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Abstract Consciousness has been proposed to be supported by electrophysiological patterns poised at criticality, a dynamical regime which exhibits adaptive computational properties, maximally complex patterns and divergent sensitivity to perturbation. Here, we investigate dynamical properties of the resting-state electroencephalogram (EEG) of healthy subjects undergoing general anesthesia with propofol, xenon or ketamine. Importantly, all participants were unresponsive under anesthesia, while consciousness was retained only during ketamine anesthesia (in the form of vivid dreams), enabling an experimental dissociation between unresponsiveness and unconsciousness. For each condition, we measure (i) avalanche criticality, (ii) chaoticity, and (iii) criticality-related metrics, revealing that states of unconsciousness are characterized by a distancing from both avalanche criticality and the edge of chaos. We then ask whether these same dynamical properties are predictive of the perturbational complexity index (PCI), a TMS-based measure that has shown remarkably high sensitivity in detecting consciousness independently of behavior. We successfully predict individual subjects’ PCI values with considerably high accuracy from resting-state EEG dynamical properties alone. Our results establish a firm link between perturbational complexity and criticality, and provide further evidence that criticality is a necessary condition for the emergence of consciousness.

Abstract Objectives Surrogate decision-making by family caregivers for patients with severe brain injury is influenced by the availability and understanding of relevant information and expectations for future rehabilitation. We aimed to compare the consistency of family caregivers’ perceptions with clinical diagnoses and to inform their expectation of prognosis in the future. Methods The Coma Recovery Scale-Revised was used to assess the diagnosis of inpatients with severe brain injury between February 2019 and February 2020. A main family caregiver was included per patient. The family caregiver’s perception of the patient’s consciousness and expectations of future recovery were collected through questionnaires and compared consistently with the clinical diagnosis. Results The final sample included 101 main family caregivers of patients (57 UWS, unresponsive wakefulness syndrome, 37 MCS, minimally conscious state, 7 EMCS, emergence from MCS) with severe brain injury. Only 57 family caregivers correctly assessed the level of consciousness as indicated by the CRS-R, showing weak consistency (Kappa = 0.217, P = 0.002). Family caregivers’ demographic characteristics and CRS-R diagnosis influenced the consistency between perception and clinical diagnosis. Family caregivers who provided hands-on care to patients showed higher levels of consistent perception (AOR = 12.24, 95% CI = 2.06-73.00, P = 0.006). Compared to UWS, the family caregivers of MCS patients were more likely to have a correct perception (OR = 7.68, 95% CI = 1.34–44.06). Family caregivers had positive expectations for patients’ recovery in terms of both communication and returning to normal life. Conclusion Nearly half of family caregivers have inadequate understanding of their relative’s level of consciousness, and most of them report overly optimistic expectations that do not align with clinical diagnosis. Providing more medical information to family caregivers to support their surrogate decision-making process is essential.

Background: The diagnosis of and life-sustaining treatment (LST) for patients with disorders of consciousness (DoC) and locked-in syndrome (LIS) have been the subject of intense debate. Objective: We aim to investigate the application of diagnostic knowledge, opinions about the administration of LST, and ethical challenges related to DoC and LIS. Design: A cross-sectional study. Methods: A survey was conducted among Chinese neurologists. Questionnaires included three vignettes (unresponsive wakefulness syndrome (UWS); minimally conscious state (MCS), and LIS). They were randomly distributed among neurologists from August 2018 to December 2019. Results: A sample of 360 questionnaires was included (response rate: 78%). Overall, 63% of the participants chose the correct diagnostic category. The neurologists who received the MCS case chose the category more accurately than the neurologists with the UWS ( p 0.05). Deciding for patients in the absence of surrogates was rated extremely challenging. Conclusion: A large proportion of Chinese neurologists in our study didn’t apply the accurate diagnostic categories to the description of DoC and LIS patients. This calls for more education and training. Most Chinese neurologists were reluctant to limit LST for patients. This may indicate that there may be a need to emphasize the allocation of more resources toward long-term care in China.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

During fainting, disconnected consciousness may emerge in the form of dream-like experiences. Characterized by extra-ordinary and mystical features, these subjective experiences have been associated to near-death-like experiences (NDEs-like). We here aim to assess brain activity during syncope-induced disconnected consciousness by means of high-density EEG monitoring. Transient loss of consciousness and unresponsiveness were induced in 27 healthy volunteers through hyperventilation, orthostasis, and Valsalva maneuvers. Upon awakening, subjects were asked to report memories, if any. The Greyson NDE scale was used to evaluate the potential phenomenological content experienced during the syncope-induced periods of unresponsiveness. EEG source reconstruction assessed cortical activations during fainting, which were regressed out with subjective reports collected upon recovery of normal consciousness. We also conducted functional connectivity, graph-theoretic and complexity analyses. High quality high-density EEG data were obtained in 22 volunteers during syncope and unresponsiveness (lasting 22±8 s). NDE-like features (Greyson NDE scale total score ≥7/32) were apparent for eight volunteers and characterized by higher activity in delta, theta and beta2 bands in temporal and frontal regions. The richness of the NDE-like content was associated with delta, theta and beta2 bands cortical current densities, in temporal, parietal and frontal lobes, including insula, right temporoparietal junction, and cingulate cortex. Our analyses also revealed a higher complexity and that networks related to delta, theta, and beta2 bands were characterized by a higher overall connectivity paralleled by a higher segregation (i.e., local efficiency) and a higher integration (i.e., global efficiency) for the NDE-like group compared to the non-NDE-like group. Fainting-induced NDE-like episodes seem to be sustained by surges of neural activity representing promising markers of disconnected consciousness.

Summary: Background: Apomorphine is a dopaminergic candidate therapy to improve recovery in patients with prolonged disorders of consciousness (PDoC). Behavioural improvements were previously described in non-controlled case series, but its efficacy and neural mechanisms remain largely unknown. This open-label controlled study using multimodal outcome measures investigates the action of apomorphine in severely brain-injured patients. Methods: Thirteen PDoC patients received 30-day subcutaneous apomorphine treatment (n = 6) or standard care (control group, n = 7) in a neurological rehabilitation centre between February 2018 and January 2021. The apomorphine group was monitored 30 days before treatment initiation, during treatment and one year after treatment. Primary outcome measure was defined as changes in behavioural diagnosis using the Coma Recovery Scale—Revised (CRS-R). CRS-R index, recovery of new conscious behaviours, DoC-feeling scores, high-density electroencephalography, and fluorodeoxyglucose positron emission tomography were employed as secondary outcome measures. The control group was monitored with repeated CRS-R only. Registration: EudraCT 2018-003144-23; Clinicaltrials.gov NCT03623828. Findings: Groups (apomorphine vs. control: odds ratio 8.9, 95% CI 3.3–17.8) and study phase (treatment vs. baseline, apomorphine group only: odds ratio 3.9, 95% CI 1.5–10.1) significantly influenced positive changes in behavioural diagnosis. At one-year post-injury, 4/6 patients in the apomorphine group and 1/7 patients in the control group had improved their diagnosis. Similarly, CRS-R index was significantly influenced by study phase (treatment vs. baseline). All items on the DoC-feeling score were rated higher after treatment than before by both family and medical staff. Patients in the apomorphine group recovered more conscious behaviours than control patients. Alpha-band whole-brain connectivity and participation coefficient, as well as alpha-band parieto-temporal connectivity and frontal participation coefficient were higher after treatment than at baseline. Whole-brain metabolism increased by a relative mean of 13.8% after treatment compared to baseline, with a significant effect of timing (pre-vs. post-treatment scans) on regional SUV. Interpretation: Long-lasting consciousness improvements were observed in patients treated with apomorphine, compared to controls and compared to baseline. Changes in brain connectivity and metabolism were observed after treatment, providing insights into possible neurophysiological mechanisms and target areas. This open-label study confirmed the feasibility and safety of apomorphine treatment, which may represent a key therapeutic option for PDoC. Funding: University and University Hospital of Liege, Belgian National Funds for Scientific Research, Fund Generet of the King Baudouin Foundation, AstraZeneca Foundation, Leon Fredericq Foundation and NeuroHealing Pharmaceuticals Inc.

For patients with disorders of consciousness (DoC), accurate assessment of residual consciousness levels and cognitive abilities is critical for developing appropriate rehabilitation interventions. In this study, we investigated the potential of electrooculography (EOG) in assessing language processing abilities and consciousness levels. Patients’ EOG data and related electrophysiological data were analysed before and after explicit language learning. The results showed distinct differences in vocabulary learning patterns among patients with varying levels of consciousness. While minimally conscious patients showed significant neural tracking of artificial words and notable learning effects similar to those observed in healthy controls, whereas patients with unresponsive wakefulness syndrome did not show such effects. Correlation analysis further indicated that EOG detected vocabulary learning effects with comparable validity to electroencephalography, reinforcing the credibility of EOG indicator as a diagnostic tool. Critically, EOG also revealed significant correlations between individual patients’ linguistic learning performance and their Oromotor/verbal function as assessed through behavioural scales. In conclusion, this study explored the differences in language processing abilities among patients with varying consciousness levels. By demonstrating the utility of EOG in evaluating consciousness and detecting vocabulary learning effects, as well as its potential to guide personalised rehabilitation, our findings indicate that EOG indicators show promise as a rapid, accurate and effective additional tool for diagnosing and managing patients with DoC.

High-order interactions are required across brain regions to accomplish specific cognitive functions. These functional interdependencies are reflected by synergistic information that can be obtained by combining the information from all the sources considered and redundant information (i.e., common information provided by all the sources). However, electroencephalogram (EEG) functional connectivity is limited to pairwise interactions thereby precluding the estimation of high-order interactions. In this multicentric study, we used measures of synergistic and redundant information to study in parallel the high-order interactions between five EEG electrodes during three non-ordinary states of consciousness (NSCs): Rajyoga meditation (RM), hypnosis, and auto-induced cognitive trance (AICT). We analyzed EEG data from 22 long-term Rajyoga meditators, nine volunteers undergoing hypnosis, and 21 practitioners of AICT. We here report the within-group changes in synergy and redundancy for each NSC in comparison with their respective baseline. During RM, synergy increased at the whole brain level in the delta and theta bands. Redundancy decreased in frontal, right central, and posterior electrodes in delta, and frontal, central, and posterior electrodes in beta1 and beta2 bands. During hypnosis, synergy decreased in mid-frontal, temporal, and mid-centro-parietal electrodes in the delta band. The decrease was also observed in the beta2 band in the left frontal and right parietal electrodes. During AICT, synergy decreased in delta and theta bands in left-frontal, right-frontocentral, and posterior electrodes. The decrease was also observed at the whole brain level in the alpha band. However, redundancy changes during hypnosis and AICT were not significant. The subjective reports of absorption and dissociation during hypnosis and AICT, as well as the mystical experience questionnaires during AICT, showed no correlation with the high-order measures. The proposed study is the first exploratory attempt to utilize the concepts of synergy and redundancy in NSCs. The differences in synergy and redundancy during different NSCs warrant further studies to relate the extracted measures with the phenomenology of the NSCs.

A fundamental challenge in neuroscience is accurately defining brain states and predicting how and where to perturb the brain to force a transition. Here, we investigated resting-state fMRI data of patients suffering from disorders of consciousness (DoC) after coma (minimally conscious and unresponsive wakefulness states) and healthy controls. We applied model-free and model-based approaches to help elucidate the underlying brain mechanisms of patients with DoC. The model-free approach allowed us to characterize brain states in DoC and healthy controls as a probabilistic metastable substate (PMS) space. The PMS of each group was defined by a repertoire of unique patterns (i.e., metastable substates) with different probabilities of occurrence. In the model-based approach, we adjusted the PMS of each DoC group to a causal whole-brain model. This allowed us to explore optimal strategies for promoting transitions by applying off-line in silico probing. Furthermore, this approach enabled us to evaluate the impact of local perturbations in terms of their global effects and sensitivity to stimulation, which is a model-based biomarker providing a deeper understanding of the mechanisms underlying DoC. Our results show that transitions were obtained in a synchronous protocol, in which the somatomotor network, thalamus, precuneus and insula were the most sensitive areas to perturbation. This motivates further work to continue understanding brain function and treatments of disorders of consciousness.

Background: Deep brain stimulation (DBS) in the centromedian-parafascicular complex (CM-pf) has been reported as a potential therapeutic option for disorders of consciousness (DoC). However, the lack of understanding of its electrophysiological characteristics limits the improvement of therapeutic effect. Objective: To investigate the CM-pf electrophysiological characteristics underlying disorders of consciousness (DoC) and its recovery. Methods: We collected the CM-pf electrophysiological signals from 23 DoC patients who underwent central thalamus DBS (CT-DBS) surgery. Five typical electrophysiological features were extracted, including neuronal firing properties, multiunit activity (MUA) properties, signal stability, spike-MUA synchronization strength (syncMUA), and the background noise level. Their correlations with the consciousness level, the outcome, and the primary clinical factors of DoC were analyzed. Results: 11 out of 23 patients (0/2 chronic coma, 5/13 unresponsive wakefulness syndrome/vegetative state (UWS/VS), 6/8 minimally conscious state minus (MCS-)) exhibited an improvement in the level of consciousness after CT-DBS. In CM-pf, significantly stronger gamma band syncMUA strength and alpha band normalized MUA power were found in MCS- patients. In addition, higher firing rates, stronger high-gamma band MUA power and alpha band normalized power, and more stable theta oscillation were correlated with better outcomes. Besides, we also identified electrophysiological properties that are correlated with clinical factors, including etiologies, age, and duration of DoC. Conclusion: We provide comprehensive analyses of the electrophysiological characteristics of CM-pf in DoC patients. Our results support the ‘mesocircuit’ hypothesis, one proposed mechanism of DoC recovery, and reveal CM-pf electrophysiological features that are crucial for understanding the pathogenesis of DoC, predicting its recovery, and explaining the effect of clinical factors on DoC.

Abstract Self-induced cognitive trance (SICT) is a voluntary non-ordinary state of consciousness characterized by a lucid yet narrowed awareness of the external surroundings. It involves a hyper-focused immersive experience of flow, expanded inner imagery, modified somatosensory processing, and an altered perception of self and time. SICT is gaining attention due to its potential clinical applications. Similar states of non-ordinary state of consciousness, such as meditation, hypnosis, and psychedelic experiences, have been reported to induce changes in the autonomic nervous system. However, the functioning of the autonomic nervous system during SICT remains poorly understood. In this study, we aimed to investigate the impact of SICT on the cardiac and respiratory signals of 25 participants proficient in SICT. To accomplish this, we measured various metrics of heart rate variability (HRV) and respiration rate variability (RRV) in three conditions: resting state, SICT, and a mental imagery task. Subsequently, we employed a machine learning framework utilizing a linear discriminant analysis classifier and a cross-validation scheme to identify the features that exhibited the best discrimination between these three conditions. The results revealed that during SICT, participants experienced an increased heart rate and a decreased level of high-frequency (HF) HRV compared to the control conditions. Additionally, specific increases in respiratory amplitude, phase ratio, and RRV were observed during SICT in comparison to the other conditions. These findings suggest that SICT is associated with a reduction in parasympathetic activity, indicative of a hyperarousal state of the autonomic nervous system during SICT.

BackgroundDisconnected consciousness describes a state in which subjective experience (i.e., consciousness) becomes isolated from the external world. It appears frequently during sleep or sedation, when subjective experiences remain vivid but are unaffected by external stimuli. Traditional methods of differentiating connected and disconnected consciousness, such as relying on behavioral responsiveness or on post-anesthesia reports, have demonstrated limited accuracy: unresponsiveness has been shown to not necessarily equate to unconsciousness and amnesic effects of anesthesia and sleep can impair explicit recollection of events occurred during sleep/sedation. Due to these methodological challenges, our understanding of the neural mechanisms underlying sensory disconnection remains limited.MethodsTo overcome these methodological challenges, we employ a distinctive strategy by combining a serial awakening paradigm with auditory stimulation during mild propofol sedation. While under sedation, participants are systematically exposed to auditory stimuli and questioned about their subjective experience (to assess consciousness) and their awareness of the sounds (to evaluate connectedness/disconnectedness from the environment). The data collected through interviews are used to categorize participants into connected and disconnected consciousness states. This method circumvents the requirement for responsiveness in assessing consciousness and mitigates amnesic effects of anesthesia as participants are questioned while still under sedation. Functional MRI data are concurrently collected to investigate cerebral activity patterns during connected and disconnected states, to elucidate sensory disconnection neural gating mechanisms. We examine whether this gating mechanism resides at the thalamic level or results from disruptions in information propagation to higher cortices. Furthermore, we explore the potential role of slow-wave activity (SWA) in inducing disconnected consciousness by quantifying high-frequency BOLD oscillations, a known correlate of slow-wave activity.DiscussionThis study represents a notable advancement in the investigation of sensory disconnection. The serial awakening paradigm effectively mitigates amnesic effects by collecting reports immediately after regaining responsiveness, while still under sedation. Ultimately, this research holds the potential to understand how sensory gating is achieved at the neural level. These biomarkers might be relevant for the development of sensitive anesthesia monitoring to avoid intraoperative connected consciousness and for the assessment of patients suffering from pathologically reduced consciousness.Clinical trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT), identifier 2020-003524-17.

Neuroimaging studies have suggested an important role for the default mode network (DMN) in disorders of consciousness (DoC). However, the extent to which DMN connectivity can discriminate DoC states-unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS)-is less evident. Particularly, it is unclear whether effective DMN connectivity, as measured indirectly with dynamic causal modelling (DCM) of resting EEG can disentangle UWS from healthy controls and from patients considered conscious (MCS+). Crucially, this extends to UWS patients with potentially "covert" awareness (minimally conscious star, MCS*) indexed by voluntary brain activity in conjunction with partially preserved frontoparietal metabolism as measured with positron emission tomography (PET+ diagnosis; in contrast to PET- diagnosis with complete frontoparietal hypometabolism). Here, we address this gap by using DCM of EEG data acquired from patients with traumatic brain injury in 11 UWS (6 PET- and 5 PET+) and in 12 MCS+ (11 PET+ and 1 PET-), alongside with 11 healthy controls. We provide evidence for a key difference in left frontoparietal connectivity when contrasting UWS PET- with MCS+ patients and healthy controls. Next, in a leave-one-subject-out cross-validation, we tested the classification performance of the DCM models demonstrating that connectivity between medial prefrontal and left parietal sources reliably discriminates UWS PET- from MCS+ patients and controls. Finally, we illustrate that these models generalize to an unseen dataset: models trained to discriminate UWS PET- from MCS+ and controls, classify MCS* patients as conscious subjects with high posterior probability (pp > .92). These results identify specific alterations in the DMN after severe brain injury and highlight the clinical utility of EEG-based effective connectivity for identifying patients with potential covert awareness.

IntroductionIn recent years, a growing number of near-death experience (NDE) testimonies have been collected worldwide due to an increasing interest in research on this phenomenon. China has many patients who survive life-threatening situations, leaving over much data on NDEs to be collected for research. In the historical context of Eastern civilization, many mentally controlled practices in China can also lead to “NDEs-like” (e.g., meditation). This study aimed (1) to translate and validate the recently developed Near-Death Experience Content (NDE-C) scale into Chinese and (2) to quantify and identify NDEs and NDEs-like in China with this new Chinese version of the NDE-C scale.MethodsHere, we presented the work that had been performed to translate the NDE-C scale into Chinese and validated this version on 79 NDE testimonies.ResultsBrislin’s back-translation model was performed to translate a Chinese version of the NDE-C scale and internal consistency (the Cronbach’s α value for the total group = 0.846) as well as the confirmatory factor analysis was conducted.DiscussionCurrently, the Chinese version of the NDE-C scale is ready for use in research practice in the context of Eastern culture, to screen people who have experienced an NDEs(-like) and to quantify their subjective experience, promoting further NDEs-related research in China.

The use of Brain–Computer Interfaces (BCI) as rehabilitation tools for chronically ill neurological patients has become more widespread. BCIs combined with other techniques allow the user to restore neurological function by inducing neuroplasticity through real-time detection of motor-imagery (MI) as patients perform therapy tasks. Twenty-five stroke patients with gait disability were recruited for this study. Participants performed 25 sessions with the MI-BCI and assessment visits to track functional changes during the therapy. The results of this study demonstrated a clinically significant increase in walking speed of 0.19 m/s, 95%CI [0.13–0.25], p

Summary: Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p

Abstract Background So far, the few prospective studies on near-death experience (NDE) were carried out only in intensive care unit (ICU) patients with homogeneous aetiologies, such as cardiac arrest or trauma survivors. The aims of this 1-year prospective and monocentric study were to investigate the incidence of NDE in ICU survivors (all aetiologies) as well as factors that may affect its frequency, and to assess quality of life up to 1 year after enrolment. Methods We enrolled adults with a prolonged ICU stay (> 7 days). During the first 7 days after discharge, all eligible patients were assessed in a face-to-face interview for NDE using the Greyson NDE scale, dissociative experiences using the Dissociative Experience Scale, and spirituality beliefs using the WHOQOL-SRPB. Medical parameters were prospectively collected. At 1-year after inclusion, patients were contacted by phone to measure quality of life using the EuroQol five-dimensional questionnaire. Results Out of the 126 included patients, 19 patients (15%) reported having experienced a NDE as identified by the Greyson NDE scale (i.e. cut-off score ≥ 7/32). In univariate analyses, mechanical ventilation, sedation, analgesia, reason for admission, primary organ dysfunction, dissociative and spiritual propensities were associated with the emergence of NDE. In multivariate logistic regression analysis, only the dissociative and spiritual propensity strongly predicted the emergence of NDE. One year later (n = 61), the NDE was not significantly associated with quality of life. Conclusions The recall of NDE is not so rare in the ICU. In our cohort, cognitive and spiritual factors outweighed medical parameters as predictors of the emergence of NDE. Trial registration This trial was registered in Clinicaltrials.gov in February 2020 ( NCT04279171 ).

rs-fMRI is used to investigate human brain connectivity changes induced by prolonged microgravity in cosmonauts before and after spaceflight, with both persistent and reversible location specific changes in connectivity being observed.

Summary: 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.

BackgroundImproving 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/designNinety 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.DiscussionThis 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.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT04401319, Clinicaltrials.gov, n° NCT04401319.

A unifying turbulent dynamics framework using both model-free and modelbased measures of whole-brain information provides insights into brain states.

Summary: Brain states are frequently represented using a unidimensional scale measuring the richness of subjective experience (level of consciousness). This description assumes a mapping between the high-dimensional space of whole-brain configurations and the trajectories of brain states associated with changes in consciousness, yet this mapping and its properties remain unclear. We combine whole-brain modeling, data augmentation, and deep learning for dimensionality reduction to determine a mapping representing states of consciousness in a low-dimensional space, where distances parallel similarities between states. An orderly trajectory from wakefulness to patients with brain injury is revealed in a latent space whose coordinates represent metrics related to functional modularity and structure-function coupling, increasing alongside loss of consciousness. Finally, we investigate the effects of model perturbations, providing geometrical interpretation for the stability and reversibility of states. We conclude that conscious awareness depends on functional patterns encoded as a low-dimensional trajectory within the vast space of brain configurations.

IntroductionLittle is known about the potential personality and psychological predictors of near-death experiences (NDEs), and fewer yet those of near-death-like experiences (NDEs-like; similar phenomenology reported after a non-life-threatening context). This study investigated whether personality traits (Openness, Extraversion, Pleasantness, Conscientiousness, and Neuroticism), dissociative experiences, Fantasy proneness, disposition toward auditory hallucinations, absorption trait, and endorsement of paranormal and spiritual beliefs could be associated with the recall of NDEs(-like).MethodsTo this aim, we invited four groups of people to retrospectively fill in questionnaires assessing the following factors: NDE experiencers (n = 63), NDE(-like) experiencers (n = 31), controls with a life-threatening situation but no NDE(-like) (n = 43), and controls without a life-threatening situation or an NDE(-like) (n = 44). We carried out univariate analyses for each factor and then performed a multiple regression analysis and a discriminant analysis.ResultsThe multivariate logistic regression analysis revealed that the endorsement of spiritual beliefs was associated with the recall of NDEs-like while Openness and Fantasy proneness were associated with the recall of NDEs. The discriminant analysis showed that these variables produce 35% of correct classification.DiscussionAlbeit retrospective, these results pave the way for future research on psychological predictors of NDEs(-like) by highlighting the influence of Spirituality, Openness, and Fantasy proneness on these phenomena.

BackgroundThe significant lack of rehabilitation prognostic data is the main reason that affects the treatment decision-making and ethical issues of patients with disorders of consciousness (DoC). Currently, the clinic's consciousness assessment tools cannot satisfy DoC patients' follow-up needs.ObjectiveThe purpose of this study is to construct a sensitive, professional, and simple telephone follow-up scale for DoC patients to follow up on the prognosis, especially the recovery of consciousness, of prolonged DoC patients transferred to community hospitals or at home.MethodsThis study is to adopt expert consultation to construct and to verify the validity and feasibility of the scale on-site.ConclusionAt present, there is a strong demand for portable, accurate, and easily operated scales. It is helpful to improve the rehabilitation data of prolonged DoC patients and provide more basis for their treatment and rehabilitation.

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.

The authors propose an explainable consciousness indicator using deep learning to quantify arousal and awareness under sleep, anesthesia, and in patients with disorders of consciousness.

Exposure to altered g-levels causes unusual sensorimotor demands that must be dealt with by the brain. This study aimed to investigate whether fighter pilots, who are exposed to frequent g-level transitions and high g-levels, show differential functional characteristics compared to matched controls, indicative of neuroplasticity. We acquired resting-state functional magnetic resonance imaging data to assess brain functional connectivity (FC) changes with increasing flight experience in pilots and to assess differences in FC between pilots and controls. We performed whole-brain exploratory and region-of-interest (ROI) analyses, with the right parietal operculum 2 (OP2) and the right angular gyrus (AG) as ROIs. Our results show positive correlations with flight experience in the left inferior and right middle frontal gyri, and in the right temporal pole. Negative correlations were observed in primary sensorimotor regions. We found decreased whole-brain functional connectivity of the left inferior frontal gyrus in fighter pilots compared to controls and this cluster showed decreased functional connectivity with the medial superior frontal gyrus. Functional connectivity increased between the right parietal operculum 2 and the left visual cortex, and between the right and left angular gyrus in pilots compared to controls. These findings suggest altered motor, vestibular, and multisensory processing in the brains of fighter pilots, possibly reflecting coping strategies to altered sensorimotor demands during flight. Altered functional connectivity in frontal areas may reflect adaptive cognitive strategies to cope with challenging conditions during flight. These findings provide novel insights into brain functional characteristics of fighter pilots, which may be of interest to humans traveling to space.

López-González et al study the fMRI brain dynamics and their underlying mechanism from patients that suffered brain injuries leading to a disorder of consciousness as well as from healthy subjects undergoing propofol-induced sedation. They show that pathological and pharmacological low-level states of consciousness display disrupted synchronization patterns, higher constraint to the anatomy and a loss of heterogeneity and stability in the structural hubs compared to conscious states.

The self-organising global dynamics underlying brain states emerge from complex recursive nonlinear interactions between interconnected brain regions. Until now, most efforts of capturing the causal mechanistic generating principles have supposed underlying stationarity, being unable to describe the non-stationarity of brain dynamics, i.e. time-dependent changes. Here, we present a novel framework able to characterise brain states with high specificity, precisely by modelling the time-dependent dynamics. Through describing a topological structure associated to the brain state at each moment in time (its attractor or 'information structure'), we are able to classify different brain states by using the statistics across time of these structures hitherto hidden in the neuroimaging dynamics. Proving the strong potential of this framework, we were able to classify resting-state BOLD fMRI signals from two classes of post-comatose patients (minimally conscious state and unresponsive wakefulness syndrome) compared with healthy controls with very high precision.

ObjectiveSpine injury is highly prevalent in patients with poly-trauma, but data on the co-occurrence of spine trauma in patients with traumatic brain injury (TBI) are scarce. In this study, we used the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) database to assess the prevalence, characteristics, and outcomes of patients with TBI and a concurrent traumatic spinal injury (TSI).MethodsData from the European multi-center CENTER-TBI study were analyzed. Adult patients with TBI (≥18 years) presenting with a concomitant, isolated TSI of at least serious severity (Abbreviated Injury Scale; AIS ≥3) were included. For outcome analysis, comparison groups of TBI patients with TSI and systemic injuries (non-isolated TSI) and without TSI were created using propensity score matching. Rates of mortality, unfavorable outcomes (Glasgow Outcome Scale Extended; GOSe < 5), and full recovery (GOSe 7–8) of all patients and separately for patients with only mild TBI (mTBI) were compared between groups at 6-month follow-up.ResultsA total of 164 (4%) of the 4,254 CENTER-TBI core study patients suffered from a concomitant isolated TSI. The median age was 53 [interquartile range (IQR): 37–66] years and 71% of patients were men. mTBI was documented in 62% of cases, followed by severe TBI (26%), and spine injuries were mostly cervical (63%) or thoracic (31%). Surgical spine stabilization was performed in 19% of cases and 57% of patients were admitted to the ICU. Mortality at 6 months was 11% and only 36% of patients regained full recovery. There were no significant differences in the 6-month rates of mortality, unfavorable outcomes, or full recovery between TBI patients with and without concomitant isolated TSI. However, concomitant non-isolated TSI was associated with an unfavorable outcome and a higher mortality. In patients with mTBI, a negative association with full recovery could be observed for both concomitant isolated and non-isolated TSI.ConclusionRates of mortality, unfavorable outcomes, and full recovery in TBI patients with and without concomitant, isolated TSIs were comparable after 6 months. However, in patients with mTBI, concomitant TSI was a negative predictor for a full recovery. These findings might indicate that patients with moderate to severe TBI do not necessarily exhibit worse outcomes when having a concomitant TSI, whereas patients with mTBI might be more affected.

Understanding recovery of consciousness and elucidating its underlying mechanism is believed to be crucial in the field of basic neuroscience and medicine. Ideas such as the global neuronal workspace (GNW) and the mesocircuit theory hypothesize that failure of recovery in conscious states coincide with loss of connectivity between subcortical and frontoparietal areas, a loss of the repertoire of functional networks states and metastable brain activation. We adopted a time-resolved functional connectivity framework to explore these ideas and assessed the repertoire of functional network states as a potential marker of consciousness and its potential ability to tell apart patients in the unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). In addition, the prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, that is so-called eigenmodes, was supplemented as potential markers. By analysing time-resolved functional connectivity from functional MRI data, we demonstrated a reduction of metastability and functional network repertoire in UWS compared to MCS patients. This was expressed in terms of diminished dwell times and loss of nonstationarity in the default mode network and subcortical fronto-temporoparietal network in UWS compared to MCS patients. We further demonstrated that these findings co-occurred with a loss of dynamic interplay between structural eigenmodes and emerging time-resolved functional connectivity in UWS. These results are, amongst others, in support of the GNW theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness.

Abstract Background Previous studies have shown that a single Coma-Recovery Scale-Revision (CRS-R) assessment can identify high rates of misdiagnosis by clinical consensus. The aim of this study was to investigate the proportion of misdiagnosis by clinical consensus compared to repeated behavior-scale assessments in patients with prolonged disorders of consciousness (DOC). Methods Patients with prolonged DOC during hospitalization were screened by clinicians, and the clinicians formed a clinical-consensus diagnosis. Trained professionals used the CRS-R to evaluate the consciousness levels of the enrolled patients repeatedly (≥5 times) within a week. Based on the repeated evaluation results, the enrolled patients with prolonged DOC were divided into unresponsive wakefulness syndrome (UWS), minimally conscious state (MCS), and emergence from MCS (EMCS). Finally, the relationship between the results of the CRS-R and the clinical consensus were analyzed. Results In this study, 137 patients with a clinical-consensus diagnosis of prolonged DOC were enrolled. It was found that 24.7% of patients with clinical UWS were actually in MCS after a single CRS-R behavior evaluation, while the repeated CRS-R evaluation results showed that the proportion of misdiagnosis of MCS was 38.2%. A total of 16.7% of EMCS patients were misdiagnosed with clinical MCS, and 1.1% of EMCS patients were misdiagnosed with clinical UWS. Conclusions The rate of the misdiagnosis by clinical consensus is still relatively high. Therefore, clinicians should be aware of the importance of the bedside CRS-R behavior assessment and should apply the CRS-R tool in daily procedures. Trial registration ClinicalTrials.gov ID: NCT04139239 ; Registered 24 October 2019 - Retrospectively registered.

Abstract Background Burnout is more common among healthcare professionals, that is an important problem of professional distress that can seriously affect healthcare professionals’ emotional state, health, medical quality and doctor-patient relationship. However, only few studies researched the burnout status of healthcare professionals who care for patients with prolonged disorders of consciousness. The aim of this study was to evaluate the level of burnout and related contributing personal and environment factors in healthcare professionals managing these patients. Methods Institution-based cross-sectional study. Maslach Burnout Inventory-Human Services Survey was used to evaluate burnout in professionals who specially care for patients with prolonged disorders of consciousness in the neurorehabilitation department. Results A total of 200 questionnaires were distributed, 121 were collected, among them 93 questionnaires could be used for further analysis. In this study, 61 participants (65.6%) showed burnout (55.2% physicians and 82.9% nurses). For the risks and Maslach Burnout Inventory scores, emotional exhaustion and depersonalization were correlated with age, gender, occupation, marital status, years of practice, and education level. Reduced personal accomplishment was correlated with marital status. The variables of age (

IntroductionA symptom cluster is very common among oncological patients: cancer-related fatigue (CRF), emotional distress, sleep difficulties, pain, and cognitive difficulties. Clinical applications of interventions based on non-ordinary states of consciousness, mostly hypnosis and meditation, are starting to be investigated in oncology settings. They revealed encouraging results in terms of improvements of these symptoms. However, these studies often focused on breast cancer patients, with methodological limitations (e.g., small sample size, no control group, and no follow-up). Another non-ordinary state of consciousness may also have therapeutic applications in oncology: self-induced cognitive trance (SICT). It seems to differ from hypnosis and meditation, as it involves the body more directly. Thus, investigating its clinical applications, along with hypnosis and meditation interventions, could improve available therapeutic options in oncology. This article details the study protocol of a preference-based longitudinal controlled superiority trial aiming to assess the effectiveness of 3 group interventions (hypnosis, meditation, and SICT) to improve oncological patients’ quality of life, and more specifically CRF, emotional distress, sleep, pain, and cognitive difficulties (primary outcomes).Methods and analysisA power analysis required a total sample of 160 patients. Main inclusion criteria are: cancer diagnosis, active treatments completed for less than a year, no practice of hypnosis, meditation, or SICT, and presence of at least one of these four symptoms: fatigue, sleep difficulties, depression, or anxiety. Each participant will choose the intervention in which they want to participate (hypnosis, mindful self-compassion meditation, SICT, or no intervention—control group). To test the effectiveness of the interventions, data will be collected by questionnaires and neurobiological measures and directly from the medical record at four time points: before inclusion in the study (baseline); immediately after the intervention; and at 3- and 12-month follow-up. The longitudinal data in each group will then be measured.DiscussionIn addition to standard cancer therapies, there is a growing interest from patients in complementary approaches, such as hypnosis, meditation, and SICT. The results of this study will be useful to increase knowledge about short- and long-term effectiveness of 3 group interventions for CRF, emotional distress, sleep, pain, and cognitive difficulties in patients with different cancers.Clinical Trial RegistrationClinicalTrials.gov/ (NCT04873661). Retrospectively registered on the 29th of April 2021. url: https://clinicaltrials.gov/ct2/show/NCT04873661

Humans undergo extreme physiological changes when subjected to long periods of weightlessness, and as we continue to become a space-faring species, it is imperative that we fully understand the physiological changes that occur in the human body, including the brain. In this study, we present findings of brain structural changes associated with long-duration spaceflight based on diffusion magnetic resonance imaging (dMRI) data. Twelve cosmonauts who spent an average of six months aboard the International Space Station (ISS) were scanned in an MRI scanner pre-flight, ten days after flight, and at a follow-up time point seven months after flight. We performed differential tractography, a technique that confines white matter fiber tracking to voxels showing microstructural changes. We found significant microstructural changes in several large white matter tracts, such as the corpus callosum, arcuate fasciculus, corticospinal, corticostriatal, and cerebellar tracts. This is the first paper to use fiber tractography to investigate which specific tracts exhibit structural changes after long-duration spaceflight and may direct future research to investigate brain functional and behavioral changes associated with these white matter pathways.

Introduction: Neurocognitive problems associated with posttraumatic stress disorder (PTSD) can interact with impairment resulting from traumatic brain injury (TBI). Research question: We aimed to identify neurocognitive problems associated with probable PTSD following TBI in a civilian sample. Material and methods: The study is part of the CENTER-TBI project (Collaborative European Neurotrauma Effectiveness Research) that aims to better characterize TBI. For this cross-sectional study, we included patients of all severities aged over 15, and a Glasgow Outcome Score Extended (GOSE) above 3. Participants were assessed at six months post-injury on the PTSD Checklist-5 (PCL-5), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT) and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Primary analysis was a complete case analysis. Regression analyses were performed to investigate the association between the PCL-5 and cognition. Results: Of the 1134 participants included in the complete case analysis, 13.5% screened positive for PTSD. Probable PTSD was significantly associated with higher TMT-(B-A) (OR ​= ​1.35, 95% CI: 1.14–1.60, p ​

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.

Sensory conflicts leading to motion sickness can occur not only between but also within sensory modalities. The vestibular organs are located in both left and right inner ears, and their misalignment can be a source of self-motion related sensory conflicts. In the current study, using inner ear magnetic resonance imaging, we examined whether morphological asymmetry of the bilateral vestibular organs was associated with motion sickness susceptibility. The results showed a larger position asymmetry of bilateral vestibular organs in individuals with high rather than low susceptibility. In addition, vestibular position asymmetry was associated with reciprocal interaction (negative resting state functional connectivity) between vestibular and visuocortical regions in lowly, but not highly, susceptible individuals. In conclusion, these findings suggest that vestibular morphological asymmetry can be a source of sensory conflicts in individuals with dysfunctional reciprocal visuo-vestibular interactions, a putative neural mechanism for resolving sensory conflicts.

Background and Objectives: Persistent post-concussive symptoms (PCS) consist of neurologic and psychological complaints persisting after a mild traumatic brain injury (mTBI). It affects up to 50% of mTBI patients, may cause long-term disability, and reduce patients' quality of life. The aim of this review was to examine the possible use of different neuroimaging modalities in PCS.Methods: Articles from Pubmed database were screened to extract studies that investigated the relationship between any neuroimaging features and symptoms of PCS. Descriptive statistics were applied to report the results.Results: A total of 80 out of 939 papers were included in the final review. Ten examined conventional MRI (30% positive finding), 24 examined diffusion weighted imaging (54.17% positive finding), 23 examined functional MRI (82.61% positive finding), nine examined electro(magneto)encephalography (77.78% positive finding), and 14 examined other techniques (71% positive finding).Conclusion: MRI was the most widely used technique, while functional techniques seem to be the most sensitive tools to evaluate PCS. The common functional patterns associated with symptoms of PCS were a decreased anti-correlation between the default mode network and the task positive network and reduced brain activity in specific areas (most often in the prefrontal cortex).Significance: Our findings highlight the importance to use functional approaches which demonstrated a functional alteration in brain connectivity and activity in most studies assessing PCS.

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.

Consciousness transiently fades away during deep sleep, more stably under anesthesia, and sometimes permanently due to brain injury. The development of an index to quantify the level of consciousness across these different states is regarded as a key problem both in basic and clinical neuroscience. We argue that this problem is ill-defined since such an index would not exhaust all the relevant information about a given state of consciousness. While the level of consciousness can be taken to describe the actual brain state, a complete characterization should also include its potential behavior against external perturbations. We developed and analyzed whole-brain computational models to show that the stability of conscious states provides information complementary to their similarity to conscious wakefulness. Our work leads to a novel methodological framework to sort out different brain states by their stability and reversibility, and illustrates its usefulness to dissociate between physiological (sleep), pathological (brain-injured patients), and pharmacologically-induced (anesthesia) loss of consciousness.

Abstract The neurobiological basis of near-death experiences (NDEs) is unknown, but a few studies attempted to investigate it by reproducing in laboratory settings phenomenological experiences that seem to closely resemble NDEs. So far, no study has induced NDE-like features via hypnotic modulation while simultaneously measuring changes in brain activity using high-density EEG. Five volunteers who previously had experienced a pleasant NDE were invited to re-experience the NDE memory and another pleasant autobiographical memory (dating to the same time period), in normal consciousness and with hypnosis. We compared the hypnosis-induced subjective experience with the one of the genuine experience memory. Continuous high-density EEG was recorded throughout. At a phenomenological level, we succeeded in recreating NDE-like features without any adverse effects. Absorption and dissociation levels were reported as higher during all hypnosis conditions as compared to normal consciousness conditions, suggesting that our hypnosis-based protocol increased the felt subjective experience in the recall of both memories. The recall of a NDE phenomenology was related to an increase of alpha activity in frontal and posterior regions. This study provides a proof-of-concept methodology for studying the phenomenon, enabling to prospectively explore the NDE-like features and associated EEG changes in controlled settings.

In recent years, specific cortical networks have been proposed to be crucial for sustaining consciousness, including the posterior hot zone and frontoparietal resting state networks (RSN). Here, we computationally evaluate the relative contributions of three RSNs – the default mode network (DMN), the salience network (SAL), and the central executive network (CEN) – to consciousness and its loss during propofol anaesthesia. Specifically, we use dynamic causal modelling (DCM) of 10 min of high-density EEG recordings (N = 10, 4 males) obtained during behavioural responsiveness, unconsciousness and post-anaesthetic recovery to characterise differences in effective connectivity within frontal areas, the posterior ‘hot zone’, frontoparietal connections, and between-RSN connections. We estimate – for the first time – a large DCM model (LAR) of resting EEG, combining the three RSNs into a rich club of interconnectivity. Consistent with the hot zone theory, our findings demonstrate reductions in inter-RSN connectivity in the parietal cortex. Within the DMN itself, the strongest reductions are in feed-forward frontoparietal and parietal connections at the precuneus node. Within the SAL and CEN, loss of consciousness generates small increases in bidirectional connectivity. Using novel DCM leave-one-out cross-validation, we show that the most consistent out-of-sample predictions of the state of consciousness come from a key set of frontoparietal connections. This finding also generalises to unseen data collected during post-anaesthetic recovery. Our findings provide new, computational evidence for the importance of the posterior hot zone in explaining the loss of consciousness, highlighting also the distinct role of frontoparietal connectivity in underpinning conscious responsiveness, and consequently, suggest a dissociation between the mechanisms most prominently associated with explaining the contrast between conscious awareness and unconsciousness, and those maintaining consciousness.

Background: After a coma, patients with severe brain injury may present disorders of consciousness (DOC). A substantial proportion of these patients also suffer from severe dysphagia. Assessment of and therapy for swallowing disabilities of patients with DOC are essential because dysphagia has major functional consequences and comorbidities. Dysphagia evaluation in patients with DOC is impeded by the lack of adapted tools. The first aim of this study was to create a new tool, the SWallowing Assessment in Disorders Of Consciousness (SWADOC), and propose a validation protocol. The SWADOC was developed to help therapists assess factors related to swallowing in patients with DOC. The second aim was to investigate the relationship between patients' level of consciousness and SWADOC items and scores.Method/Design: In this multicenter prospective cohort, 104 patients with DOC will be tested three times over five consecutive days with the SWADOC. Statistical analyses will focus on the reliability and validity of the SWADOC, especially the intrarater and interrater reliability, internal consistency, measures of dispersion, and concurrent validity with the Facial Oral Tract Therapy Swallowing Assessment of Saliva (FOTT-SAS). The level of consciousness will be assessed with the Simplified Evaluation of CONsciousness Disorders (SECONDs) and the Coma Recovery Scale-Revised (CRS-R).Discussion: The assessment of swallowing abilities among patients with DOC is the first necessary step toward the development of a customized dysphagia care plan. A validated scoring tool will be essential for clinicians to better assess dysphagia in patients with DOC and document the evolution of their disorders.Trial Registration: NCT04706689.

Transcranial direct-current stimulation (tDCS) over the prefrontal cortex can improve signs of consciousness in patients in a minimally conscious state. Transcranial pulsed-current stimulation (tPCS) over the mastoids can modulate brain activity and connectivity in healthy controls. This study investigated the feasibility of tPCS as a therapeutic tool in patients with disorders of consciousness (DoC) and compared its neurophysiological and behavioral effects with prefrontal tDCS. This pilot study was a randomized, double-blind sham-controlled clinical trial with three sessions: bi-mastoid tPCS, prefrontal tDCS, and sham. Electroencephalography (EEG) and behavioral assessments were collected before and after each stimulation session. Post minus pre differences were compared using Kruskal–Wallis and Wilcoxon signed-rank tests. Twelve patients with DoC were included in the study (eight females, four traumatic brain injury, 50.3 ± 14 y.o., 8.8 ± 10.5 months post-injury). We did not observe any side-effects following tPCS, nor tDCS, and confirmed their feasibility and safety. We did not find a significant effect of the stimulation on EEG nor behavioral outcomes for tPCS. However, consistent with prior findings, our exploratory analyses suggest that tDCS induces behavioral improvements and an increase in theta frontal functional connectivity.

Patients with locked-in syndrome (LIS) may suffer from pain, which can significantly affect their daily life and well-being. In this study, we aim to investigate the presence and the management of pain in LIS patients. Fifty-one participants completed a survey collecting socio-demographic information and detailed reports regarding pain perception and management (type and frequency of pain, daily impact of pain, treatments). Almost half of the LIS patients reported experiencing pain (49%) that affected their quality of life, sleep and cognition. The majority of these patients reported that they did not communicate their pain to clinical staff. Out of the 25 patients reporting pain, 18 (72%) received treatment (60% pharmacological, 12% non-pharmacological) and described the treatment efficacy as ‘moderate’. In addition, 14 (56%) patients were willing to try other non-pharmacological treatments, such as hypnosis or meditation. This study provides a comprehensive characterization of pain perception in LIS patients and highlights the lack of guidelines for pain detection and its management. This is especially pertinent given that pain affects diagnoses, by either inducing fatigue or by using pharmacological treatments that modulate the levels of wakefulness and concentration of such patients.