Search

Brain connectivity, allowing information to be shared between distinct cortical areas and thus to be processed in an integrated way, has long been considered critical for consciousness. However, the relationship between functional intercortical interactions and the structural connections thought to underlie them is poorly understood. In the present work, we explore both functional (with an EEG-based metric: the median weighted symbolic mutual information in the theta band) and structural (with a brain MRI-based metric: fractional anisotropy) connectivities in a cohort of 78 patients with disorders of consciousness. Both metrics could distinguish patients in a vegetative state from patients in minimally conscious state. Crucially, we discovered a significant positive correlation between functional and structural connectivities. Furthermore, we showed that this structure-function relationship is more specifically observed when considering structural connectivity within the intra- and inter-hemispheric long-distance cortico-cortical bundles involved in the Global Neuronal Workspace (GNW) theory of consciousness, thus supporting predictions of this model. Altogether, these results support the interest of multimodal assessments of brain connectivity in refining the diagnostic evaluation of patients with disorders of consciousness., Competing Interests: Declarations. Ethical approval: This study was approved by the institutional review board of the Pitié-Salpêtrière University Hospital (PSL – 2023 – R – CONS-CONNECT), in agreement with the French data protection authority (MR004). Consent to participate: This research study was conducted retrospectively from data obtained for clinical purposes. All participants, or their relatives if they did not recover from their disorder of consciousness, received information of the possible use of their health data collected as part of routine care, and did not object. Competing interests: L.P. is co-founder of BrainTale. V.P. is co-founder and employee of BrainTale. The other authors report no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To investigate patients with disorders of consciousness (DoC) for residual awareness, guidelines recommend quantifying glucose brain metabolism using positron emission tomography. However, this is not feasible in the intensive care unit (ICU). Cerebral blood flow (CBF) assessed by arterial spin labeling magnetic resonance imaging (ASL-MRI) could serve as a proxy for brain metabolism and reflect consciousness levels in acute DoC. We hypothesized that ASL-MRI would show compromised CBF in coma and unresponsive wakefulness states (UWS) but relatively preserved CBF in minimally conscious states (MCS) or better., Methods: We consecutively enrolled ICU patients with acute DoC and categorized them as being clinically unresponsive (i.e., coma or UWS [≤ UWS]) or low responsive (i.e., MCS or better [≥ MCS]). ASL-MRI was then acquired on 1.5 T or 3 T. Healthy controls were investigated with both 1.5 T and 3 T ASL-MRI., Results: We obtained 84 ASL-MRI scans from 59 participants, comprising 36 scans from 35 patients (11 women [31.4%]; median age 56 years, range 18-82 years; 24 ≤ UWS patients, 12 ≥ MCS patients; 32 nontraumatic brain injuries) and 48 scans from 24 healthy controls (12 women [50%]; median age 50 years, range 21-77 years). In linear mixed-effects models of whole-brain cortical CBF, patients had 16.2 mL/100 g/min lower CBF than healthy controls (p = 0.0041). However, ASL-MRI was unable to discriminate between ≤ UWS and ≥ MCS patients (whole-brain cortical CBF: p = 0.33; best hemisphere cortical CBF: p = 0.41). Numerical differences of regional CBF in the thalamus, amygdala, and brainstem in the two patient groups were statistically nonsignificant., Conclusions: CBF measurement in ICU patients using ASL-MRI is feasible but cannot distinguish between the lower and the upper ends of the acute DoC spectrum. We suggest that pilot testing of diagnostic interventions at the extremes of this spectrum is a time-efficient approach in the continued quest to develop DoC neuroimaging markers in the ICU., Competing Interests: Conflict of interest: The authors report no competing interests. Ethical approval/informed consent: This study was approved by the Ethics Committee of the Capital Region of Denmark (H-21015473)., (© 2024. The Author(s).)

The Coma Recovery Scale-revised (CRS-r) is the gold standard for the behavioral assessment of patients with Disorders of Consciousness (DoCs). However, the misdiagnosis rate is around 40%. For this reason, recent guidelines suggested enhancing the assessment with neurophysiological measures: among these, surface electromyography (sEMG) represents a convenient bedside solution. This work presents the use of the STRIVEfc system, a wearable device that allows CRS-r administration while recording four sEMG signals. STRIVEfc was employed in 40 sessions on 33 DoCs patients and the sEMG was analyzed to look for voluntary and consistent over threshold (OT) muscular activities. Their duration, amplitude, and number were retained and compared between patients in Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS), revealing more numerous and significantly longer OTs in the latter group. Lastly, the EMG information was exploited to enrich the behavioral assessment by building the instrumented CRS-r score (ICRS-r). In 9/16 UWS sessions, the ICRS-r score suggested a higher-level functioning, not translated into a behavioral response, compatible with MCS diagnosis. Overall, the use of STRIVEfc allows to reveal hidden muscular patterns not detectable by the clinician, thus improving the characterization of DoCs patient's functional capabilities and supporting the diagnostic process., (© 2024. The Author(s).)

Background and Objectives: Despite the fact that the parietal cortex is associated with consciousness, the underlying mechanisms of parietal repetitive transcranial magnetic stimulation (rTMS) have not yet been specifically investigated. The present study aims to examine the effects of parietal rTMS on patients with disorders of consciousness (DoC) and identify a novel potential target., Methods: Twenty minimally conscious state (MCS) patients were stochastically assigned to a real or sham rTMS group in a controlled trial. The real rTMS group was administered over the parietal cortex, with a frequency of 10 Hz and a rest motor threshold of 90 %. The sham rTMS group was identical to the real rTMS group without magnetic stimulation over the cortex. Pre- and post-treatment resting-state electrophysiological (EEG) data and coma recovery scale-revised (CRS-R) score were gathered. Microstate analyses were calculated to evaluate the brain activity dynamics., Results: The real rTMS treatment improved the CRS-R scores. There were notable alterations in the mean microstate duration (MMD) of microstate B in the real rTMS group. The sham rTMS group did not exhibit such changes in CRS-R score or EEG results, which were not statistically significant. Furthermore, the MMD and RTC of microstate E were found to be negatively correlated with baseline CRS-R scores., Conclusion: Parietal rTMS can induce behavioral improvement and brain activity dynamics in patients with MCS. EEG microstates can be used as a valuable method to study neurophysiological mechanisms behind MCS. And the parietal cortex represents an alternative for rTMS therapy protocols., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

We aimed to investigate the electrocardiogram (ECG) features in persons with chronic disorders of consciousness (DOC, ≥ 29 days since injury, DSI) resulted from the most severe brain damages. The ECG data from 30 patients with chronic DOC and 18 healthy controls (HCs) were recorded during resting wakefulness state for about five minutes. The patients were classified into vegetative state (VS) and minimally conscious state (MCS). Eight ECG metrics were extracted for comparisons between the subject subgroups, and regression analysis of the metrics were conducted on the DSI (29-593 days). The DOC patients exhibit a significantly higher heart rate (HR, p = 0.009) and lower values for SDNN (p = 0.001), CVRR (p = 0.009), and T-wave amplitude (p < 0.001) compared to the HCs. However, there're no significant differences in QRS, QT, QTc, or ST amplitude between the two groups (p > 0.05). Three ECG metrics of the DOC patients-HR, SDNN, and CVRR-are significantly correlated with the DSI. The ECG abnormalities persist in chronic DOC patients. The abnormalities are mainly manifested in the rhythm features HR, SDNN and CVRR, but not the waveform features such as QRS width, QT, QTc, ST and T-wave amplitudes., (© 2024. International Federation for Medical and Biological Engineering.)

Background: Patients with brain injury who are unresponsive to commands may perform cognitive tasks that are detected on functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). This phenomenon, known as cognitive motor dissociation, has not been systematically studied in a large cohort of persons with disorders of consciousness., Methods: In this prospective cohort study conducted at six international centers, we collected clinical, behavioral, and task-based fMRI and EEG data from a convenience sample of 353 adults with disorders of consciousness. We assessed the response to commands on task-based fMRI or EEG in participants without an observable response to verbal commands (i.e., those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus) and in participants with an observable response to verbal commands. The presence or absence of an observable response to commands was assessed with the use of the Coma Recovery Scale-Revised (CRS-R)., Results: Data from fMRI only or EEG only were available for 65% of the participants, and data from both fMRI and EEG were available for 35%. The median age of the participants was 37.9 years, the median time between brain injury and assessment with the CRS-R was 7.9 months (25% of the participants were assessed with the CRS-R within 28 days after injury), and brain trauma was an etiologic factor in 50%. We detected cognitive motor dissociation in 60 of the 241 participants (25%) without an observable response to commands, of whom 11 had been assessed with the use of fMRI only, 13 with the use of EEG only, and 36 with the use of both techniques. Cognitive motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In contrast, responses on task-based fMRI or EEG occurred in 43 of 112 participants (38%) with an observable response to verbal commands., Conclusions: Approximately one in four participants without an observable response to commands performed a cognitive task on fMRI or EEG as compared with one in three participants with an observable response to commands. (Funded by the James S. McDonnell Foundation and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Unconsciousness in severe acquired brain injury (sABI) patients occurs with different cognitive and neural profiles. Perturbational approaches, which enable the estimation of proxies for brain reorganization, have added a new avenue for investigating the non-behavioural diagnosis of consciousness. In this prospective observational study, we conducted a comparative analysis of the topological patterns of heartbeat-evoked potentials (HEP) between patients experiencing a prolonged disorder of consciousness (pDoC) and patients emerging from a minimally consciousness state (eMCS). A total of 219 sABI patients were enrolled, each undergoing a synchronous EEG-ECG resting-state recording, together with a standardized consciousness diagnosis. A number of graph metrics were computed before/after the HEP (Before/After) using the R-peak on the ECG signal. The peak value of the global field power of the HEP was found to be significantly higher in eMCS patients with no difference in latency. Power spectrum was not able to discriminate consciousness neither Before nor After. Node assortativity and global efficiency were found to vary with different trends at unconsciousness. Lastly, the Perturbational Complexity Index of the HEP was found to be significantly higher in eMCS patients compared with pDoC. Given that cortical elaboration of peripheral inputs may serve as a non-behavioural determinant of consciousness, we have devised a low-cost and translatable technique capable of estimating causal proxies of brain functionality with an endogenous, non-invasive stimulus. Thus, we present an effective means to enhance consciousness assessment by incorporating the interaction between the autonomic nervous system (ANS) and central nervous system (CNS) into the loop., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Identifying covert consciousness in intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can detect residual consciousness in ICU patients with DoC., Methods: We prospectively enrolled clinically low-response or unresponsive patients with traumatic or nontraumatic DoC from ICUs of a tertiary referral center. Age-matched and sex-matched healthy volunteers served as controls. Patients were categorized into clinically unresponsive (coma or unresponsive wakefulness syndrome) or clinically low-responsive (minimally conscious state or better). Using automated pupillometry, we recorded pupillary dilation to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with task-specific success criteria (e.g., ≥ 3 of 5 pupillary dilations on five consecutive mental arithmetic tasks)., Results: We obtained 699 pupillometry recordings at 178 time points from 91 ICU patients with brain injury (mean age 60 ± 13.8 years, 31% women, and 49.5% nontraumatic brain injuries). Recordings were also obtained from 26 matched controls (59 ± 14.8 years, 38% women). Passive paradigms yielded limited distinctions between patients and controls. However, active paradigms enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥ 3 pupillary dilations were seen in 17.8% of clinically unresponsive patients and 50.0% of clinically low-responsive patients (odds ratio 4.56, 95% confidence interval 2.09-10.10; p < 0.001). In comparison, 76.9% healthy controls responded with ≥ 3 pupillary dilations (p = 0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman's rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho = 1, p = 0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior 2 weeks before overt signs of awareness, suggesting prolonged cognitive motor dissociation., Conclusions: Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence covert consciousness, in ICU patients with acute DoC., (© 2024. The Author(s).)

Prolonged disorder of consciousness (DoC) is a rising challenge. Pediatric data on diagnosis and prognosis of prolonged DoC were too limited and heterogeneous, making it difficult to define the natural course and evaluate the prognosis. The present study explored the emergence from the Minimally Conscious State (eMCS) incidence at different months postinjury drawing the natural course, and detected the predictors of the incidence in children with prolonged DoC. A hospital-based prospective cohort study was conducted. Kaplan-Meier curves, as well as univariate and multivariate COX regression analysis, were performed. The study enrolled 383 pediatric DoC individuals, including 220 males (57.4%), with an average age of 3.9 (1.9-7.3) years. The median duration between onset and rehabilitation is 30.0 (21.0-46.0) days. At enrollment, the ratio of vegetative state/unresponsive wakefulness syndrome (VS/WUS) to MCS is 78.9%-21.1%. Traumatic brain injury and infection are the major etiologies (36.8% and 37.1%, respectively), followed by hypoxia cerebral injury (12.3%). For children with prolonged DoC, the cumulative incidence of eMCS at months 3, 6, 12, and 24 was 0.510, 0.652, 0.731, 0.784 VS 0.290, 0.418, 0.539, 0.603 in the traumatic VS non-traumatic subgroup, respectively. For children in a persistent vegetative state (PVS), the cumulative incidence of emergence at months in 3, 6, 12, 24, 36 and 48 was testified as 0.439, 0.591, 0.683, 0.724, 0.743 and 0.743 in the traumatic subgroup, and 0.204, 0.349, 0.469, 0.534, 0.589 and 0.620 in the non-traumatic subgroup. Participants who exhibit any of the following four demographical and/or clinical characteristics-namely, older than 4 years at onset, accepted rehabilitation within 28 days of onset, remained MCS at enrollment, or with etiology of traumatic brain injuries-had a significantly positive outcome of consciousness recovery (eMCS). Moreover, both prolongation of the central somatosensory conductive time (CCT) (level 2) and absence of N20 (level 3) independently predict a negative outcome. In children with prolonged DoC, we found that 12 months postinjury was critical to eMCS, and a preferred timepoint to define chronic vegetative state (VS). The characteristics including age, etiology, time before rehabilitation, consciousness state, and SEP results were useful predictors of conscious recovery.Trial registration Registered 06/11/2018, the registration number is chiCTR1800019330 (chictr.org.cn). Registered prospectively., (© 2024. The Author(s).)

Although auditory stimuli benefit patients with disorders of consciousness (DOC), the optimal stimulus remains unclear. We explored the most effective electroencephalography (EEG)-tracking method for eliciting brain responses to auditory stimuli and assessed its potential as a neural marker to improve DOC diagnosis. We collected 58 EEG recordings from patients with DOC to evaluate the classification model's performance and optimal auditory stimulus. Using non-linear dynamic analysis (approximate entropy [ApEn]), we assessed EEG responses to various auditory stimuli (resting state, preferred music, subject's own name [SON], and familiar music) in 40 patients. The diagnostic performance of the optimal stimulus-induced EEG classification for vegetative state (VS)/unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) was compared with the Coma Recovery Scale-Revision in 18 patients using the machine learning cascade forward backpropagation neural network model. Regardless of patient status, preferred music significantly activated the cerebral cortex. Patients in MCS showed increased activity in the prefrontal pole and central, occipital, and temporal cortices, whereas those in VS/UWS showed activity in the prefrontal and anterior temporal lobes. Patients in VS/UWS exhibited the lowest preferred music-induced ApEn differences in the central, middle, and posterior temporal lobes compared with those in MCS. The resting state ApEn value of the prefrontal pole (0.77) distinguished VS/UWS from MCS with 61.11% accuracy. The cascade forward backpropagation neural network tested for ApEn values in the resting state and preferred music-induced ApEn differences achieved an average of 83.33% accuracy in distinguishing VS/UWS from MCS (based on K-fold cross-validation). EEG non-linear analysis quantifies cortical responses in patients with DOC, with preferred music inducing more intense EEG responses than SON and familiar music. Machine learning algorithms combined with auditory stimuli showed strong potential for improving DOC diagnosis. Future studies should explore the optimal multimodal sensory stimuli tailored for individual patients.Trial registration: The study is registered in the Chinese Registry of Clinical Trials (Approval no: KYLL-2023-414, Registration code: ChiCTR2300079310)., (© 2024. The Author(s).)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ihalainen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Within the continuum of consciousness, patients in a Minimally Conscious State (MCS) may exhibit high-level behavioral responses (MCS+) or may not (MCS-). The evaluation of residual consciousness and related classification is crucial to propose tailored rehabilitation and pharmacological treatments, considering the inherent differences among groups in diagnosis and prognosis. Currently, differential diagnosis relies on behavioral assessments posing a relevant risk of misdiagnosis. In this context, EEG offers a non-invasive approach to model the brain as a complex network. The search for discriminating features could reveal whether behavioral responses in post-comatose patients have a defined physiological background. Additionally, it is essential to determine whether the standard behavioral assessment for quantifying responsiveness holds physiological significance., Methods: In this prospective observational study, we investigated whether low-density EEG-based graph metrics could discriminate MCS+/- patients by enrolling 57 MCS patients (MCS-: 30; males: 28). At admission to intensive rehabilitation, 30 min resting-state closed-eyes EEG recordings were performed together with consciousness diagnosis following international guidelines. After EEG preprocessing, graphs' metrics were estimated using different connectivity measures, at multiple connection densities and frequency bands (α,θ,δ). Metrics were also provided to cross-validated Machine Learning (ML) models with outcome MCS+/-., Results: A lower level of brain activity integration was found in the MCS- group in the α band. Instead, in the δ band MCS- group presented an higher level of clustering (weighted clustering coefficient) respect to MCS+. The best-performing solution in discriminating MCS+/- through the use of ML was an Elastic-Net regularized logistic regression with a cross-validation accuracy of 79% (sensitivity and specificity of 74% and 85% respectively)., Conclusion: Despite tackling the MCS+/- differential diagnosis is highly challenging, a daily-routine low-density EEG might allow to differentiate across these differently responsive brain networks., Significance: Graph-theoretical features are shown to discriminate between these two neurophysiologically similar conditions, and may thus support the clinical diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aims to describe resting state networks (RSN) in patients with disorders of consciousness (DOC)s after acute severe traumatic brain injury (TBI)., Methods: Adult patients with TBI with a GCS score <8 who remained in a coma, minimally conscious state (MCS), or unresponsive wakefulness syndrome (UWS), between 2017 and 2020 were included. Blood-oxygen-level dependent imaging was performed to compare their RSN with 10 healthy volunteers., Results: Of a total of 293 patients evaluated, only 13 patients were included according to inclusion criteria: 7 in coma (54%), 2 in MCS (15%), and 4 (31%) had an UWS. RSN analysis showed that the default mode network (DMN) was present and symmetric in 6 patients (46%), absent in 1 (8%), and asymmetric in 6 (46%). The executive control network (ECN) was present in all patients but was asymmetric in 3 (23%). The right ECN was absent in 2 patients (15%) and the left ECN in 1 (7%). The medial visual network was present in 11 (85%) patients. Finally, the cerebellar network was symmetric in 8 patients (62%), asymmetric in 1 (8%), and absent in 4 (30%)., Conclusions: A substantial impairment in activation of RSN is demonstrated in patients with DOC after severe TBI in comparison with healthy subjects. Three patterns of activation were found: normal/complete activation, 2) asymmetric activation or partially absent, and 3) absent activation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Research on disorders of consciousness in children is scarce and includes disparate and barely comparable participants and assessment instruments and therefore provides inconclusive information on the clinical progress and recovery in this population. This study retrospectively investigated the neurobehavioral progress and the signs of transition between states of consciousness in a group of children admitted to a rehabilitation program either with an unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS)., Methods: Systematic weekly assessments were conducted with the Coma Recovery Scale-Revised (CRS-R) until emergence from MCS, discharge, or death., Results: Twenty-one children, nine admitted with a UWS and 12 admitted in an MCS, were included in the study. Four children with a UWS transitioned to an MCS with a CRS-R of 10 (9.2 to 12.2) by showing visual pursuit, visual fixation, or localization to noxious stimulation. Twelve children emerged from the MCS with a CRS-R of 20.5 (19 to 21.7). Children who emerged from the MCS had had a shorter time postinjury and higher CRS-R at admission, compared with those who did not emerge., Conclusions: Almost half of the children who were admitted with a UWS transitioned to an MCS, and almost all who were admitted in an MCS emerged from this state. Children who emerged had shorter times since injury and higher scores on the CRS-R at admission, compared with those who did not emerge., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Assessing recovery potential in patients with disorders of consciousness (DoC) is pivotal for guiding clinical and ethical decisions. We conducted a mega-analysis of individual patient data to understand (1) if a time threshold exists, beyond which regaining consciousness is almost impossible, and (2) how recovery varies based on factors such as diagnosis, etiology, age, sex, and neuropsychological status., Methods: A systematic literature search revealed a total of 3290 patients. In this sample, we performed a Cox proportional hazards analysis for interval censored data., Results: We observed a late saturation of probability to regain consciousness in Kaplan-Meier curves, and the annual rate of recovery was remarkably stable, in that approximately 35% of patients regained consciousness per year. Patients in minimally conscious state (MCS) recovered more frequently than patients in unresponsive wakefulness syndrome (UWS). No significant difference was observed between the recovery dynamics of MCS subgroups: MCS+ and MCS-. Patients with hypoxic brain lesions showed worse recovery rate than patients with traumatic brain injury and patients with vascular brain lesions, while the latter two categories did not differ from each other. Male patients had moderately better chance to regain consciousness. While younger UWS patients recovered more frequently than older patients, it was not the case in MCS., Interpretation: Our findings highlight the necessity for neurologists to exercise caution when making negative predictions in individual cases, challenge traditional beliefs regarding recovery timelines, and underscore the importance of conducting detailed and prolonged assessments to better understand recovery prospects in DoC., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Recovery of consciousness after coma remains one of the most challenging areas for accurate diagnosis and effective therapeutic engagement in the clinical neurosciences. Recovery depends on preservation of neuronal integrity and evolving changes in network function that re-establish environmental responsiveness. It typically occurs in defined steps: it begins with eye opening and unresponsiveness in a vegetative state, then limited recovery of responsiveness characterizes the minimally conscious state, and this is followed by recovery of reliable communication. This review considers several points for novel interventions, for example, in persons with cognitive motor dissociation in whom a hidden cognitive reserve is revealed. Circuit mechanisms underlying restoration of behavioral responsiveness and communication are discussed. An emerging theme is the possibility to rescue latent capacities in partially damaged human networks across time. These opportunities should be exploited for therapeutic engagement to achieve individualized solutions for restoration of communication and environmental interaction across varying levels of recovery., Competing Interests: Declaration of interests N.D.S. is a listed inventor on a patent application WO2023/043786 describing detailed methods of integrating magnetic resonance imaging, biophysical modeling, and electrophysiological methods for localization and placement of DBS electrodes in the CL/DTTm of the human thalamus as described in the paper cited in the review, Schiff et al.(21) N.D.S. is also a listed inventor on a related patent application WO2021/195062 and an issued US Patent 9,9592,383. All patents have been assigned by N.D.S. to Cornell University., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The objective of this study was to investigate brain activation and functional network patterns during musical interventions in different frequency bands using functional near-infrared spectroscopy, and to provide a basis for more effective music therapy strategy selection for patients in minimally conscious state (MCS). Twenty six MCS patients and 20 healthy people were given music intervention with low frequency (31-180 Hz), medium frequency (180-4k Hz), and high frequency (4k-22k Hz) audio. In MCS patients, low frequency music intervention induced activation of left prefrontal cortex and left primary sensory cortex (S1), also a left-hemisphere lateralization effect of dorsolateral prefrontal cortex (DLPFC). And the functional connectivity of right DLPFC-right S1 was significantly improved by high frequency music intervention. The low frequency and high frequency music may contribute more than medium frequency music to the recovery of consciousness. This study also validated the effectiveness of fNIRS in studies of brain function in MCS patients., (© 2024 Wiley‐VCH GmbH.)

Background: The complexity of the neurophysiological mechanisms underlying human consciousness is widely acknowledged, with information processing and flow originating in cortex conceived as a core mechanism of consciousness emergence. Combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is considered as a promising technique to understand the effective information flow associated with consciousness., Objectives: To investigate information flow with TMS-EEG and its relationship to different consciousness states., Methods: We applied an effective information flow analysis by combining time-varying multivariate adaptive autoregressive model and adaptive directed transfer function on TMS-EEG data of frontal, motor and parietal cortex in patients with disorder of consciousness (DOC), including 14 vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, 21 minimally conscious state (MCS) patients, and 22 healthy subjects., Results: TMS in DOC patients, particularly VS/UWS, induced a significantly weaker effective information flow compared to healthy subjects. The bidirectional directed information flow was lost in DOC patients with TMS of frontal, motor and parietal cortex. The interactive ROI rate of the information flow network induced by TMS of frontal and parietal cortex was significantly lower in VS/UWS than in MCS. The interactive ROI rate correlated with DOC clinical scales., Conclusions: TMS-EEG revealed a physiologically relevant correlation between TMS-induced information flow and levels of consciousness. This suggests that breakdown of effective cortical information flow serves as a viable marker of human consciousness., Significance: Findings offer a unique perspective on the relevance of information flow in DOC, thus providing a novel way of understanding the physiological basis of human consciousness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Non-invasive brain stimulation is considered as a promising technology for treating patients with disorders of consciousness (DOC). Various approaches and protocols have been proposed; however, few of them have shown potential effects on patients with vegetative state (VS). This study aimed to explore the neuro-modulation effects of intermittent theta burst stimulation (iTBS) on the brains of patients with VS and to provide a pilot investigation into its possible role in treating such patients., Methods: We conducted a sham-controlled crossover study, a real and a sham session of iTBS were delivered over the left dorsolateral prefrontal cortex of such patients. A measurement of an electroencephalography (EEG) and a behavioral assessment of the Coma Recovery Scale-Revised (CRS-R) were applied to evaluate the modulation effects of iTBS before and after stimulation., Results: No meaningful changes of CRS-R were found. The iTBS altered the spectrum, complexity and functional connectivity of the patients. The real stimulation induced a trend of decreasing of delta power at T1 and T2 in the frontal region, significant increasing of permutation entropy at the T2 in the left frontal region. In addition, brain functional connectivity, particularly inter-hemispheric connectivity, was strengthened between the electrodes of the frontal region. The sham stimulation, however, did not induce any significant changes of the brain activity., Conclusions: One session of iTBS significantly altered the oscillation power, complexity and functional connectivity of brain activity of VS patients. It may be a valuable tool on modulating the brain activities of patients with VS.

Numerous studies have shown that musical stimulation can activate corresponding functional brain areas. Electroencephalogram (EEG) activity during musical stimulation can be used to assess the consciousness states of patients with disorders of consciousness (DOC). In this study, a musical stimulation paradigm and verifiable criteria were used for consciousness assessment. Twenty-nine participants (13 healthy subjects, 6 patients in a minimally conscious state (MCS) and 10 patients in a vegetative state (VS)) were recruited, and EEG signals were collected while participants listened to preferred and relaxing music. Fusion features based on differential entropy (DE), common spatial pattern (CSP), and EEG-based network pattern (ENP) features were extracted from EEG signals, and a convolutional neural network-long short-term memory (CNN-LSTM) model was employed to classify preferred and relaxing music.The results showed that the average classification accuracy for healthy subjects reached 85.58%. For two of the patients in the MCS group, the classification accuracies reached 78.18% and 66.14%, and they were diagnosed with emergence from MCS (EMCS) two months later. The accuracies of three patients in the VS group were 58.18%, 64.32% and 62.05%, with two patients showing slight increases in scale scores. Our study suggests that musical stimulation could be an effective method for consciousness detection, with significant diagnostic implications for patients with DOC.

Objective: This study aimed to assess the prognosis of patients with disorders of consciousness (DoC) using auditory stimulation with electroencephalogram (EEG) recordings., Methods: We enrolled 72 patients with DoC in the study, which involved subjecting patients to auditory stimulation while EEG responses were recorded. Coma Recovery Scale-Revised (CRS-R) scores and Glasgow Outcome Scale (GOS) were determined for each patient and followed up for three months. A frequency spectrum analysis was performed on the EEG recordings. Finally, the power spectral density (PSD) index was used to predict the prognosis of patients with DoC based on a support vector machine (SVM) model., Results: Power spectral analyses revealed that the cortical response to auditory stimulation showed a decreasing trend with decreasing consciousness levels. Auditory stimulation-induced changes in absolute PSD at the delta and theta bands were positively correlated with the CRS-R and GOS scores. Furthermore, these cortical responses to auditory stimulation had a good ability to discriminate between good and poor prognoses of patients with DoC., Conclusions: Auditory stimulation-induced changes in the PSD were highly predictive of DoC outcomes., Significance: Our findings showed that cortical responses to auditory stimulation may be an important electrophysiological indicator of prognosis in patients with DoC., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: As consciousness recovery is not only dynamic but also involves interactions between various brain regions, elucidating the mechanism of recovery requires tracking cortical activity in spatio-temporal dimensions., Methods: We tracked the cortical activities of 40 patients (mean age: 54.38 years; 28 males; 21 patients with minimally conscious states) with disorders of consciousness, and collected a total of 156 electroencephalographic signals. We investigated the longitudinal changes in EEG nonlinear dynamic features (i.e., approximate entropy, sample entropy, and Lempel-Ziv complexity) and relative wavelet energy along with consciousness recovery., Results: Global EEG features showed a non-monotonic trend during consciousness recovery (P < 0.05). When the level of consciousness of patients was transferred to a minimally conscious state from an unresponsive wakefulness syndrome/ vegetative state, an inflection point appeared in the EEG features. The EEG feature change trends between the injured and uninjured areas were dissimilar (P < 0.05). Importantly, the degree of dissimilarity increased non-monotonically across the levels of consciousness (P < 0.05)., Conclusions: EEG recovery was non-monotonic and dissimilar in spatio-temporal dimensions, with an inflection point., Significance: These findings further clarify the process of consciousness recovery and provide assistance in exploring the mechanism of consciousness recovery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: We investigated differences in the ascending reticular activating system (ARAS) between vegetative state (VS) and minimally conscious state (MCS) in patients with traumatic brain injury (TBI) by using diffusion tensor tractography., Methods: We recruited TBI patients and normal subjects. We reconstructed the lower ARAS and five parts of upper ARAS [prefrontal cortex (PFC), premotor cortex, primary motor cortex, primary somatosensory cortex, and posterior parietal cortex]., Results: Significant differences were observed in the fractional anisotropy (FA) and fiber number (FN) values of the five parts of upper ARAS between the VS and control groups and between the MCS and control groups (P < 0.05), but no differences were detected in the lower ARAS (P > 0.05). The FA and FN values of the PFC in the upper ARAS were significantly different between the VS and MCS groups (P < 0.05). No other significant differences in FA and FN values were detected among the other segments of the upper ARAS or in the lower ARAS (P > 0.05)., Conclusion: The results indicate that the prefrontal portion of the upper ARAS is the critical area for distinguishing between VS and MCS in patients with TBI., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Spontaneous transient states were recently identified by functional magnetic resonance imaging and magnetoencephalography in healthy subjects. They organize and coordinate neural activity in brain networks. How spontaneous transient states are altered in abnormal brain conditions is unknown. Here, we conducted a transient state analysis on resting-state electroencephalography (EEG) source space and developed a state transfer analysis to patients with disorders of consciousness (DOC). They uncovered different neural coordination patterns, including spatial power patterns, temporal dynamics, spectral shifts, and connectivity construction varies at potentially very fast (millisecond) time scales, in groups with different consciousness levels: healthy subjects, patients in minimally conscious state (MCS), and patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS). Machine learning based on transient state features reveal high classification accuracy between MCS and VS/UWS. This study developed methodology of transient states analysis on EEG source space and abnormal brain conditions. Findings correlate spontaneous transient states with human consciousness and suggest potential roles of transient states in brain disease assessment., Competing Interests: Declaration of Competing Interest The other authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Rationale: It is estimated that about 6 million people suffer from severe traumatic brain injury (TBI) each year (73 cases per 100,000 people). TBI may affect emotional, sensory-motor, cognitive, and psychological functions with a consequent worsening of both patient and his/her caregiver's quality of life. In recent years, technological innovations allowed the development of new, advanced sensory stimulation systems, such as Neurowave, to further stimulate residual cognitive abilities and, at the same time, evaluate residual cognition., Patient Concern: An 69-year-old Italian man entered our neurorehabilitation unit with a diagnosis of minimally conscious state following severe TBI. He breathed spontaneously via tracheostomy and was fed via percutaneous gastrostomy. At the neurological examination, the patient showed severe tetraparesis as he showed fluctuating alertness and responsiveness to external stimuli and opened the eyes without stimulation., Diagnosis: Patient was affected by subarachnoid hemorrhage and frontotemporal bilateral hematoma, which were surgically treated with decompressive craniotomy and subsequent cranioplasty about 6 months before., Interventions: The patient underwent a neuropsychological and clinical evaluation before (T0) and after a conventional rehabilitation cycle (T1), and after a Neurowave emotional stimulation-supported rehabilitative cycle (T2)., Outcomes: Following conventional rehabilitation (T1), the patient achieved a partial improvement in behavioral responsiveness; there was also a mild improvement in the caregiver's distress. Conversely, Neurowave emotional stimulation session determined (at T2) a significant improvement of the patient's behavioral responsiveness, cognition, and in the caregiver's distress. The P300 recording in response to the NES showed a significant change of P300 magnitude and latency., Discussion: Our data suggest that emotional-integrated sensory stimulation using adequate visual stimuli represents a beneficial, complementary rehabilitative treatment for patients in minimally conscious state following a severe TBI. This may occur because stimuli with emotional salience can provide a reliable motivational resource to stimulate motor and cognitive recovery following severe TBI., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Transcranial direct current stimulation (tDCS) applied over the prefrontal cortex has been shown to improve behavioral responsiveness in patients with disorders of consciousness following severe brain injury, especially those in minimally conscious state (MCS). However, one potential barrier of clinical response to tDCS is the timing of stimulation with regard to the fluctuations of vigilance that characterize this population. Indeed, a previous study showed that the vigilance of MCS patients has periodic average cycles of 70 min (range 57-80 min), potentially preventing them to be in an optimal neural state to benefit from tDCS when applied randomly. To tackle this issue, we propose a new protocol to optimize the application of tDCS by selectively stimulating at high and low vigilance states. Electroencephalography (EEG) real-time spectral entropy will be used as a marker of vigilance and to trigger tDCS, in a closed-loop fashion. We will conduct a randomized controlled crossover clinical trial on 16 patients in prolonged MCS who will undergo three EEG-tDCS sessions 5 days apart (1. tDCS applied at high vigilance; 2. tDCS applied at low vigilance; 3. tDCS applied at a random moment). Behavioral effects will be assessed using the Coma Recovery Scale-Revised at baseline and right after the stimulations. EEG will be recorded throughout the session and for 30 min after the end of the stimulation. This unique and novel approach will provide patients' tailored treatment options, currently lacking in the field of disorders of consciousness., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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

Background: After a period of coma, a proportion of individuals with severe brain injury remain in an altered state of consciousness before regaining partial or complete recovery. Individuals with disorders of consciousness (DOC) classically receive hydration and nutrition through an enteral-feeding tube. However, the real impact of the level of consciousness on an individual's swallowing ability remains poorly investigated., Objective: We aimed to document the incidence and characteristics of dysphagia in DOC individuals and to evaluate the link between different components of swallowing and the level of consciousness., Methods: We analyzed clinical data on the respiratory status, oral feeding and otolaryngologic examination of swallowing in DOC individuals. We analyzed the association of components of swallowing and participant groups (i.e., unresponsive wakefulness syndrome [UWS] and minimally conscious state [MCS])., Results: We included 92 individuals with DOC (26 UWS and 66 MCS). Overall, 99% of the participants showed deficits in the oral and/or pharyngeal phase of swallowing. As compared with the MCS group, the UWS group more frequently had a tracheostomy (69% vs 24%), with diminished cough reflex (27% vs 54%) and no effective oral phase (0% vs 21%)., Conclusion: Almost all DOC participants had severe dysphagia. Some components of swallowing (i.e., tracheostomy, cough reflex and efficacy of the oral phase of swallowing) were related to consciousness. In particular, no UWS participant had an efficient oral phase, which suggests that its presence may be a sign of consciousness. In addition, no UWS participant could be fed entirely orally, whereas no MCS participant orally received ordinary food. Our study also confirms that objective swallowing assessment can be successfully completed in DOC individuals and that specific care is needed to treat severe dysphagia in DOC., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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 met`abolism 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., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 the authors.)

Abstract: We report on a patient with hypoxic-ischemic brain injury (HI-BI) who showed recovery from a minimally consciousness state over 6 years concurrent with recovery of an injured ascending reticular activating system (ARAS), which was demonstrated on diffusion tensor tractography (DTT).A 31-year-old female patient, who suffered from HI-BI, showed impaired consciousness with a minimally conscious state: intermittently obeying simple motor tasks, such as "please grasp my hand." Her consciousness showed recovery with the passage of time; rapid recovery was observed during the recent 2 years.In the upper ARAS, the neural connectivity to both the basal forebrain and prefrontal cortex had increased on 8-year DTT compared with 1.5-year DTT. In the lower dorsal and ventral ARAS, no significant change was observed between 1.5 and 8 years DTTs.Recovery of an injured ARAS was demonstrated in a patient who showed recovery from a minimally consciousness state over 6 years following HI-BI. Our results suggest the brain target areas for recovery of impaired awareness in patients with disorders of consciousness., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To prospectively investigate relationships of cortical somatosensory evoked potential (SEP) amplitudes with consciousness recovery and disability in the year following brain injury in patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS)., Methods: SEPs of 42 patients with VS/UWS were recorded 51.7 ± 23.3 days post-injury. N20-P25 amplitudes were compared between patients with and without consciousness recovery at 6 months and 1 year post-injury., Results: SEPs were present in 21 patients and bilaterally absent in 21 patients. N20-P25 amplitudes were significantly higher in patients who recovered consciousness than in those who died or did not recover consciousness at 6 months (median, 4.6 vs. 1.9 μV; P = 0.004) and 1 year (median, 4.6 vs. 2.1 μV; P = 0.02) after injury. The lowest N20-P25 amplitude in a patient who recovered consciousness was 2.15 μV. N20-P25 amplitudes correlated significantly with Coma Recovery Scale-Revised and Disability Rating Scale scores at 6 months and 1 year post-injury (both P < 0.05)., Conclusions: In patients with VS/UWS, SEP amplitudes are related to consciousness recovery and disability at 6 months and 1 year post-injury., Significance: The evaluation of SEP amplitudes can help to refine prognoses for patients with VS/UWS., Competing Interests: Declaration of Competing Interest None of the authors have potential conflicts of interest to be disclosed. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The brain exhibits a complex temporal structure which translates into a hierarchy of distinct neural timescales. An open question is how these intrinsic timescales are related to sensory or motor information processing and whether these dynamics have common patterns in different behavioral states. We address these questions by investigating the brain's intrinsic timescales in healthy controls, motor (amyotrophic lateral sclerosis, locked-in syndrome), sensory (anesthesia, unresponsive wakefulness syndrome), and progressive reduction of sensory processing (from awake states over N1, N2, N3). We employed a combination of measures from EEG resting-state data: auto-correlation window (ACW), power spectral density (PSD), and power-law exponent (PLE). Prolonged neural timescales accompanied by a shift towards slower frequencies were observed in the conditions with sensory deficits, but not in conditions with motor deficits. Our results establish that the spontaneous activity's intrinsic neural timescale is related to the neural capacity that specifically supports sensory rather than motor information processing in the healthy brain., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Many patients with severe coronavirus disease 2019 (COVID-19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID-19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID-19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness. ANN NEUROL 2020;88:851-854., (© 2020 American Neurological Association.)

Covert measures of information-processing are valuable tools to support assessment of patients' disorders of consciousness because of their potential in revealing what seem to be hidden. Those measures allow to overcome some limitations of traditional behavioural methods, which are often biased by difficulties in detecting reliable patients' responses. Therefore, we aimed at exploring patterns of psychophysiological responses (electroencephalography - EEG, skin conductance level - SCL, skin conductance response - SCR, heart rate - HR) marking potentially-preserved processing of personally-relevant stimuli in a sample of VS patients. In particular, we compared the processing of own vs. other names due to the intrinsic salience, relevance, and familiarity of such stimuli. Analysis of electroencephalography, skin conductance and heart rate modulations highlighted a consistent pattern of increased skin conductance and heart rate measures in response to patients' own name with respect to other names. Further, we observed increased delta and decreased alpha activity over frontal areas in response to their own name with respect to other names. Own-name stimuli might preserve their peculiar qualification even after severe brain damage and might call on residual attention orientation and preferred coding resources, suggesting the existence of partly preserved information-processing pathways that extends beyond basic auditory sensory processing.

Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)-also coined unresponsive wakefulness syndrome (UWS)-and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15-20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

After severe brain injury, it can be difficult to determine the state of consciousness of a patient, to determine whether the patient is unresponsive or perhaps minimally conscious 1 , and to predict whether they will recover. These diagnoses and prognoses are crucial, as they determine therapeutic strategies such as pain management, and can underlie end-of-life decisions 2,3 . Nevertheless, there is an error rate of up to 40% in determining the state of consciousness in patients with brain injuries 4,5 . Olfaction relies on brain structures that are involved in the basic mechanisms of arousal 6 , and we therefore hypothesized that it may serve as a biomarker for consciousness 7 . Here we use a non-verbal non-task-dependent measure known as the sniff response 8-11 to determine consciousness in patients with brain injuries. By measuring odorant-dependent sniffing, we gain a sensitive measure of olfactory function 10-15 . We measured the sniff response repeatedly over time in patients with severe brain injuries and found that sniff responses significantly discriminated between unresponsive and minimally conscious states at the group level. Notably, at the single-patient level, if an unresponsive patient had a sniff response, this assured future regaining of consciousness. In addition, olfactory sniff responses were associated with long-term survival rates. These results highlight the importance of olfaction in human brain function, and provide an accessible tool that signals consciousness and recovery in patients with brain injuries.

Rationale: We report a stroke patient who showed increased thalamocortical connectivity to the medial prefrontal cortex (mPFC) with recovery of impaired consciousness that was demonstrated on diffusion tensor tractography (DTT) of the ascending reticular activating system (ARAS)., Patients Concerns: A 48-year-old male patient underwent craniectomy and hematoma removal for spontaneous intracerebral hemorrhage in the right basal ganglia and thalamus. When he started rehabilitation at 5 weeks after onset he was in a vegetative state with a Coma Recovery Scale-Revised score of 6., Diagnoses: The patient was diagnosed spontaneous intracerebral hemorrhage in the right basal ganglia and thalamus., Interventions: He underwent comprehensive rehabilitation including neurotropic durgs, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation of the left prefrontal lobe (Brodmann area 10)., Outcomes: After 5 weeks of rehabilitation, the patient had recovered to a nearly normal conscious state with a Coma Recovery Scale-Revised score of 22. On 10-week DTT, thickening of the lower dorsal ARAS was observed on both sides compared with 5-week DTT. Decreased neural connectivity to the left PFC was observed on 5-week DTT whereas decreased neural connectivity to the left PFC was increased on 10-week DTT, especially the mPFC., Lessons: Increased thalamocortical connectivity to the mPFC was demonstrated in a stroke patient who showed concomitant recovery from a vegetative state to a nearly normal conscious state. The results suggest that the increased neural connectivity to the mPMC contributed to recovery of consciousness in this patient.

Background: We investigated the relationship between three language-dependent behaviors (i.e., command-following, intelligible verbalization, and intentional communication) and the functional status of patients with disorders of consciousness (DoC). We hypothesized that patients in minimally conscious state (MCS) who retain behavioral evidence of preserved language function would have similar levels of functional disability, while patients who lack these behaviors would demonstrate significantly greater disability. We reasoned that these results could then be used to establish empirically-based diagnostic criteria for MCS+., Methods: In this retrospective cohort study we included rehabilitation inpatients diagnosed with DoC following severe-acquired brain injury (MCS = 57; vegetative state/unresponsive wakefulness syndrome [VS/UWS] = 63); women: 46; mean age: 47 ± 19 years; traumatic etiology: 68; time post-injury: 40 ± 23 days). We compared the scores of the Disability Rating Scale score (DRS) at time of transition from VS/UWS to MCS or from MCS- to MCS+, and at discharge between groups., Results: Level of disability on the DRS was similar in patients with any combination of the three language-related behaviors. MCS patients with no behavioral evidence of language function (i.e., MCS-) were more functionally impaired than patients with MCS+ at time of transition and at discharge., Conclusions: Command-following, intelligible verbalization, and intentional communication are not associated with different levels of functional disability. Thus, the MCS+ syndrome can be diagnosed based on the presence of any one of these language-related behaviors. Patients in MCS+ may evidence less functional disability compared to those in MCS who fail to demonstrate language function (i.e., MCS-).

Recent evidence suggests that the quantity and quality of conscious experience may be a function of the complexity of activity in the brain and that consciousness emerges in a critical zone between low and high-entropy states. We propose fractal shapes as a measure of proximity to this critical point, as fractal dimension encodes information about complexity beyond simple entropy or randomness, and fractal structures are known to emerge in systems nearing a critical point. To validate this, we tested several measures of fractal dimension on the brain activity from healthy volunteers and patients with disorders of consciousness of varying severity. We used a Compact Box Burning algorithm to compute the fractal dimension of cortical functional connectivity networks as well as computing the fractal dimension of the associated adjacency matrices using a 2D box-counting algorithm. To test whether brain activity is fractal in time as well as space, we used the Higuchi temporal fractal dimension on BOLD time-series. We found significant decreases in the fractal dimension between healthy volunteers (n = 15), patients in a minimally conscious state (n = 10), and patients in a vegetative state (n = 8), regardless of the mechanism of injury. We also found significant decreases in adjacency matrix fractal dimension and Higuchi temporal fractal dimension, which correlated with decreasing level of consciousness. These results suggest that cortical functional connectivity networks display fractal character and that this is associated with level of consciousness in a clinically relevant population, with higher fractal dimensions (i.e. more complex) networks being associated with higher levels of consciousness. This supports the hypothesis that level of consciousness and system complexity are positively associated, and is consistent with previous EEG, MEG, and fMRI studies., Competing Interests: The authors have declared that no competing interests exist.

Determining the level of consciousness in patients with disorders of consciousness (DOC) remains challenging. To address this challenge, resting-state fMRI (rs-fMRI) has been widely used for detecting the local, regional, and network activity differences between DOC patients and healthy controls. Although substantial progress has been made towards this endeavor, the identification of robust rs-fMRI-based biomarkers for level of consciousness is still lacking. Recent developments in machine learning show promise as a tool to augment the discrimination between different states of consciousness in clinical practice. Here, we investigated whether machine learning models trained to make a binary distinction between conscious wakefulness and anesthetic-induced unconsciousness would then be capable of reliably identifying pathologically induced unconsciousness. We did so by extracting rs-fMRI-based features associated with local activity, regional homogeneity, and interregional functional activity in 44 subjects during wakefulness, light sedation, and unresponsiveness (deep sedation and general anesthesia), and subsequently using those features to train three distinct candidate machine learning classifiers: support vector machine, Extra Trees, artificial neural network. First, we show that all three classifiers achieve reliable performance within-dataset (via nested cross-validation), with a mean area under the receiver operating characteristic curve (AUC) of 0.95, 0.92, and 0.94, respectively. Additionally, we observed comparable cross-dataset performance (making predictions on the DOC data) as the anesthesia-trained classifiers demonstrated a consistent ability to discriminate between unresponsive wakefulness syndrome (UWS/VS) patients and healthy controls with mean AUC's of 0.99, 0.94, 0.98, respectively. Lastly, we explored the potential of applying the aforementioned classifiers towards discriminating intermediate states of consciousness, specifically, subjects under light anesthetic sedation and patients diagnosed as having a minimally conscious state (MCS). Our findings demonstrate that machine learning classifiers trained on rs-fMRI features derived from participants under anesthesia have potential to aid the discrimination between degrees of pathological unconsciousness in clinical patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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

Background: We report on a stroke patient with disorder of consciousness (DOC) who underwent repetitive transcranial magnetic stimulation (rTMS) and showed recovery of an injured upper ascending reticular activating system (ARAS) injury, which was demonstrated by using serial diffusion tensor tractography (DTT)., Case Presentation: A 45-year-old male patient was diagnosed as subarachnoid and intracerebral hemorrhages in the left fronto-parieto-temporal lobes. At 5 months after onset, the patient exhibited a persistent vegetative state, with a Coma Recovery Scale-Revised (CRS-R) score of 4. He underwent comprehensive rehabilitative therapy that included drugs for recovery of impaired consciousness and rTMS of the right dorsolateral prefrontal lobe. He recovered to a minimally conscious state (CRS-R: 13) at 7 months after onset and was transferred to a local rehabilitation hospital where he underwent similar rehabilitation but without rTMS. At 9 months after onset, his CRS-R score remained at 13. He was then readmitted to our hospital and underwent rehabilitation with rTMS until 10 months after onset. His CRS-R remained at 13, but his higher cognition had improved. The tract volume (TV) of the neural tract in the right prefrontal lobe in the upper ARAS on the 7-month DTT was higher than that on the 5-month DTT. However, compared to the 7-month DTT, the right prefrontal lobe TV was lower on the 9-month DTT. On the 10-month DTT, the TV of that neural tract had again increased., Conclusions: Increases in neural TV in the right prefrontal lobe of the upper ARAS that were associated with the periods of rTMS application were demonstrated in a stroke patient with DOC.

Background: Although emergence from the minimally conscious state (eMCS) is associated with symptoms including disorientation, memory and attention impairment, restlessness, and significant functional disability, the neurobehavioral profile of eMCS has not been empirically characterized., Objective: Determine degree of cognitive impairment, presence of clinical symptoms and functional disability at time eMCS in patients with traumatic and non-traumatic brain injury (TBI, nTBI)., Methods: Retrospective observational study of 169 adults (median [interquartile range] age: 51 [29, 62] years; male: 116; TBI: 103) who emerged from MCS based on the Coma Recovery Scale-Revised while in an inpatient Disorders of Consciousness program. Outcome measures include the Confusion Assessment Protocol (CAP) and Disability Rating Scale (DRS)., Results: CAP administration was attempted in 54 subjects. Twenty-eight subjects had valid scores on all CAP items, with a median [interquartile range] of 4 [3-5] symptoms of confusion. Scores in 93% of this subsample were consistent with an acute confusional state. The most common symptoms were cognitive impairment (98% of subjects), disorientation (93%), and agitation (69%). The median DRS score upon emergence from MCS was 14.5 [13, 16], indicating severe disability (n = 140)., Conclusions: eMCS is associated with an acute confusional state and severe disability. This finding may inform the lower boundary of confusion as well as approach to treatment and caregiver education.

Objective: Due to the problems with behavioral diagnosis of patients with prolonged DOC (disorders of consciousness), complementary approaches based on objective measurement of neural function are necessary. In this pilot study, we assessed the sensitivity of auditory chirp-evoked responses to the state of patients with severe brain injury as measured with CRS-R (Coma Recovery Scale - Revised)., Methods: A convenience sample of fifteen DOC patients was included in the study. Auditory stimuli, chirp-modulated at 1-120 Hz were used to evoke auditory steady-state response (ASSR). Phase-locking index (PLI) estimates within low gamma and high gamma windows were evaluated., Results: The PLI estimates within a narrow low gamma 38-42 Hz window positively correlated with the CRS-R total score and with the scores of the Auditory and Visual Function subscales. In the same low gamma window, significant difference in the PLIs was found between minimally conscious (MCS) and vegetative state (VS) patients. We did not observe any between-group differences nor any significant correlations with CRS-R scores in the high gamma window (80-110 Hz)., Conclusions: Our results support the notion that the activity around 40 Hz may serve as a possible marker of the integrity of thalamocortical networks in prolonged DOC patients., Significance: Auditory steady-state responses at gamma-band frequencies highlight the role of upper parts of auditory system in evaluation of the level of consciousness in DOC patients., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: In patients with disorders of consciousness (DOC), properties of functional brain networks at rest are informative of the degree of consciousness impairment and of long-term outcome. Here we investigate whether connectivity differences between patients with favorable and unfavorable outcome are already present within 24 h of coma onset., Methods: We prospectively recorded 63-channel electroencephalography (EEG) at rest during the first day of coma after cardiac arrest. We analyzed 98 adults, of whom 57 survived beyond unresponsive wakefulness. Functional connectivity was estimated by computing the 'debiased weighted phase lag index' over epochs of five seconds duration. We evaluated the network's topological features, including clustering coefficient, path length, modularity and participation coefficient and computed their variance over time. Finally, we estimated the predictive value of these topological features for patients' outcomes by splitting the patient sample in training and test datasets., Results: Group-level analysis revealed lower clustering coefficient, higher modularity and path length variance in patients with favorable compared to those with unfavorable outcomes (p < 0.01). Within all features, the path length variance in the network provided the best positive predictive value (PPV) for favorable outcome and specificity for unfavorable outcome in the test dataset (PPV: 0.83, p < 0.01; specificity: 0.86, p < 0.01) with above-chance negative predictive value and accuracy. Of note, the exclusion of patients with epileptiform activity (20 in total) eliminates all false positive predictions (n = 6) for path length variance., Interpretation: Topological features of functional connectivity differ as a function of long-term outcome in patients on the first day of coma. These differences are not interpretable in terms of consciousness levels as all patients were in a deep unconscious state. The time variance of path length is informative of comatose patients' outcome, as patients with favorable outcome exhibit a richer repertoire of path length than those with unfavorable outcomes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Modern eye tracking technology provides a means for communication with patients suffering from disorders of consciousness (DoC) or remaining in locked-in-state. However, being able to use an eye tracker for controlling text-based contents by such patients requires preserved reading ability in the first place. To our knowledge, this aspect, although of great social importance, so far has seemed to be neglected. In the paper, we presented the possibility of using an eye-tracking technology for assessing reading comprehension skills in post-comatose patients with minimal consciousness. We prepared various syllable-, word- and sentence-based tasks, controlled by gaze, used for assessing the reading comprehension skills. The obtained results showed that people with minimal consciousness preserved the reading comprehension skills, in most cases to a high extent, but had difficulties with recognizing errors in the written text. The ability to maintain attention during performing the tasks was in statistically significant correlation with motivation, and that one was in a statistically significant correlation with the reading ability. The results indicate that post-comatose patients with minimal consciousness can read words and sentences, hence some useful hints may be provided for the development of gaze tracking-based human-computer interfaces for these people.

Background: The vegetative state, also known as the unresponsive wakefulness syndrome, is one of the worst possible outcomes of acquired brain injury and confronts rehabilitation specialists with various challenges. Emergence to (minimal) consciousness is classically considered unlikely beyond 3-6 months after non-traumatic or 12 months after traumatic etiologies. A growing body of evidence suggests that these timeframes are too narrow, but evidence regarding chances of recovery is still limited., Objective: To identify the moment of recovery of consciousness in documented cases of late emergence from a vegetative state., Methods: Four cases of apparent late recovery of consciousness, identified within a prospective cohort study, were studied in-depth by analyzing medical, paramedical and nursing files and interviewing the patients' families about their account of the process of recovery., Results: All patients were found to have shown signs of consciousness well within the expected time frame (5 weeks-2 months post-ictus). These behaviors, however, went unnoticed or were misinterpreted, leading to a diagnostic delay of several months to over 5 years. Absence of appropriate diagnostics, the use of erroneous terminology, sedative medication but also patient-related factors such as hydrocephalus, language barriers and performance fluctuations are hypothesized to have contributed to the delay., Conclusions: Delayed recognition of signs of consciousness in patients in a vegetative state may not only lead to suboptimal clinical care, but also to distorted prognostic figures. Discriminating late recovery from the delayed discovery of consciousness, therefore, is vital to both clinical practice and science.

Introduction: Altered states of consciousness have traditionally been associated with poor prognosis. At present, clinical differences between these entities are beginning to be established., Method: Our study included 37 patients diagnosed with vegetative state/unresponsive wakefulness syndrome (UWS) and 43 in a minimally conscious state (MCS) according to the Coma Recovery Scale-Revised (CRS-R). All patients were followed up each month for at least 6 months using the CRS-R. We recorded the time points when vegetative state progressed from 'persistent' to 'permanent' based on the cut-off points established by the Multi-Society-Task-Force: 12 months in patients with traumatic injury and 3 months in those with non-traumatic injury. A logistic regression model was used to determine the factors potentially predicting which patients will emerge from MCS., Results: In the UWS group, 23 patients emerged from UWS but only 9 emerged from MCS. Of the 43 patients in the MCS group, 26 patients emerged from that state during follow-up. Eight of the 23 patients (34.7%) who emerged from UWS and 17 of the 35 (48.6%) who emerged from MCS recovered after the time points proposed by the Multi-Society-Task-Force. According to the multivariate regression analysis, aetiology (P<.01), chronicity (P=.01), and CRS-R scores at admission (P<.001) correctly predicted emergence from MCS in 77.5% of the cases., Conclusions: UWS and MCS are different clinical entities in terms of diagnosis and outcomes. Some of the factors traditionally associated with poor prognosis, such as time from injury and likelihood of recovery, should be revaluated., (Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Diagnosis of consciousness in patients with prolonged disorders of consciousness (PDOC) remains challenging since their responsiveness is often very impaired, while their assessment depends on observable behavior. The aim of this proof-of-concept study was to evaluate whether low- and medium-rate amplitude-modulated (AM) auditory steady-state responses (ASSRs) can be sensitive to the state of PDOC patients and may thus serve as a diagnostic tool which does not explicitly depend on a patient's cooperation. EEG was recorded from nine unresponsive wakefulness syndrome/vegetative state (UWS/VS) and eight minimally conscious state (MCS)/emergence from MCS patients during stimulation with two-minute trains of simple tones, amplitude modulated (AM) by 4 Hz, 6 Hz, 8 Hz, 12 Hz, 20 Hz, 40 Hz. The obtained ASSRs were then related to the Coma Recovery Scale - Revised (CRS-R) diagnosis and its total score. We observed significant correlations between mean inter-trial phase coherence (PC) (averaged across all stimulation frequencies) and total CRS-R score, as well as between 40 Hz relative power (RP) and total CRS-R score. Moreover, both parameters significantly differed between the patient groups. Our preliminary results suggest that a passive auditory stimulation protocol consisting of low- and medium-rate ASSRs might be used as an objective estimate of the level of neural dysfunction in PDOC patients. Consequently, the integrity of the auditory system appears to be an important predictor of the actual state of consciousness in PDOC patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)