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Background: Improving the functional recovery of patients with DoC remains one of the greatest challenges of the field. Different theories exist about the role of the anterior (prefrontal areas) versus posterior (parietal areas) parts of the brain as hotspots for the recovery of consciousness. Repetitive transcranial magnetic stimulation (rTMS) is a powerful non-invasive brain stimulation technique for the treatment of DoC. However, a direct comparison of the effect of TMS treatment on the front versus the back of the brain has yet to be performed. In this study, we aim to assess the short- and long-term effects of frontal and parietal rTMS on DoC recovery and characterize responders phenotypically. Methods/design: Ninety patients with subacute and prolonged DoC will be included in a two-part multicenter prospective study. In the first phase (randomized controlled trial, RCT), patients will undergo four rTMS sessions in a crossover design over 10 days, targeting (i) the left dorsolateral prefrontal cortex (DLPFC) and (ii) the left angular gyrus (AG), as well as (iii & iv) their sham alternatives. In the second phase (longitudinal personalized trial), patients will receive personalized stimulations for 20 working days targeting the brain area that showed the best results in the RCT and will be randomly assigned to either active or sham intervention. The effects of rTMS on neurobehavioral and neurophysiological functioning in patients with DoC will be evaluated using clinical biomarkers of responsiveness (i.e., the Coma Recovery Scale- Revised; CRS-R), and electrophysiological biomarkers (e.g., power spectra, functional and effective connectivity, perturbational complexity index before and after intervention). Functional long-term outcomes will be assessed at 3 and 6 months post-intervention. Adverse events will be recorded during the treatment phase. Discussion: This study seeks to identify which brain region (front or back) is best to stimulate for the treatment of patients with DoC using rTMS, and to characterize the neural correlates of its action regarding recovery of consciousness and functional outcome. In addition, we will define the responders' profile based on patients' characteristics and functional impairments; and develop biomarkers of responsiveness using EEG analysis according to the clinical responsiveness to the treatment. [ABSTRACT FROM AUTHOR]

Background. Many patients with severe brain damage may survive and remain in a prolonged disorder of consciousness (PDoC), impacting the quality of life (QoL) and needs of their family caregivers. However, the current literature on the factors influencing these needs is contradictory. We aim to describe the needs, QoL, and emotional distress of caregivers of patients with PDoC. Methods. Questionnaires investigating the importance and satisfaction of six categories of needs (i.e., health information, emotional, instrumental, and professional supports, community support network, and involvement in care), QoL, and emotional distress were completed by the main caregivers of PDoC patients. Results. We analyzed 177 questionnaires. Seventy-nine percent of the needs were considered as important or very important, and 44% were partially met or unmet. The needs for health information and professional support were the most important, while the needs for involvement in care and for health information were the most satisfied. Mean QoL was low and emotional distress high. Variables such as care setting and time since brain injury affected the level of QoL and distress. Conclusion. The needs for health information and professional support should receive particular attention. Given their low QoL and high distress, adequate support structures should be provided to caregivers of PDoC patients. [ABSTRACT FROM AUTHOR]

Background: The accurate assessment of patients with disorders of consciousness (DOC) is a challenge to most experienced clinicians. As a potential clinical tool, functional magnetic resonance imaging (fMRI) could detect residual awareness without the need for the patients' actual motor responses. Methods: We adopted a simple active fMRI motor paradigm (hand raising) to detect residual awareness in these patients. Twenty-nine patients were recruited. They met the diagnosis of minimally conscious state (MCS) (male = 6, female = 2; n = 8), vegetative state/unresponsive wakefulness syndrome (VS/UWS) (male = 17, female = 4; n = 21). Results: We analyzed the command-following responses for robust evidence of statistically reliable markers of motor execution, similar to those found in 15 healthy controls. Of the 29 patients, four (two MCS, two VS/UWS) could adjust their brain activity to the "hand-raising" command, and they showed activation in motor-related regions (which could not be discovered in the own-name task). Conclusion: Longitudinal behavioral assessments showed that, of these four patients, two in a VS/UWS recovered to MCS and one from MCS recovered to MCS+ (i.e., showed command following). In patients with no response to hand raising task, six VS/UWS and three MCS ones showed recovery in follow-up procedure. The simple active fMRI "hand-raising" task can elicit brain activation in patients with DOC, similar to those observed in healthy volunteers. Activity of the motor-related network may be taken as an indicator of high-level cognition that cannot be discerned through conventional behavioral assessment. [ABSTRACT FROM AUTHOR]

Despite recent advances in our understanding of consciousness disorders, accurate diagnosis of severely brain-damaged patients is still a major clinical challenge. We here present the case of a patient who was considered in an unresponsive wakefulness syndrome/vegetative state for 20 years. Repeated standardized behavioral examinations combined to neuroimaging assessments allowed us to show that this patient was in fact fully conscious and was able to functionally communicate. We thus revised the diagnosis into an incomplete locked-in syndrome, notably because the main brain lesion was located in the brainstem. Clinical examinations of severe brain injured patients suffering from serious motor impairment should systematically include repeated standardized behavioral assessments and, when possible, neuroimaging evaluations encompassing magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography. [ABSTRACT FROM AUTHOR]

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor disablities, and thus assessing their spared cognitive abilities can be difficult. Recent research from several groups has shown that non-invasive brain-computer interface (BCI) technology can provide assessments of these patients' cognitive function that can supplement information provided through conventional behavioral assessment methods. In rare cases, BCIs may provide a binary communication mechanism. Here, we present results from a vibrotactile BCI assessment aiming at detecting command-following and communication in 12 unresponsive wakefulness syndrome (UWS) patients. Two different paradigms were administered at least once for every patient: (i) VT2 with two vibro-tactile stimulators fixed on the patient's left and right wrists and (ii) VT3 with three vibro-tactile stimulators fixed on both wrists and on the back. The patients were instructed to mentally count either the stimuli on the left or right wrist, which may elicit a robust P300 for the target wrist only. The EEG data from -100 to +600ms around each stimulus were extracted and sub-divided into 8 data segments. This data was classified with linear discriminant analysis (using a 10 × 10 cross validation) and used to calibrate a BCI to assess command following and YES/NO communication abilities. The grand average VT2 accuracy across all patients was 38.3%, and the VT3 accuracy was 26.3%. Two patients achieved VT3 accuracy ≥80% and went through communication testing. One of these patients answered 4 out of 5 questions correctly in session 1, whereas the other patient answered 6/10 and 7/10 questions correctly in sessions 2 and 4. In 6 other patients, the VT2 or VT3 accuracy was above the significance threshold of 23% for at least one run, while in 4 patients, the accuracy was always below this threshold. The study highlights the importance of repeating EEG assessments to increase the chance of detecting command-following in patients with severe brain injury. Furthermore, the study shows that BCI technology can test command following in chronic UWS patients and can allow some of these patients to answer YES/NO questions. [ABSTRACT FROM AUTHOR]

Event-related potentials (ERP) have been proposed to improve the differential diagnosis of non-responsive patients. We investigated the potential of the P300 as a reliable marker of conscious processing in patients with locked-in syndrome (LIS). Eleven chronic LIS patients and 10 healthy subjects (HS) listened to a complex-tone auditory oddball paradigm, first in a passive condition (listen to the sounds) and then in an active condition (counting the deviant tones). Seven out of nine HS displayed a P300 waveform in the passive condition and all in the active condition. HS showed statistically significant changes in peak and area amplitude between conditions. Three out of seven LIS patients showed the P3 waveform in the passive condition and five of seven in the active condition. No changes in peak amplitude and only a significant difference at one electrode in area amplitude were observed in this group between conditions. We conclude that, in spite of keeping full consciousness and intact or nearly intact cortical functions, compared to HS, LIS patients present less reliable results when testing with ERP, specifically in the passive condition. We thus strongly recommend applying ERP paradigms in an active condition when evaluating consciousness in non-responsive patients. [ABSTRACT FROM AUTHOR]

Background: Detecting signs of consciousness in patients in a vegetative state/unresponsive wakefulness syndrome (UWS/VS) or minimally conscious state (MCS) is known to be very challenging. Plotkin et al. (2010) recently showed the possibility of using a breathing-controlled communication device in patients with locked in syndrome. We here aim to test a breathing-based "sniff controller" that could be used as an alternative diagnostic tool to evaluate response to command in severely brain damaged patients with chronic disorders of consciousness (DOC). Methods: Twenty-five DOC patients were included. Patients' resting breathing-amplitude was measured during a 5 min resting condition. Next, they were instructed to end the presentation of a music sequence by sniffing vigorously. An automated detection of changes in breathing amplitude (i.e., >1.5 SD of resting) ended the music and hence provided positive feedback to the patient. Results: None of the 11 UWS/VS patients showed a sniff-based response to command. One out of 14 patients with MCS was able to willfully modulate his breathing pattern to answer the command on 16/19 trials (accuracy 84%). Interestingly, this patient failed to show any other motor response to command. Discussion: We here illustrate the possible interest of using breathing-dependent response to command in the detection of residual cognition in patients with DOC after severe brain injury. [ABSTRACT FROM AUTHOR]

Background: Misdiagnosis rate is high in patients with disorders of consciousness, potentially leading to an inappropriate clinical management of these patients. Sensitive standardised rating scales offer some protections from these diagnostic errors. In this context, the use of the Coma Recovery Scale-Revised (CRS-R) has strongly been recommended by the American Congress of Rehabilitation Medicine. Objective: Here, we present the work that has been performed to translate this important diagnostic tool in Chinese. Methods: The scale has been translated from its original English version to Chinese by a team of native Chinese speakers in agreement with an expert highly trained in the use of the original version of the CRS-R and, then, back-translated to English by four independent translators blinded to the original version. The resulting translation has been sent to the original author for final approval. Results and conclusion: The Chinese version of the CRS-R is now available for use in clinical practise. Further investigations will nevertheless be needed in order to show that its psychometric properties are identical to the original English version. [ABSTRACT FROM AUTHOR]

Background: This review discusses the advantages of transcranial magnetic stimulation combined with high-density electroencephalography (TMS-hdEEG) over other current techniques of brain imaging. Methods and results: Its application was reviewed, focusing particularly on disorders of consciousness, in the perspective of recent theories of consciousness. Assessment of non-communicative patients with disorders of consciousness remains a clinical challenge and objective measures of the level of consciousness are still needed. Current theories suggest that a key requirement for consciousness is the brain's capacity to rapidly integrate information across different specialized cortical areas. TMS-EEG allows the stimulation of any given cortical area and the recording of the immediate electrical cortical response. This technique has recently been successfully employed to measure changes in brain complexity under physiological, pharmacological and pathological conditions. Conclusions: This suggests that TMS-EEG is a reliable tool to discriminate between conscious and unconscious patients at the single subject level. Future works are needed to validate and implement this technique as a clinical tool. [ABSTRACT FROM AUTHOR]

Background: The assessment of pain and nociception in non-communicative patients with disorders of consciousness (DOC) is a real challenge for clinicians. It is, therefore, important to develop sensitive standardized tools usable at the bedside. Objectives: This review aims to provide an overview of the current knowledge about pain processing and assessment in patients with DOC. Methods: A search was performed on PubMed using MeSH terms including vegetative state, unresponsive wakefulness syndrome, minimally conscious state, consciousness disorders, pain, nociception, neuroimaging and pain assessment. Results: Neuroimaging studies investigating pain processing in patients with DOC and their implication for clinicians are reviewed. Current works on the development of standardized and sensitive tools for assessing nociception are described. Conclusion: The suggested pain perception capacity highlighted by neuroimaging studies in patients in a MCS and in some patients in a VS/UWS supports the idea that these patients need analgesic treatment and monitoring. The first tool which has been developed to assess nociception and pain in patients with DOC is the NCS. Its revised version represents a rapid, standardized and sensitive scale which can be easily implemented in a clinical setting. Complementary pain assessments are also under validation in order to offer more options to clinicians. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to validate the use of electromyography (EMG) for detecting responses to command in patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in minimally conscious state (MCS). Methods: Thirty-eight patients were included in the study (23 traumatic, 25 patients >1 year post-onset), 10 diagnosed as being in VS/UWS, eight in MCS− (no response to command) and 20 in MCS+ (response to command). Eighteen age-matched controls participated in the experiment. The paradigm consisted of three commands (i.e. 'Move your hands', 'Move your legs' and 'Clench your teeth') and one control sentence (i.e. 'It is a sunny day') presented in random order. Each auditory stimulus was repeated 4 times within one block with a stimulus-onset asynchrony of 30 seconds. Results: Post-hoc analyses with Bonferroni correction revealed that EMG activity was higher solely for the target command in one patient in permanent VS/UWS and in three patients in MCS+. Conclusion: The use of EMG could help clinicians to detect conscious patients who do not show any volitional response during standard behavioural assessments. However, further investigations should determine the sensitivity of EMG as compared to neuroimaging and electrophysiological assessments. [ABSTRACT FROM AUTHOR]

Background: Over the last two decades, there has been a considerable increase in knowledge of brain function in patients with disorders of consciousness following a coma. Differentiating between patients in unresponsive wakefulness syndrome and in minimally conscious state still represents a major clinical, legal and ethical challenge. Objectives: This review focuses on recent behavioural and neuroimaging studies in this specific population. Results: The growing interest in the use of neuroimaging techniques as new diagnostic tools has stimulated research in this area and created further challenges to clinical categorization and management. This study proposes a diagnostic procedure combining the use of behavioural scales and neuroimaging techniques. In cases of dissociation between behavioural and ancillary test results, it is suggested that a diagnostic label of 'non-behavioural MCS' (MCS*) be used to provide a more clinically accurate diagnosis (and, in theory, prognosis) when the bedside exam shows no evidence of consciousness, yet the neurodiagnostic work-up does. Conclusion: More neuroimaging research is needed before clinical implementation to reach the single-subject diagnosis level, as well as to address the sensitivity and specificity of each technique, whether single or combined. [ABSTRACT FROM AUTHOR]

Significant advances have been made in the behavioral assessment and clinical management of disorders of consciousness (DOC). In addition, functional neuroimaging paradigms are now available to help assess consciousness levels in this challenging patient population. The success of these neuroimaging approaches as diagnostic markers is, however, intrinsically linked to understanding the relationships between consciousness and the brain. In this context, a combined theoretical approach to neuroimaging studies is needed. The promise of such theoretically based markers is illustrated by recent findings that used a perturbational approach to assess the levels of consciousness. Further research on the contents of consciousness in DOC is also needed. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated resting-state abnormalities in midline regions in vegetative state/unresponsive wakefulness syndrome and minimally conscious state patients. However, the functional implications of these resting-state abnormalities remain unclear. Recent findings in healthy subjects have revealed a close overlap between the neural substrate of self-referential processing and the resting-state activity in cortical midline regions. As such, we investigated task-related neural activity during active self-referential processing and various measures of resting-state activity in 11 patients with disorders of consciousness (DOC) and 12 healthy control subjects. Overall, the results revealed that DOC patients exhibited task-specific signal changes in anterior and posterior midline regions, including the perigenual anterior cingulate cortex (PACC) and posterior cingulate cortex (PCC). However, the degree of signal change was significantly lower in DOC patients compared with that in healthy subjects. Moreover, reduced signal differentiation in the PACC predicted the degree of consciousness in DOC patients. Importantly, the same midline regions (PACC and PCC) in DOC patients also exhibited severe abnormalities in the measures of resting-state activity, that is functional connectivity and the amplitude of low-frequency fluctuations. Taken together, our results provide the first evidence of neural abnormalities in both the self-referential processing and the resting state in midline regions in DOC patients. This novel finding has important implications for clinical utility and general understanding of the relationship between the self, the resting state, and consciousness. Hum Brain Mapp 35:1997-2008, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Although disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [18F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following. [ABSTRACT FROM AUTHOR]

Background Electroencephalography (EEG) is best suited for long-term monitoring of brain functions in patients with disorders of consciousness (DOC). Mathematical tools are needed to facilitate efficient interpretation of long-duration sleep-wake EEG recordings. Methods Starting with matching pursuit (MP) decomposition, we automatically detect and parametrize sleep spindles, slow wave activity, K-complexes and alpha, beta and theta waves present in EEG recordings, and automatically construct profiles of their time evolution, relevant to the assessment of residual brain function in patients with DOC. Results Above proposed EEG profiles were computed for 32 patients diagnosed as minimally conscious state (MCS, 20 patients), vegetative state/unresponsive wakefulness syndrome (VS/UWS, 11 patients) and Locked-in Syndrome (LiS, 1 patient). Their interpretation revealed significant correlations between patients' behavioral diagnosis and: (a) occurrence of sleep EEG patterns including sleep spindles, slow wave activity and light/deep sleep cycles, (b) appearance and variability across time of alpha, beta, and theta rhythms. Discrimination between MCS and VS/UWS based upon prominent features of these profiles classified correctly 87% of cases. Conclusions Proposed EEG profiles offer user-independent, repeatable, comprehensive and continuous representation of relevant EEG characteristics, intended as an aid in differentiation between VS/UWS and MCS states and diagnostic prognosis. To enable further development of this methodology into clinically usable tests, we share user-friendly software for MP decomposition of EEG (http://braintech.pl/svarog) and scripts used for creation of the presented profiles (attached to this article). [ABSTRACT FROM AUTHOR]

Abstract: Background: Transcranial magnetic stimulation (TMS) has been frequently used to explore changes in the human motor cortex in different conditions, while the extent of motor cortex reorganization in patients in vegetative state (VS) (now known as unresponsive wakefulness syndrome, UWS) and minimally conscious (MCS) states due to severe brain damage remains largely unknown. Objective/hypothesis: It was hypothesized that cortical motor excitability would be decreased and would correlate to the level of consciousness in patients with disorders of consciousness. Methods: Corticospinal excitability was assessed in 47 patients (24 VS/UWS and 23 MCS) and 14 healthy controls. The test parameters included maximal peak-to-peak M-wave (M max), F-wave persistence, peripheral and central motor conduction times, sensory (SEP) and motor evoked (MEP) potential latencies and amplitudes, resting motor threshold (RMT), stimulus/response curves, and short latency afferent inhibition (SAI). TMS measurements were correlated to the level of consciousness (assessed using the Coma Recovery Scale-Revised). Results: On average, the patient group had lower M max, lower MEP and SEP amplitudes, higher RMTs, narrower stimulus/response curves, and reduced SAI compared to the healthy controls (P < 0.05). The SAI alterations were correlated to the level of consciousness (P < 0.05). Conclusions: The findings demonstrated the impairment of the cortical inhibitory circuits in patients with disorders of consciousness. Moreover, the significant relationship was found between cortical inhibition and clinical consciousness dysfunction. [Copyright &y& Elsevier]

Background: At present, there is no consensus on how to clinically assess localisation to sound in patients recovering from coma. We here studied auditory localisation using the patient's own name as compared to a meaningless sound (i.e., ringing bell). Methods: Eighty-six post-comatose patients diagnosed with a vegetative state/unresponsive wakefulness syndrome or a minimally conscious state were prospectively included. Localisation of auditory stimulation (i.e., head or eyes orientation toward the sound) was assessed using the patient's own name as compared to a ringing bell. Statistical analyses used binomial testing with bonferroni correction for multiple comparisons. Results: 37 (43%) out of the 86 studied patients showed localisation to auditory stimulation. More patients (n=34, 40%) oriented the head or eyes to their own name as compared to sound (n=20, 23%; p<0.001). Conclusions: When assessing auditory function in disorders of consciousness, using the patient's own name is here shown to be more suitable to elicit a response as compared to neutral sound. [ABSTRACT FROM AUTHOR]

Background: Recent neuroimaging research has strikingly demonstrated the existence of covert awareness in some patients with disorders of consciousness (DoC). These findings have highlighted the potential for the development of simple brain-computer interfaces (BCI) as a diagnosis in behaviourally unresponsive patients. Objectives: This study here reviews current EEG-based BCIs that hold potential for assessing and eventually assisting patients with DoC. It highlights key areas for further development that might eventually make their application feasible in this challenging patient group. Methods: The major types of BCIs proposed in the literature are considered, namely those based on the P3 potential, sensorimotor rhythms, steady state oscillations and slow cortical potentials. In each case, a brief overview of the relevant literature is provided and then their relative merits for BCI applications in DoC are considered. Results: A range of BCI designs have been proposed and tested for enabling communication in fully conscious, paralysed patients. Although many of these have potential applicability for patients with DoC, they share some key challenges that need to be overcome, including limitations of stimulation modality, feedback, user training and consistency. Conclusion: Future work will need to address the technical and practical challenges facing reliable implementation at the patient's bedside. [ABSTRACT FROM AUTHOR]

Abstract: The past 15years have provided an unprecedented collection of discoveries that bear upon our scientific understanding of recovery of consciousness in the human brain following severe brain damage. Highlighted among these discoveries are unique demonstrations that patients with little or no behavioral evidence of conscious awareness may retain critical cognitive capacities and the first scientific demonstrations that some patients, with severely injured brains and very longstanding conditions of limited behavioral responsiveness, may nonetheless harbor latent capacities for significant recovery. Included among such capacities are particularly human functions of language and higher-level cognition that either spontaneously or through direct interventions may reemerge even at long time intervals or remain unrecognized. Collectively, these observations have reframed scientific inquiry and further led to important new insights into mechanisms underlying consciousness in the human brain. These studies support a model of consciousness as the emergent property of the collective behavior of widespread frontoparietal network connectivity modulated by specific forebrain circuit mechanisms. We here review these advances in measurement and the scientific and broader implications of this rapidly progressing field of research. [Copyright &y& Elsevier]

The existence of normal sleep in patients in a vegetative state is still a matter of debate. Previous electrophysiological sleep studies in patients with disorders of consciousness did not differentiate patients in a vegetative state from patients in a minimally conscious state. Using high-density electroencephalographic sleep recordings, 11 patients with disorders of consciousness (six in a minimally conscious state, five in a vegetative state) were studied to correlate the electrophysiological changes associated with sleep to behavioural changes in vigilance (sustained eye closure and muscle inactivity). All minimally conscious patients showed clear electroencephalographic changes associated with decreases in behavioural vigilance. In the five minimally conscious patients showing sustained behavioural sleep periods, we identified several electrophysiological characteristics typical of normal sleep. In particular, all minimally conscious patients showed an alternating non-rapid eye movement/rapid eye movement sleep pattern and a homoeostatic decline of electroencephalographic slow wave activity through the night. In contrast, for most patients in a vegetative state, while preserved behavioural sleep was observed, the electroencephalographic patterns remained virtually unchanged during periods with the eyes closed compared to periods of behavioural wakefulness (eyes open and muscle activity). No slow wave sleep or rapid eye movement sleep stages could be identified and no homoeostatic regulation of sleep-related slow wave activity was observed over the night-time period. In conclusion, we observed behavioural, but no electrophysiological, sleep wake patterns in patients in a vegetative state, while there were near-to-normal patterns of sleep in patients in a minimally conscious state. These results shed light on the relationship between sleep electrophysiology and the level of consciousness in severely brain-damaged patients. We suggest that the study of sleep and homoeostatic regulation of slow wave activity may provide a complementary tool for the assessment of brain function in minimally conscious state and vegetative state patients. [ABSTRACT FROM AUTHOR]

Summary: From a behavioral as well as neurobiological point of view, sleep and consciousness are intimately connected. A better understanding of sleep cycles and sleep architecture of patients suffering from disorders of consciousness (DOC) might therefore improve the clinical care for these patients as well as our understanding of the neural correlations of consciousness. Defining sleep in severely brain-injured patients is however problematic as both their electrophysiological and sleep patterns differ in many ways from healthy individuals. This paper discusses the concepts involved in the study of sleep of patients suffering from DOC and critically assesses the applicability of standard sleep criteria in these patients. The available literature on comatose and vegetative states as well as that on locked-in and related states following traumatic or non-traumatic severe brain injury will be reviewed. A wide spectrum of sleep disturbances ranging from almost normal patterns to severe loss and architecture disorganization are reported in cases of DOC and some patterns correlate with diagnosis and prognosis. At the present time the interactions of sleep and consciousness in brain-injured patients are a little studied subject but, the authors suggest, a potentially very interesting field of research. [Copyright &y& Elsevier]

The ‘default network’ is defined as a set of areas, encompassing posterior-cingulate/precuneus, anterior cingulate/mesiofrontal cortex and temporo-parietal junctions, that show more activity at rest than during attention-demanding tasks. Recent studies have shown that it is possible to reliably identify this network in the absence of any task, by resting state functional magnetic resonance imaging connectivity analyses in healthy volunteers. However, the functional significance of these spontaneous brain activity fluctuations remains unclear. The aim of this study was to test if the integrity of this resting-state connectivity pattern in the default network would differ in different pathological alterations of consciousness. Fourteen non-communicative brain-damaged patients and 14 healthy controls participated in the study. Connectivity was investigated using probabilistic independent component analysis, and an automated template-matching component selection approach. Connectivity in all default network areas was found to be negatively correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative then coma patients. Furthermore, precuneus connectivity was found to be significantly stronger in minimally conscious patients as compared with unconscious patients. Locked-in syndrome patient’s default network connectivity was not significantly different from controls. Our results show that default network connectivity is decreased in severely brain-damaged patients, in proportion to their degree of consciousness impairment. Future prospective studies in a larger patient population are needed in order to evaluate the prognostic value of the presented methodology. [ABSTRACT FROM PUBLISHER]

The bedside detection of awareness in disorders of consciousness (DOC) caused by acquired brain injury is not an easy task. For this reason, differential diagnosis using neuroimaging and electrophysiological tools in search for objective markers of consciousness is being employed. However, such tools cannot be considered as diagnostic per se, but as assistants to the clinical evaluation, which, at present, remains the gold standard. Regarding therapeutic management in DOC, no evidence-based recommendations can be made in favor of a specific treatment. The present review summarizes clinical and paraclinical studies that have been conducted with neuroimaging and electrophysiological techniques in search of residual awareness in DOC. We discuss the medical, scientific and ethical implications that derive from these studies and we argue that, in the future, the role of neuroimaging and electrophysiology will be important not only for the diagnosis and prognosis of COD but also in establishing communication with these challenging patients. [ABSTRACT FROM AUTHOR]

Primary objective: The aim of the present study was to explore the concurrent validity, inter-rater agreement and diagnostic sensitivity of a French adaptation of the Coma Recovery Scale-Revised (CRS-R) as compared to other coma scales such as the Glasgow Coma Scale (GCS), the Full Outline of UnResponsiveness scale (FOUR) and the Wessex Head Injury Matrix (WHIM). Research design: Multi-centric prospective study. Method and procedures: To test concurrent validity and diagnostic sensitivity, the four behavioural scales were administered in a randomized order in 77 vegetative and minimally conscious patients. Twenty-four clinicians with different professional backgrounds, levels of expertise and CRS-R experience were recruited to assess inter-rater agreement. Main outcomes and results: Good concurrent validity was obtained between the CRS-R and the three other standardized behavioural scales. Inter-rater reliability for the CRS-R total score and sub-scores was good, indicating that the scale yields reproducible findings across examiners and does not appear to be systematically biased by profession, level of expertise or CRS-R experience. Finally, the CRS-R demonstrated a significantly higher sensitivity to detect MCS patients, as compared to the GCS, the FOUR and the WHIM. Conclusion: The results show that the French version of the CRS-R is a valid and sensitive scale which can be used in severely brain damaged patients by all members of the medical staff. [ABSTRACT FROM AUTHOR]

Abstract: The clinical and para-clinical examination of residual self-consciousness in non-communicative severely brain damaged patients (i.e., coma, vegetative state and minimally conscious state) remains exceptionally challenging. Passive presentation of the patient’s own name and own face are known to be effective attention-grabbing stimuli when clinically assessing consciousness at the patient’s bedside. Event-related potential and functional neuroimaging studies using such self-referential stimuli are currently being used to disentangle the cognitive hierarchy of self-processing. We here review neuropsychological, neuropathological, electrophysiological and neuroimaging studies using the own name and own face paradigm obtained in conscious waking, sleep, pharmacological coma, pathological coma and related disorders of consciousness. Based on these results we discuss what we currently do and do not know about the functional significance of the neural network involved in “automatic” and “conscious” self-referential processing. [Copyright &y& Elsevier]

The interest of functional imaging in patients in a vegetative state is twofold. First, the vegetative state continues to represent a major clinical and ethical problem, in terms of diagnosis, prognosis, treatment, everyday management and end-of-life decisions. Second, it offers a lesional approach to the study of human consciousness and adds to the international research effort on identifying the neural correlate of consciousness. Cerebral metabolism has been shown to be massively reduced in the vegetative state. However, recovery of consciousness from vegetative state seems not always associated with substantial changes in global metabolism. Recent PET data indicate that some vegetative patients are unconscious not just because of a global loss of neuronal function, but due to an altered activity in a critical fronto-parietal cortical network and to abolished functional connections within this network and with non-specific thalamic nuclei. Recovery of consciousness was shown to be paralleled by a restoration of this cortico-thalamo-cortical interaction. Despite the metabolic impairment, external stimulation still induces neuronal activation as shown by both auditory and noxious stimuli. However, this activation is limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. [ABSTRACT FROM AUTHOR]

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n=14), MCS (n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers (n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.

• More than two thirds of individuals with disorders of consciousness (DOC) present spastic muscle overactivity (SMO). • Management of SMO in DOC patients is a challenge. • Transcranial direct-current stimulation (tDCS) of the primary motor cortex (M1) has reduced SMO in individuals with stroke. • M1 tDCS in a small sample of individuals with DOC showed promise to reduce SMO. 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. We aimed to determine the feasibility of a single session of transcranial direct current stimulations (tDCS) to reduce spasticity in chronic patients with DOC. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Given the fact that clinical bedside examinations can have a high rate of misdiagnosis, machine learning techniques based on neuroimaging and electrophysiological measurements are increasingly being considered for comatose patients and patients with unresponsive wakefulness syndrome, a minimally conscious state or locked-in syndrome. Machine learning techniques have the potential to move from group-level statistical results to personalized predictions in a clinical setting. They have been applied for the purpose of (1) detecting changes in brain activation during functional tasks, equivalent to a behavioral command-following test and (2) estimating signs of consciousness by analyzing measurement data obtained from multiple subjects in resting state. In this review, we provide a comprehensive overview of the literature on both approaches and discuss the translation of present findings to clinical practice. We found that most studies struggle with the difficulty of establishing a reliable behavioral assessment and fluctuations in the patient's levels of arousal. Both these factors affect the training and validation of machine learning methods to a considerable degree. In studies involving more than 50 patients, small to moderate evidence was found for the presence of signs of consciousness or good outcome, where one study even showed strong evidence for good outcome. [ABSTRACT FROM AUTHOR]