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This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

The assessment and management of pain and nociception is very challenging in patients unable to communicate functionally such as patients with disorders of consciousness (DoC) or in locked-in syndrome (LIS). In a clinical setting, the detection of signs of pain and nociception by the medical staff is therefore essential for the wellbeing and management of these patients. However, there is still a lot unknown and a lack of clear guidelines regarding the assessment, management and treatment of pain and nociception in these populations. The purpose of this narrative review is to examine the current knowledge regarding this issue by covering different topics such as: the neurophysiology of pain and nociception (in healthy subjects and patients), the source and impact of nociception and pain in DoC and LIS and, finally, the assessment and treatment of pain and nociception in these populations. In this review we will also give possible research directions that could help to improve the management of this specific population of severely brain damaged patients. [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]

Diagnostic and prognostic assessment of patients with disorders of consciousness (DoC) presents ethical and clinical implications as they may affect the course of medical treatment and the decision to withdraw life-sustaining therapy. There has been increasing research in this field to lower misdiagnosis rates by developing standardized and consensual tools to detect consciousness. In this article, we summarize recent evidence regarding behavioral signs that are not yet included in the current clinical guidelines but could detect consciousness. The new potential behavioral signs of consciousness described here are as follows: resistance to eye opening, spontaneous eye blink rate, auditory localization, habituation of auditory startle reflex, olfactory sniffing, efficacy of swallowing/oral feeding, leg crossing, facial expressions to noxious stimulation, and subtle motor behaviors. All of these signs show promising results in discriminating patients' level of consciousness. Multimodal studies with large sample sizes in different centers are needed to further evaluate whether these behaviors reliably indicate the presence of consciousness. Future translation of these research findings into clinical practice has potential to improve the accuracy of diagnosis and prognostication for patients with DoC. [ABSTRACT FROM AUTHOR]

Keywords: repeated examinations; random responsiveness; diagnosis; Coma Recovery Scale-Revised; disorders of consciousness; minimally conscious state EN repeated examinations random responsiveness diagnosis Coma Recovery Scale-Revised disorders of consciousness minimally conscious state 1 4 4 09/21/21 20210917 NES 210917 In the original article, there was a mistake in the legend for Table 5 as published. [Extracted from the article]

Objective: The aim of this study was to develop a general method to estimate the minimal number of repeated examinations needed to detect patients with random responsiveness, given a limited rate of missed diagnosis. Methods: Basic statistical theory was applied to develop the method. As an application, 100 patients with disorders of consciousness (DOC) were assessed with the Coma Recovery Scale–Revised (CRS-R). DOC patients were supposed to be examined for 13 times over 20 days, while anyone who was diagnosed as a minimally conscious state (MCS) in a round would no longer be examined in the subsequent rounds. To test the validation of this method, a series of the stochastic simulation was completed by computer software under all the conditions of possible combinations of three kinds of distributions for p , five values of p , and four sizes of the sample and repeated for 100 times. Results: A series of formula was developed to estimate the probability of a positive response to a single examination given by a patient and the minimal number of successive examinations needed based on the numbers of patients detected in the first i (i =1, 2,.) rounds of repeated examinations. As applied to the DOC patients assessed with the CRS-R, with a rate of missed diagnosis < 0.0001, the estimate of the minimal number of examinations was six in traumatic brain injury patients and five in non-traumatic brain injury patients. The outcome of the simulation showed that this method performed well under various conditions possibly occurring in practice. Interpretation: The method developed in this paper holds in theory and works well in application and stochastic simulation. It could be applied to any other kind of examinations for random responsiveness, not limited to CRS-R for detecting MCS; this should be validated in further research. [ABSTRACT FROM AUTHOR]

The neural monitoring of visceral inputs might play a role in first-person perspective (i.e., the unified viewpoint of subjective experience). In healthy participants, how the brain responds to heartbeats, measured as the heartbeat-evoked response (HER), correlates with perceptual, bodily, and self-consciousness. Here we show that HERs in resting-state EEG data distinguishes between postcomatose male and female human patients (n = 68, split into training and validation samples) with the unresponsive wakefulness syndrome and in patients in a minimally conscious state with high accuracy (random forest classifier, 87% accuracy, 96% sensitivity, and 50% specificity in the validation sample). Random EEG segments not locked to heartbeats were useful to predict unconsciousness/consciousness, but HERs were more accurate, indicating that HERs provide specific information on consciousness. HERs also led to more accurate classification than heart rate variability. HER-based consciousness scores correlate with glucose metabolism in the default-mode network node located in the right superior temporal sulcus, as well as with the right ventral occipitotemporal cortex. These results were obtained when consciousness was inferred from brain glucose metabolism measured with positron emission topography. HERs reflected the consciousness diagnosis based on brain metabolism better than the consciousness diagnosis based on behavior (Coma Recovery Scale-Revised, 77% validation accuracy). HERs thus seem to capture a capacity for consciousness that does not necessarily translate into intentional overt behavior. These results confirm the role of HERs in consciousness, offer new leads for future bedside testing, and highlight the importance of defining consciousness and its neural mechanisms independently from behavior. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Disorders of consciousness (DoC) are the hallmark of severe acquired brain injuries characterized by abnormal activity in important brain areas and disruption within and between brain networks. As DoC's therapeutic arsenal is limited, new potential therapies such as transcutaneous auricular vagal nerve stimulation (taVNS) have recently been explored. The potential of taVNS in the process of consciousness recovery has been highlighted in recent studies with DoC patients. However, it is not clear how taVNS plays a role in the recovery of consciousness. In this article, we first describe the neural correlates of consciousness, the vagus nerve anatomy and functions, along with the results of functional magnetic resonance imaging studies using taVNS. Based on consciousness recovery and taVNS mechanisms, we propose the Vagal Cortical Pathways model. This model highlights four consecutive pathways (A. Lower brainstem activation, B. Upper brainstem activation, C. Norepinephrine pathway, and D. Serotonin pathway) likely to have an impact on patients with a brain injury and DoC. Additionally, we suggest six different mechanisms of action: (1) Activation of the ascending reticular activating system; (2) Activation of the thalamus; (3) Re-establishment of the cortico-striatal-thalamic-cortical loop; (4) Promotion of negative connectivity between external and default mode networks by the activation of the salience network; (5) Increase in activity and connectivity within the external network through the norepinephrine pathway; and (6) Increase in activity within the default mode network through the serotonin pathway. This model aims to explain the potential therapeutic effects that taVNS has on brain activity in the process of consciousness recovery. [ABSTRACT FROM AUTHOR]

Persons diagnosed with disorders of consciousness (DOC) typically suffer from motor and cognitive disabilities. Recent research has shown that non-invasive brain-computer interface (BCI) technology could help assess these patients' cognitive functions and command following abilities. 20 DOC patients participated in the study and performed 10 vibro-tactile P300 BCI sessions over 10 days with 8–12 runs each day. Vibrotactile tactors were placed on the each patient's left and right wrists and one foot. Patients were instructed, via earbuds, to concentrate and silently count vibrotactile pulses on either their left or right wrist that presented a target stimulus and to ignore the others. Changes of the BCI classification accuracy were investigated over the 10 days. In addition, the Coma Recovery Scale-Revised (CRS-R) score was measured before and after the 10 vibro-tactile P300 sessions. In the first run, 10 patients had a classification accuracy above chance level (>12.5%). In the best run, every patient reached an accuracy ≥60%. The grand average accuracy in the first session for all patients was 40%. In the best session, the grand average accuracy was 88% and the median accuracy across all sessions was 21%. The CRS-R scores compared before and after 10 VT3 sessions for all 20 patients, are showing significant improvement (p = 0.024). Twelve of the twenty patients showed an improvement of 1 to 7 points in the CRS-R score after the VT3 BCI sessions (mean: 2.6). Six patients did not show a change of the CRS-R and two patients showed a decline in the score by 1 point. Every patient achieved at least 60% accuracy at least once, which indicates successful command following. This shows the importance of repeated measures when DOC patients are assessed. The improvement of the CRS-R score after the 10 VT3 sessions is an important issue for future experiments to test the possible therapeutic applications of vibro-tactile and related BCIs with a larger patient group. [ABSTRACT FROM AUTHOR]

The assessment of the consciousness level of Unresponsive Wakefulness Syndrome (UWS) patients often depends on a subjective interpretation of the observed spontaneous and volitional behavior. To date, the misdiagnosis level is around 30%. The aim of this study was to observe the behavior of UWS patients, during the administration of noxious stimulation by a Trace Conditioning protocol, assessed by the Galvanic Skin Response (GSR) and Heart Rate Variability (HRV) entropy. We recruited 13 Healthy Control (HC) and 30 UWS patients at 31 ± 9 days from the acute event evaluated by Coma Recovery Scale–Revised (CRS-R) and Nociception Coma Scale (NCS). Two different stimuli [musical stimulus (MUS) and nociceptive stimulus (NOC)], preceded, respectively by two different tones, were administered following the sequences (A) MUS1 – NOC1 – MUS2 – MUS3 – NOC2 – MUS4 – NOC3 – NOC*, and (B) MUS1*, NOC1*, NOC2*, MUS2*, NOC3*, MUS3*, NOC4*, MUS4*. All the (*) indicate the only tones administration. CRS-R and NCS assessments were repeated for three consecutive weeks. MUS4, NOC3, and NOC* were compared for GSR wave peak magnitude, time to reach the peak, and time of wave's decay by Wilcoxon's test to assess the Conditioned Response (CR). The Sample Entropy (SampEn) was recorded in baseline and both sequences. Machine Learning approach was used to identify a rule to discriminate the CR. The GSR magnitude of CR was higher comparing music stimulus (p < 0.0001) and CR extinction (p < 0.002) in nine patients and in HC. Patients with CR showed a higher SampEn in sequence A compared to patients without CR. Within the third and fourth weeks from protocol administration, eight of the nine patients (88.9%) evolved into MCS. The Machine-learning showed a high performance to differentiate presence/absence of CR (≥95%). The possibility to observe the CR to the noxious stimulus, by means of the GSR and SampEn, can represent a potential method to reduce the misdiagnosis in UWS patients. [ABSTRACT FROM AUTHOR]

Primary Objective: Patients with disorders of consciousness (DOC) face a lack of treatments and risk of misdiagnosis, potentially due to motor impairment. Transcranial direct current stimulation (tDCS) showed promising results over the prefrontal cortex in DOC and over the primary motor cortex (M1) in stroke. Tis pilot study aimed at evaluating the behavioral effects of M1 tDCS in patients with DOC. Research Design: In this randomized double-blind sham-controlled crossover trial, we included 10 patients (49 ± 22 years, 7 ± 13 months since injury, 4 unresponsive wakefulness syndrome, 6 minimally conscious state, 5 traumatic etiologies). Methods and Procedures: One session of tDCS (2 mA for 20 min) and one session of sham tDCS were applied over M1 in a randomized order with a washout period of minimum 24 h and behavioral effects were assessed using the CRS-R. At the group level, no treatment effect was identified on the total score (p = .55) and on the motor subscale (p = .75). Two patients responded to tDCS by showing a new sign of consciousness (visual pursuit and object localization). Conclusions: One session of M1 tDCS failed to improve behavioral responsiveness in patients with DOC. Other application strategies should be tested. [ABSTRACT FROM AUTHOR]

Objective: To detect the initiation of swallowing in patients with disorders of consciousness (DOC) as well as the relationship between the initiation of swallowing and the prognosis of DOC patients. Methods: Nineteen DOC patients were included in this study, and a self-controlled trial compared five different stimuli. The five different stimuli were as follows: (1) one command, as recommended by the Coma Recovery Scale-Revised (CRS-R), which was "open your mouth"; (2) placing a spoon in front of the patient's mouth without a command; (3) placing a spoon filled with water in front of the patient's mouth without a command; (4) one command—"there is a spoon; open your mouth"—with a spoon in front of the patient's mouth; (5) one command, "there is a spoon with water; open your mouth," with a spoon filled with water in front of the patient's mouth. All 19 patients were given these five stimuli randomly, and any one of the commands was presented four times to a patient, one at a time, at 15-s intervals. The sensitivity and specificity of the initiation of swallowing in detecting conscious awareness were determined. Results: None of the patients responded to the first four stimuli. However, six patients showed initiated swallowing toward the fifth stimulus. Among those six, five patients showed improvement in their consciousness state 6 months later. The sensitivity and specificity of the initiation of swallowing for DOC patients was 83.33% [95% CIs (36%, 100%)] and 92.31% [95% CIs (64%, 100%)], respectively. Conclusions: The initiation of swallowing can be an early indication of conscious behavior and can likely provide evidence of conscious awareness. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03508336; Date of registration: 2018/4/16. [ABSTRACT FROM AUTHOR]

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

Determining the state of consciousness in patients with disorders of consciousness is a challenging practical and theoretical problem. Recent findings suggest that multiple markers of brain activity extracted from the EEG may index the state of consciousness in the human brain. Furthermore, machine learning has been found to optimize their capacity to discriminate different states of consciousness in clinical practice. However, it is unknown how dependable these EEG markers are in the face of signal variability because of different EEG configurations, EEG protocols and subpopulations from different centres encountered in practice. In this study we analysed 327 recordings of patients with disorders of consciousness (148 unresponsive wakefulness syndrome and 179 minimally conscious state) and 66 healthy controls obtained in two independent research centres (Paris Pitié-Salpêtrière and Liège). We first show that a non-parametric classifier based on ensembles of decision trees provides robust out-of-sample performance on unseen data with a predictive area under the curve (AUC) of ~0.77 that was only marginally affected when using alternative EEG configurations (different numbers and positions of sensors, numbers of epochs, average AUC = 0.750 ± 0.014). In a second step, we observed that classifiers based on multiple as well as single EEG features generalize to recordings obtained from different patient cohorts, EEG protocols and different centres. However, the multivariate model always performed best with a predictive AUC of 0.73 for generalization from Paris 1 to Paris 2 datasets, and an AUC of 0.78 from Paris to Liège datasets. Using simulations, we subsequently demonstrate that multivariate pattern classification has a decisive performance advantage over univariate classification as the stability of EEG features decreases, as different EEG configurations are used for feature-extraction or as noise is added. Moreover, we show that the generalization performance from Paris to Liège remains stable even if up to 20% of the diagnostic labels are randomly flipped. Finally, consistent with recent literature, analysis of the learned decision rules of our classifier suggested that markers related to dynamic fluctuations in theta and alpha frequency bands carried independent information and were most influential. Our findings demonstrate that EEG markers of consciousness can be reliably, economically and automatically identified with machine learning in various clinical and acquisition contexts. [ABSTRACT FROM AUTHOR]

We assess cerebral integrity with cortical and subcortical FDG-PET and cortical electroencephalography (EEG) within the mesocircuit model framework in patients with disorders of consciousness (DoCs). The mesocircuit hypothesis proposes that subcortical activation facilitates cortical function. We find that the metabolic balance of subcortical mesocircuit areas is informative for diagnosis and is associated with four EEG-based power spectral density patterns, cortical metabolism, and α power in healthy controls and patients with a DoC. Last, regional electrometabolic coupling at the cortical level can be identified in the θ and α ranges, showing positive and negative relations with glucose uptake, respectively. This relation is inverted in patients with a DoC, potentially related to altered orchestration of neural activity, and may underlie suboptimal excitability states in patients with a DoC. By understanding the neurobiological basis of the pathophysiology underlying DoCs, we foresee translational value for diagnosis and treatment of patients with a DoC. [Display omitted] • Biologically founded EEG spectral regimes are related to cortical glucose uptake • Subcortical metabolism correlates with cortical α power, glucose uptake, and consciousness • Cortical α is negatively and θ is positively related to cortical glucose uptake in controls • Cortical electrometabolic coupling is inverted in patients with a severe brain injury Patients with disorders of consciousness are characterized by reduced cerebral function as measured by glucose uptake and electrical activity. Annen et al. characterize the role of subcortical areas in sustaining cortical function and quantify electrometabolic coupling in healthy conscious and reduced conscious states after coma. [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]

Spasticity is a motor disorder frequently encountered after a lesion involving the central nervous system. It is hypothesized to arise from an anarchic reorganization of the pyramidal and parapyramidal fibers and leads to hypertonia and hyperreflexia of the affected muscular groups. While this symptom and its management is well-known in patients suffering from stroke, multiple sclerosis or spinal cord lesion, little is known regarding its appropriate management in patients presenting disorders of consciousness after brain damage. Objectives: Our aim was to review the occurrence of spasticity in patients with disorders of consciousness and the therapeutic interventions used to treat it. Methods: We conducted a systematic review using the PubMed online database. It returned 157 articles. After applying our inclusion criteria (i.e., studies about patients in coma, unresponsive wakefulness syndrome or minimally conscious state, with spasticity objectively reported as a primary or secondary outcome), 18 studies were fully reviewed. Results: The prevalence of spasticity in patients with disorders of consciousness ranged from 59% to 89%. Current treatment options include intrathecal baclofen and soft splints. Several treatment options still need further investigation; including acupuncture, botulin toxin or cortical activation by thalamic stimulation. Conclusion: The small number of articles available in the current literature highlights that spasticity is poorly studied in patients with disorders of consciousness although it is one of the most common motor disorders. While treatments such as intrathecal baclofen and soft splints seem effective, large randomized controlled trials have to be done and new therapeutic options should be explored. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Transcranial direct current stimulation (tDCS) is a non-invasive technique recently employed in disorders of consciousness, and determining a transitory recovery of signs of consciousness in almost half of minimally conscious state (MCS) patients. Although the rising evidences about its possible role in the treatment of many neurological and psychiatric conditions exist, no evidences exist about brain functional connectivity substrates underlying tDCS response. We retrospectively evaluated resting state functional Magnetic Resonance Imaging (fMRI) of 16 sub-acute and chronic MCS patients (6 tDCS responders) who successively received a single left dorsolateral prefrontal cortex (DLPFC) tDCS in a double-blind randomized cross-over trial. A seed-based approach for regions of left extrinsic control network (ECN) and default-mode network (DMN) was performed. tDCS responders showed an increased left intra-network connectivity for regions co-activated with left DLPFC, and significantly with left inferior frontal gyrus. Non-responders (NR) MCS patients showed an increased connectivity between left DLPFC and midline cortical structures, including anterior cingulate cortex and precuneus. Our findings suggest that a prior high connectivity with regions belonging to ECN can facilitate transitory recovery of consciousness in a subgroup of MCS patients that underwent tDCS treatment. Therefore, resting state-fMRI could be very valuable in detecting the neuronal conditions necessary for tDCS to improve behavior in MCS. [ABSTRACT FROM AUTHOR]

Background: For patients with disorders of consciousness such as coma, a vegetative state or a minimally conscious state, one challenge is to detect and assess the residual cognitive functions in their brains. Number processing and mental calculation are important brain functions but are difficult to detect in patients with disorders of consciousness using motor response-based clinical assessment scales such as the Coma Recovery Scale-Revised due to the patients' motor impairments and inability to provide sufficient motor responses for number- and calculation-based communication.Methods: In this study, we presented a hybrid brain-computer interface that combines P300 and steady state visual evoked potentials to detect number processing and mental calculation in Han Chinese patients with disorders of consciousness. Eleven patients with disorders of consciousness who were in a vegetative state (n = 6) or in a minimally conscious state (n = 3) or who emerged from a minimally conscious state (n = 2) participated in the brain-computer interface-based experiment. During the experiment, the patients with disorders of consciousness were instructed to perform three tasks, i.e., number recognition, number comparison, and mental calculation, including addition and subtraction. In each experimental trial, an arithmetic problem was first presented. Next, two number buttons, only one of which was the correct answer to the problem, flickered at different frequencies to evoke steady state visual evoked potentials, while the frames of the two buttons flashed in a random order to evoke P300 potentials. The patients needed to focus on the target number button (the correct answer). Finally, the brain-computer interface system detected P300 and steady state visual evoked potentials to determine the button to which the patients attended, further presenting the results as feedback.Results: Two of the six patients who were in a vegetative state, one of the three patients who were in a minimally conscious state, and the two patients that emerged from a minimally conscious state achieved accuracies significantly greater than the chance level. Furthermore, P300 potentials and steady state visual evoked potentials were observed in the electroencephalography signals from the five patients.Conclusions: Number processing and arithmetic abilities as well as command following were demonstrated in the five patients. Furthermore, our results suggested that through brain-computer interface systems, many cognitive experiments may be conducted in patients with disorders of consciousness, although they cannot provide sufficient behavioral responses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Preferred music is a highly emotional and salient stimulus, which has previously been shown to increase the probability of auditory cognitive event-related responses in patients with disorders of consciousness (DOC). To further investigate whether and how music modifies the functional connectivity of the brain in DOC, five patients were assessed with both a classical functional connectivity scan (control condition), and a scan while they were exposed to their preferred music (music condition). Seedbased functional connectivity (left or right primary auditory cortex), and mean network connectivity of three networks linked to conscious sound perception were assessed. The auditory network showed stronger functional connectivity with the left precentral gyrus and the left dorsolateral prefrontal cortex during music as compared to the control condition. Furthermore, functional connectivity of the external network was enhanced during the music condition in the temporo-parietal junction. Although caution should be taken due to small sample size, these results suggest that preferred music exposure might have effects on patients auditory network (implied in rhythm and music perception) and on cerebral regions linked to autobiographical memory. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]