a reliable diagnosis., Methods: One hundred twenty-three adult patients with chronic disorders of consciousness were referred to our tertiary center. They were assessed at least six times with the CRS-R within a 10-day period. Clinical diagnoses based on one, two, three, four, and five Coma Recovery Scale-Revised assessments were compared with a reference diagnosis (ie, the highest behavioral diagnosis obtained after six evaluations) using nonparametric statistics. Results were considered significant at p < 0.05 corrected for multiple comparisons., Results: The number of assessments had a significant effect on the clinical diagnosis. Up to the fourth examination, the diagnosis was still statistically different from the reference diagnosis based on six CRS-R assessments. Compared to this reference diagnosis, the first evaluation led to 36% of misdiagnoses., Interpretation: The number of CRS-R assessments has an impact on the clinical diagnosis of patients with chronic disorders of consciousness. Up to the fourth examinations, behavioral fluctuations may still impact the diagnostic accuracy. We here suggest performing at least five assessments in each patient with disorders of consciousness within a short time interval (eg, 2 weeks) to reduce misdiagnosis. Ann Neurol 2017;81:883-889 Ann Neurol 2017;81:883-889., (© 2017 American Neurological Association.)

Visual pursuit is a key marker of residual consciousness in patients with disorders of consciousness (DOC). Currently, its assessment relies on subjective clinical decisions. In this study, we explore the variability of such clinical assessments, and present an easy-to-use device composed of cameras and video processing algorithms that could help the clinician to improve the detection of visual pursuit in a clinical context. Visual pursuit was assessed by an experienced research neuropsychologist on 31 patients with DOC and on 23 healthy subjects, while the device was used to simultaneously record videos of both one eye and the mirror. These videos were then scored by three researchers: the experienced research neuropsychologist who did the clinical assessment, another experienced research neuropsychologist, and a neurologist. For each video, a consensus was decided between the three persons, and used as the gold standard of the presence or absence of visual pursuit. Almost 10% of the patients were misclassified at the bedside according to their consensus. An automatic classifier analyzed eye and mirror trajectories, and was able to identify patients and healthy subjects with visual pursuit, in total agreement with the consensus on video. In conclusion, our device can be used easily in patients with DOC while respecting the current guidelines of visual pursuit assessment. Our results suggest that our material and our classification method can identify patients with visual pursuit, as well as the three researchers based on video recordings can.

Objective: Visual pursuit should be tested with a mirror in patients with disorders of consciousness. This stimulus was indeed more efficient than a person or an object, and the auto-referential aspect was supposed to be the key feature. The present study tested the hypothesis that the mirror was more efficient because of its self-aspect., Methods: The mirror was compared (1) to the patient's picture and to the picture of a famous face, in 22 patients in minimally conscious state and (2) to the patient's picture and a fake mirror, which had dynamical and bright aspects of the mirror, without reflecting the face, in 26 other patients in minimally conscious state., Results: The mirror was more efficient than the patient's picture, which was not statistically different from the famous face. The second part of the study confirmed the statistical difference between the mirror and the picture. However, the fake mirror was neither statistically different from the mirror nor from the picture., Conclusions: Although our results suggest that the hypothesis proposed by previous studies was partly wrong, they confirm that the mirror is the best stimulus to use when assessing visual pursuit.

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 determine the frequency with which specific Coma Recovery Scale-Revised (CRS-R) subscale scores co-occur as a means of providing clinicians and researchers with an empirical method of assessing CRS-R data quality., Design: We retrospectively analyzed CRS-R subscale scores in hospital inpatients diagnosed with disorders of consciousness (DOCs) to identify impossible and improbable subscore combinations as a means of detecting inaccurate and unusual scores. Impossible subscore combinations were based on violations of CRS-R scoring guidelines. To determine improbable subscore combinations, we relied on the Mahalanobis distance, which detects outliers within a distribution of scores. Subscore pairs that were not observed at all in the database (ie, frequency of occurrence=0%) were also considered improbable., Setting: Specialized DOC program and university hospital., Participants: Patients diagnosed with DOCs (N=1190; coma: n=76, vegetative state: n=464, minimally conscious state: n=586, emerged from minimally conscious state: n=64; 794 men; mean age, 43±20y; traumatic etiology: n=747; time postinjury, 162±568d)., Interventions: Not applicable., Main Outcome Measure: Impossible and improbable CRS-R subscore combinations., Results: Of the 1190 CRS-R profiles analyzed, 4.7% were excluded because they met scoring criteria for impossible co-occurrence. Among the 1137 remaining profiles, 12.2% (41/336) of possible subscore combinations were classified as improbable., Conclusions: Clinicians and researchers should take steps to ensure the accuracy of CRS-R scores. To minimize the risk of diagnostic error and erroneous research findings, we have identified 9 impossible and 36 improbable CRS-R subscore combinations. The presence of any one of these subscore combinations should trigger additional data quality review., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Between pathologically impaired consciousness and normal consciousness exists a scarcely researched transition zone, referred to as emergence from minimally conscious state, in which patients regain the capacity for functional communication, object use, or both. We investigated neural correlates of consciousness in these patients compared with patients with disorders of consciousness and healthy controls, by multimodal imaging., Methods: In this cross-sectional, multimodal imaging study, patients with unresponsive wakefulness syndrome, patients in a minimally conscious state, and patients who had emerged from a minimally conscious state, diagnosed with the Coma Recovery Scale-Revised, were recruited from the neurology department of the Centre Hospitalier Universitaire de Liège, Belgium. Key exclusion criteria were neuroimaging examination in an acute state, sedation or anaesthesia during scanning, large focal brain damage, motion parameters of more than 3 mm in translation and 3° in rotation, and suboptimal segmentation and normalisation. We acquired resting state functional and structural MRI data and (18)F-fluorodeoxyglucose (FDG) PET data; we used seed-based functional MRI (fMRI) analysis to investigate positive default mode network connectivity (within-network correlations) and negative default mode network connectivity (between-network anticorrelations). We correlated FDG-PET brain metabolism with fMRI connectivity. We used voxel-based morphometry to test the effect of anatomical deformations on functional connectivity., Findings: We recruited a convenience sample of 58 patients (21 [36%] with unresponsive wakefulness syndrome, 24 [41%] in a minimally conscious state, and 13 [22%] who had emerged from a minimally conscious state) and 35 healthy controls between Oct 1, 2009, and Oct 31, 2014. We detected consciousness-level-dependent increases (from unresponsive wakefulness syndrome, minimally conscious state, emergence from minimally conscious state, to healthy controls) for positive and negative default mode network connectivity, brain metabolism, and grey matter volume (p<0·05 false discovery rate corrected for multiple comparisons). Positive default mode network connectivity differed between patients and controls but not among patient groups (F test p<0·0001). Negative default mode network connectivity was only detected in healthy controls and in those who had emerged from a minimally conscious state; patients with unresponsive wakefulness syndrome or in a minimally conscious state showed pathological between-network positive connectivity (hyperconnectivity; F test p<0·0001). Brain metabolism correlated with positive default mode network connectivity (Spearman's r=0·50 [95% CI 0·26 to 0·61]; p<0·0001) and negative default mode network connectivity (Spearman's r=-0·52 [-0·35 to -0·67); p<0·0001). Grey matter volume did not differ between the studied groups (F test p=0·06)., Interpretation: Partial preservation of between-network anticorrelations, which are seemingly of neuronal origin and cannot be solely explained by morphological deformations, characterise patients who have emerged from a minimally conscious state. Conversely, patients with disorders of consciousness show pathological between-network correlations. Apart from a deeper understanding of the neural correlates of consciousness, these findings have clinical implications and might be particularly relevant for outcome prediction and could inspire new therapeutic options., Funding: Belgian National Funds for Scientific Research (FNRS), European Commission, Natural Sciences and Engineering Research Council of Canada, James McDonnell Foundation, European Space Agency, Mind Science Foundation, French Speaking Community Concerted Research Action, Fondazione Europea di Ricerca Biomedica, University and University Hospital of Liège (Liège, Belgium), and University of Western Ontario (London, ON, Canada)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) was recently shown to promote recovery of voluntary signs of consciousness in some patients in minimally conscious state (MCS). However, it remains unclear why clinical improvement is only observed in a subgroup of patients., Objectives: In this retrospective study, we investigated the relationship between tDCS responsiveness and neuroimaging data from MCS patients., Methods: Structural Magnetic Resonance Imaging (MRI), Fluorodeoxyglucose Positron emission tomography (FDG-PET) and clinical electroencephalography (EEG) were acquired in 21 sub-acute and chronic MCS patients (8 tDCS responders) who subsequently (<48 h) received left dorsolateral prefrontal (DLPF) tDCS in a double-blind randomized cross-over trial. The behavioral data have been published elsewhere (Thibaut et al., Neurology, 2014)., Results: Grey matter atrophy was observed in non-responders as compared with responders in the left DLPF cortex, the medial-prefrontal cortex, the cingulate cortex, the hippocampi, part of the rolandic regions, and the left thalamus. FDG-PET showed hypometabolism in non-responders as compared with responders in the left DLPF cortex, the medial-prefrontal cortex, the precuneus, and the thalamus. EEG did not show any difference between the two groups., Conclusion: Our findings suggest that the transient increase of signs of consciousness following left DLPF tDCS in patients in MCS require grey matter preservation and residual metabolic activity in cortical and subcortical brain areas known to be involved in attention and working memory. These results further underline the critical role of long-range cortico-thalamic connections in consciousness recovery, providing important information for guidelines on the use of tDCS in disorders of consciousness., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Spasticity is a frequent complication after severe brain injury, which may impede the rehabilitation process and diminish the patients' quality of life., Aim: We here investigate the presence of spasticity in a population of non-communicative patients with disorders of consciousness. We also evaluate the correlation between spasticity and potential factors of co-morbidity, frequency of physical therapy, time since insult, presence of pain, presence of tendon retraction, etiology and diagnosis., Design: Cross-sectional study., Setting: University Hospital of Liège, Belgium., Population: Sixty-five patients with chronic (>3 months post insult) disorders of consciousness were included (22 women; mean age: 44±14 y; 40 with traumatic etiology; 40 in a minimally conscious state; time since insult: 39±37 months)., Methods: Spasticity was measured with the Modified Ashworth Scale (MAS) and pain was assessed using the Nociception Coma Scale-Revised (NCS-R)., Results: Out of 65 patients, 58 demonstrated signs of spasticity (89%; MAS≥1), including 40 who showed severe spasticity (61.5%; MAS≥3). Patients with spasticity receiving anti-spastic medication were more spastic than unmedicated patients. A negative correlation was observed between the severity of spasticity and the frequency of physical therapy. MAS scores correlated positively with time since injury and NCS-R scores. We did not observe a difference of spasticity between the diagnoses., Conclusion: A large proportion of patients with disorders of consciousness develop severe spasticity, possibly affecting their functional recovery and their quality of life. The observed correlation between degrees of spasticity and pain scores highlights the importance of pain management in these patients with altered states of consciousness. Finally, the relationship between spasticity and treatment (i.e., pharmacological and physical therapy) should be further investigated in order to improve clinical care., Clinical Rehabilitation Impact: Managing spasticity at first signs could improve rehabilitation of patients with disorders of consciousness and maximize their chances of recovery. In addition, decreasing this trouble could allow a better quality of life for these non-communicative patients.

Objective: To assess the effectiveness of soft splints on spasticity and hand opening in chronic patients with upper limb spasticity and disorders of consciousness (vegetative state/unresponsive wakefulness syndrome-VS/UWS and minimally conscious state-MCS)., Methods: In this prospective single-blind controlled trial, a blind evaluator assessed spasticity (Modified Ashworth Scale and Modified Tardieu Scale), range of motion (ROM) at the metacarpophalangeal, wrist and elbow joints and the patients' hand opening before and after soft splinting, manual stretching and a control condition (i.e. no treatment), as well as 60 minutes later., Subjects: Seventeen patients with chronic (>3 months) disorders of consciousness were included (five VS/UWS; seven women; mean age = 42 ± 12 years; time since insult = 35 ± 31 months). Patients received either passive splinting, manual stretching treatment or no treatment., Results: Thirty minutes of soft splinting or 30 minutes of manual stretching both improved spasticity of the finger flexors. An increase of hand opening ability was observed after 30 minutes of soft splinting., Conclusion: Thirty minutes of soft splint application reduces spasticity and improves hand opening of patients with chronic disorders of consciousness. Soft splinting is well tolerated and does not require supervision.

Background: Visual fixation plays a key role in the differentiation between vegetative state/unresponsive wakefulness (VS/UWS) syndrome and minimally conscious state (MCS). However, the use of different stimuli changes the frequency of visual fixation occured in patients, thereby possibly affecting the accuracy of the diagnosis. In order to establish a standardized assessment of visual fixation in patients in disorders of consciousness (DOC), we compared the frequency of visual fixation elicited by mirror,a ball and a light., Method: Visual fixation was assessed in eighty-one post-comatose patients diagnosed with a MCS or VS/UWS. Occurrence of fixation to different stimuli was analysis used Chi-square testing., Result: 40 (49%) out of the 81 patients showed fixation to visual stimuli. Among those, significantly more patients (39, 48%) had visual fixation elicited by mirror compared to a ball (23, 28%) and mirror compared to a light (20, 25%)., Conclusion: The use of a mirror during the assessment of visual fixation showed higher positive response rate, compared to other stimuli in eliciting a visual fixating response. Therefore, fixation elicited by a mirror can be a very sensitive and accurate test to differentiate the two disorders of consciousness.

Objectives: The aim of this study was to determine whether the assessment of pursuit eye movements in patients in minimally conscious state (MCS) is influenced by the choice of the visual stimulus (study 1) and by the moving plane (study 2)., Methods: Patients with MCS (MCS- and MCS+) in the acute (<1 month post-injury) or chronic (>1 month) setting were assessed. The Coma Recovery Scale-Revised (CRS-R) procedure was used to test visual pursuit of a moving mirror, object and person (study 1, n = 88) and to test vertical and horizontal visual tracking (study 2, n = 94)., Results: Study 1: Patients with visual pursuit tracked preferentially the moving mirror over the moving person or object. Study 2: Patients displaying visual pursuit, especially in MCS- and in chronic setting, preferentially tracked on the horizontal rather than the vertical plane., Conclusion: The findings confirm the importance of using a mirror to assess visual pursuit in patients in MCS and of initiating testing using the horizontal plane, specifically in patients in MCS- and those in chronic setting. Assessment should then be done on the vertical plane if visual pursuit is not detected on the horizontal plane.