Vegetative State/unresponsive Wakefulness Syndrome Research Articles

Factors influencing recovery in a pediatric sample with disorders of consciousness: insights from an observational study

ABSTRACT Objective To estimate rates and time to reach emergence of consciousness from vegetative state/unresponsive wakefulness syndrome (VS/UWS), and explore factors associated with improved recovery in children and adolescents with disorders of consciousness (DoC) following severe traumatic and non-traumatic brain injury. Methods Analytical, retrospective, cohort study. Clinical records of consecutively referred patients admitted in VS/UWS to a neurological rehabilitation institute in Argentina, between 2005 and 2021 were reviewed. Seventy children and adolescents were included in the analysis. A specialized 12-week rehabilitation program was administered, and emergence was defined by scores ≥44 points on the Western Neuro Sensory Stimulation Profile (WNSSP), sustained for at least 3 weeks on consecutive weekly evaluations. Results Emergence from VS/UWS to consciousness occurred within 5.4 (SD 2.6) weeks in almost one-third of patients. Multivariate Cox regression analysis showed emergence was significantly lower in patients with hypoxic ischemic encephalopathy compared to patients with other non-traumatic etiologies [HRadj 0.23 (95% CI 0.06–0.89); p = 0.03)]. Conclusions Our findings reinforce growing evidence on the impact of etiology on DoC recovery in pediatric populations, ultimately influencing treatment and family-related decisions in child neurorehabilitation.

Behavioral Assessment With the Coma Recovery Scale-Revised Is Safe and Feasible in Critically Ill Patients With Disorders of Consciousness.

Accurate classification of disorders of consciousness (DoC) is key in developing rehabilitation plans after brain injury. The Coma Recovery Scale-Revised (CRS-R) is a sensitive measure of consciousness validated in the rehabilitation phase of care. We tested the feasibility, safety, and impact of CRS-R-guided rehabilitation in the ICU for patients with DoC after acute hemorrhagic stroke. Retrospective cohort study. This single-center study was conducted in the neurocritical care unit at the University of Maryland Medical Center. We analyzed records from consecutive patients with subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH), who underwent serial CRS-R assessments during ICU admission from April 1, 2018, to December 31, 2021, where CRS-R less than 8 is vegetative state/unresponsive wakefulness syndrome (VS/UWS); CRS-R greater than or equal to 8 is a minimally conscious state (MCS). None. Outcomes included adverse events during CRS-R evaluations and associations between CRS-R and discharge disposition, therapy-based function, and mobility. We examined the utility of CRS-R compared with other therapist clinical assessment tools in predicting discharge disposition. Seventy-six patients (22 SAH, 54 ICH, median age = 59, 50% female) underwent 276 CRS-R sessions without adverse events. Discharge to acute rehabilitation occurred in 4.4% versus 41.9% of patients with a final CRS-R less than 8 and CRS-R greater than or equal to 8, respectively (odds ratio [OR] 13.4; 95% CI, 2.7-66.1; p < 0.001). Patients with MCS on final CRS-R completed more therapy sessions during hospitalization and had improved mobility and functional performance. Compared with other therapy assessment tools, the CRS-R had the best performance in predicting discharge disposition (area under the curve: 0.83; 95% CI, 0.72-0.94; p < 0.0001). Early neurorehabilitation guided by CRS-R appears to be feasible and safe in the ICU following hemorrhagic stroke complicated by DoC and may enhance access to inpatient rehabilitation, with the potential for lasting benefit on recovery. Further research is needed to assess generalizability and understand the impact on long-term outcomes.

Breakdown of effective information flow in disorders of consciousness: Insights from TMS-EEG

BackgroundThe 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. ObjectivesTo investigate information flow with TMS-EEG and its relationship to different consciousness states. MethodsWe 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. ResultsTMS 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. ConclusionsTMS-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. SignificanceFindings 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.

Assessment of Frequency and Predictive Value of Comorbidities in Patients With Disorders of Consciousness in the Acute Setting.

Medical comorbidities are frequent in patients with disorders of consciousness (DoC) and their impact on outcomes is under investigation. The aim of this study was to investigate patients with DoC in the acute stage and the influence of comorbidities. Patients admitted to intensive care units and neurological units with a diagnosis of coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), and minimally conscious state (MCS) were investigated through the Glasgow Coma Scale (GCS), the Coma Recovery Scale - Revised (CRS-R) and the Comorbidities Coma Scale (CoCos). Forty-three patients (21 men and 22 women; mean age at admission: 60.4 ± 21.0) were included in the study. The most frequent diagnosis at admission was coma (72%) followed by VS/UWS (14%) and MCS (14%). The most frequent brain injury was subarachnoid hemorrhage (46%). At the 6-month follow-up, 19 patients had died (44%), 15 showed a full recovery of consciousness (35%), 7 were in a condition of emergence from MCS (16%), and 2 showed a persistent VS/UWS (5%). Forty-two (98%) patients showed at least one comorbidity: presence of life-support device (92.9%), anemia (76.2%), arterial hypertension (66,7%), hydrocephalus (45.3%), and respiratory infections (45.2%) were those most frequently reported. At the Multivariable Cox regression, the presence of renal disease (hazard ratio [HR] 33.37; p = 0.033) and malnutrition (HR 14.52; p = 0.001) were predictors of missed recovery of full consciousness. Although adverse outcomes are generally predicted by the severity of brain damage, the presence of medical comorbidities in an acute phase could influence outcomes and long-term prognosis.

Dissociations between spontaneous electroencephalographic features and the perturbational complexity index in the minimally conscious state.

The analysis of spontaneous electroencephalogram (EEG) is a cornerstone in the assessment of patients with disorders of consciousness (DoC). Although preserved EEG patterns are highly suggestive of consciousness even in unresponsive patients, moderately or severely abnormal patterns are difficult to interpret. Indeed, growing evidence shows that consciousness can be present despite either large delta or reduced alpha activity in spontaneous EEG. Quantifying the complexity of EEG responses to direct cortical perturbations (perturbational complexity index [PCI]) may complement the observational approach and provide a reliable assessment of consciousness even when spontaneous EEG features are inconclusive. To seek empirical evidence of this hypothesis, we compared PCI with EEG spectral measures in the same population of minimally conscious state (MCS) patients (n= 40) hospitalized in rehabilitation facilities. We found a remarkable variability in spontaneous EEG features across MCS patients as compared with healthy controls: in particular, a pattern of predominant delta and highly reduced alpha power-more often observed in vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients-was found in a non-negligible number of MCS patients. Conversely, PCI values invariably fell above an externally validated empirical cutoff for consciousness in all MCS patients, consistent with the presence of clearly discernible, albeit fleeting, behavioural signs of awareness. These results confirm that, in some MCS patients, spontaneous EEG rhythms may be inconclusive about the actual capacity for consciousness and suggest that a perturbational approach can effectively compensate for this pitfall with practical implications for the individual patient's stratification and tailored rehabilitation.

Variability of large timescale functional networks in patients with disorders of consciousness.

Most brain function assessments for disorders of consciousness (DOC) utilized quantified characteristics, measured only once, ignoring the variation of patients' brain states. The study aims to investigate the brain activities of patients with DOC from a new perspective: variability of a large timescale functional network. Forty-nine patients were enrolled in this study and performed a 1-week behavioral assessment. Subsequently, each patient received electroencephalography (EEG) recordings five times daily at 2-h intervals. Functional connectivity and networks were measured by weighted phase lag index and complex network parameters (characteristic path length, cluster coefficient, and betweenness centrality). The relative coefficient of variation (CV) of network parameters was measured to evaluate functional network variability. Functional networks of patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS) showed significantly higher segregation (characteristic path length) and lower centrality (betweenness centrality) than emerging from the minimal conscious state (EMCS) and minimal conscious state (MCS), as well as lower integration (cluster coefficient) than MCS. The functional networks of VS/UWS patients consistently presented the highest variability in segregation and integration (i.e., highest CV values of characteristic path length and cluster coefficient) on a larger time scale than MCS and EMCS. Moreover, the CV values of characteristic path length and cluster coefficient showed a significant inverse correlation with the Coma Recovery Scale-Revised scores (CRS-R). The CV values of network betweenness centrality, particularly of the cento-parietal region, showed a positive correlation with the CRS-R. The functional networks of VS/UWS patients present the most invariant segregation and integration but divergent centrality on the large time scale networks than MCS and EMCS. The variations observed within large timescale functional networks significantly correlate with the degree of consciousness impairment. This finding augments our understanding of the neurophysiological mechanisms underpinning disorders of consciousness.

The accuracy of different mismatch negativity amplitude representations in predicting the levels of consciousness in patients with disorders of consciousness.

The mismatch negativity (MMN) index has been used to evaluate consciousness levels in patients with disorders of consciousness (DoC). Indeed, MMN has been validated for the diagnosis of vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS). In this study, we evaluated the accuracy of different MMN amplitude representations in predicting levels of consciousness. Task-state electroencephalography (EEG) data were obtained from 67 patients with DoC (35 VS and 32 MCS). We performed a microstate analysis of the task-state EEG and used four different representations (the peak amplitude of MMN at electrode Fz (Peak), the average amplitude within a time window -25- 25 ms entered on the latency of peak MMN component (Avg for peak ± 25 ms), the average amplitude of averaged difference wave for 100-250 ms (Avg for 100-250 ms), and the average amplitude difference between the standard stimulus ("S") and the deviant stimulus ("D") at the time corresponding to Microstate 1 (MS1) (Avg for MS1) of the MMN amplitude to predict the levels of consciousness. The results showed that among the four microstates clustered, MS1 showed statistical significance in terms of time proportion during the 100-250 ms period. Our results confirmed the activation patterns of MMN through functional connectivity analysis. Among the four MMN amplitude representations, the microstate-based representation showed the highest accuracy in distinguishing different levels of consciousness in patients with DoC (AUC = 0.89). We discovered a prediction model based on microstate calculation of MMN amplitude can accurately distinguish between MCS and VS states. And the functional connection of the MS1 is consistent with the activation mode of MMN.

Breakdown of oscillatory effective networks in disorders of consciousness.

Combining transcranial magnetic stimulation with electroencephalography (TMS-EEG), oscillatory reactivity can be measured, allowing us to investigate the interaction between local and distant cortical oscillations. However, the extent to which human consciousness is related to these oscillatory effective networks has yet to be explored. We tend to investigate the link between oscillatory effective networks and brain consciousness, by monitoring the global transmission of TMS-induced oscillations in disorders of consciousness (DOC). A cohort of DOC patients was included in this study, which included 28 patients with a minimally conscious state (MCS) and 20 patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS). Additionally, 25 healthy controls were enrolled. The oscillatory reactivity to single-pulse TMS of the frontal, sensorimotor and parietal cortex was measured using event-related spectral perturbation of TMS-EEG. The temporal-spatial properties of the oscillatory reactivity were illustrated through life time, decay gradients and accumulative power. In DOC patients, an oscillatory reactivity was observed to be temporally and spatially suppressed. TMS-EEG of DOC patients showed that the oscillations did not travel as far in healthy controls, in terms of both temporal and spatial dimensions. Moreover, cortical theta reactivity was found to be a reliable indicator in distinguishing DOC versus healthy controls when TMS of the parietal region and in distinguishing MCS versus VS/UWS when TMS of the frontal region. Additionally, a positive correlation was observed between the Coma Recovery Scale-Revised scores of the DOC patients and the cortical theta reactivity. The findings revealed a breakdown of oscillatory effective networks in DOC patients, which has implications for the use of TMS-EEG in DOC evaluation and offers a neural oscillation viewpoint on the neurological basis of human consciousness.

Possibilities and prospects for assessing pain nociception in patients with chronic disorders of consciousness

The objective was to study the possibilities of assessing pain nociception in patients with chronic disorders of consciousness (CDC) using the ANI index and to identify differences depending on the level of CDC, to create systems for objectification of pain sensations of patients with CDC. Materials and methods. The study included 29 patients with CDC. Group 1 (9 patients) – vegetative state / unresponsive wakefulness syndrome (VS/UWS), group 2 (20 patients) – minimally conscious state (MCS) – “plus”. The pain stimulus (PS) consisted in pressing on the nail phalanx of the hand with a reflex hammer. The ANI index was recorded three times: at rest (ANI 1), during the application of PS (ANI 2), 30 minutes after the application of PS (ANI 3). The assessment on the pain scale (NCS-R) was performed once during the application of PS. Statistical processing was carried out using the R programming language, a package of applied statistical programs SPSS STATISTICS.Results. The average values of the index difference ANI 2 and ANI 1 in group 1 differed, ANI 2 – ANI 3 had no differences. The average values of the ANI 3 index in groups 1 and 2 differed statistically significantly. A rank correlation between the ANI index and the NCS-R score existed in group 1 in the period after the application of BS. A statistically significant negative correlation was found in group 1 during the application of BS. When comparing the ANI index and the difference between the CRS-R index at discharge and admission, it was found that in group 2, the greater the difference between the CRS-R index at discharge and admission, the lower the value of the ANI index at all stages of the study, and in group 1 the opposite relationship was obtained. In group 1, there was a statistical relationship between the Kerdo index (IR) and the difference between the indices ANI 2 and ANI 1, ANI 2 and ANI 1 and IR, for group 2, the relationship could not be established.Conclusion. The data obtained during the study indicate that there are certain differences in the response to PS in patients in the VS / UWS and MCS ≪plus≫. Сreation of systems for objectification of pain sensations of patients in the VS / UWS will contribute to improving their quality of life.

EEG complexity correlates with residual consciousness level of disorders of consciousness

Background and objectiveElectroencephalography (EEG) and neuroimaging measurements have been highly encouraged to be applied in clinics of disorders of consciousness (DOC) to improve consciousness detection. We tested the relationships between neural complexity measured on EEG and residual consciousness levels in DOC patients.MethodsResting-state EEG was recorded from twenty-five patients with DOC. Lempel–Ziv complexity (LZC) and permutation Lempel–Ziv complexity (PLZC) were measured on the EEG, and their relationships were analyzed with the consciousness levels of the patients.ResultsPLZC and LZC values significantly distinguished patients with a minimally conscious state (MCS), vegetative state/unresponsive wakefulness syndrome (VS/UWS), and healthy controls. PLZC was significantly correlated with the Coma Recovery Scale-Revised (CRS-R) scores of DOC patients in the global brain, particularly in electrodes locating in the anterior and posterior brain regions. Patients with higher CRS-R scores showed higher PLZC values. The significant difference in PLZC values between MCS and VS/UWS was mainly located in the bilateral frontal and right hemisphere regions.ConclusionNeural complexity measured on EEG correlates with residual consciousness levels of DOC patients. PLZC showed higher sensitivity than LZC in the classification of consciousness levels.

Brain-derived neutrophic factor, glutamate and markers of apoptosis in the blood of patients with prolonged disorders of consciousness

Aim of the work was to analyze the content of factors with neuroprotective, neurotoxic and apoptotic eff ects in the blood of patients with prolonged disorders of consciousness (pDOC), depending on the level of consciousness disorder and neuroprotective therapy.Material and methods. Research included 53 patients with pDOC, who were divided into 2 groups. Group 1 included 19 vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, group 2–34 minimally conscious state (MCS “minus” and “plus”) patients. Firstly at admission and then at the end of treatment course (after 1 month on average), plasma concentrations of brain neurotrophic factor (BDNF), apoptosis antigen (APO-1), apoptosisinducing ligand (Fas-L) and glutamate were studied. Control group consisted of 16 patients without measured once.Results. Decrease of BDNF serum level was revealed in patients with pDOC,which was less pronounced those who had TBI as a etiological factor of pDOC. BDNF level signifi cantly increased after a month against the background of neuroprotective therapy. Glutamate level was higher in the fi rst group (VS/UWS). No signifi cant diff erence in the content of apoptosis factors was observed.Conclusion. In patients with pDOC, decrease serum BDNF level was observed, less pronounced in TBI as etiology of pDOC. In patients who matched MCS criteria at the admission, there was a signifi cant increase of BDNF serum level during treatment course, which could indicate that patients with a higher initial level of consciousness have better potential for realizing the eff ect of neuroprotective therapy. Levels of apoptosis factors did not correspond to the consciousness level.

An innovative approach for the evaluation of prolonged disorders of consciousness using NF-L and GFAP biomarkers: a pivotal study

Behavioral assessments during the clinical evaluation in prolonged disorders of consciousness patients could be not sufficient for a correct diagnosis and prognostication. To this aim, we used an innovative approach, involving the ultra-sensitive determination of biological markers, correlating them with imaging parameters to investigate the prolonged disorders of consciousness (pDoC).We assessed the serum concentration of neurofilament light chain(NF-L) and glial fibrillary acidic protein (GFAP) in pDoC (n = 16), and healthy controls (HC, n = 6) as well as several clinical imaging parameters such as Fractional Anisotropy (FA), Whole Brain SUV, and White Matter Hyperintensities volumes (WMH) using PET-MRI acquisition. As for differential diagnosis task, only the imaging WMH volume was able to discriminate between vegetative state/unresponsive wakefulness syndrome (VS/UWS), and minimally conscious state (MCS) patients (p-value < 0.01), while all selected markers (both imaging and in vitro) were able to differentiate between pDoC patients and HC. At subject level, serum NF-L concentrations significantly differ according to clinical progression and consciousness recovery (p-value < 0.01), highlighting a potential play for the longitudinal management of these patients.

Altered functional connectivity and regional brain activity in a triple-network model in minimally conscious state and vegetative-state/unresponsive wakefulness syndrome patients: A resting-state functional magnetic resonance imaging study.

The purpose of this study was to investigate changes in functional connectivity and regional brain activity between and within the default mode network (DMN), salience network (SN), and executive control network (ECN) among individuals with disorders of consciousness (DOC) in the conditions of minimally conscious state (MCS) and vegetative-state/unresponsive wakefulness syndrome (VS/UWS). Twenty-five VS/UWS patients, 14 MCS patients, and 30 healthy individuals as normal control, completed resting-state fMRI scans. ROI-wise functional connectivity and fractional amplitude of low-frequency fluctuation (fALFF) were implemented to examine group differences. All ROI-wise and fALFF analyses masks were identified from the triple-network model. ROI-wise analyses indicated significantly decreased functional connectivity between posterior cingulate cortex (DMN)-left anterior insula (SN), right anterior insula (SN)-left dorsolateral prefrontal cortex (ECN), and right anterior insula (SN)-right amygdala (SN) in VS/UWS patients compared to MCS patients. Moreover, fALFF were observed reduced in the triple-network across all DOC patients, and as the clinical manifestations of DOC deteriorated from MCS to VS/UWS, fALFF in dorsal DMN, anterior/posterior SN, and left ECN became significantly reduced. Moreover, a positive correlation between fALFF of the left ECN and Coma Recovery Scale-Revised (CRS-R) total scores was found across all DOC patients. These findings contribute to a better understanding of the underlying neural mechanism of functional connectivity and regional brain activity in DOC patients, and this triple-network model provides new connectivity pattern changes that may be integrated in future diagnostic tools based on the neural signatures of conscious states.

Long-term functional prognosis and related factors of spinal cord stimulation in patients with disorders of consciousness.

IntroductionThe treatment of patients with disorders of consciousness (DoC) remains a challenging issue, and spinal cord stimulation (SCS) has been reported to be a promising treatment for DoC in some studies.AimsThis study explores the efficiency of SCS in treating patients with DoC at different consciousness levels, including the vegetative state/unresponsive wakefulness syndrome (VS/UWS) and the minimally conscious state (MCS) and summarizes and analyzes the long‐term effect and related factors of SCS in patients with DoC.ResultsAn overall positive outcome was reached in 35 of 110 patients (31.8%). Among patients with positive outcomes, the MCS group improved 45.53% more than VS/UWS group, and this difference was statistically significant. In terms of the recommendation standard, positive outcomes occurred in 33 patients (94.3%) in the highly recommended group and 2 patients (5.7%) in the weakly recommended group (p < 0.001). After adjustment for potential covariables, young age (age ≤ 19 years old) (p = 0.045) and MCS (p < 0.001) were significantly correlated with positive outcome. A nomogram based on age, state of consciousness, and pathogeny showed good predictive performance, with a c‐index of 0.794. The Hosmer–Lemeshow goodness‐of‐fit test showed that the model was well calibrated (χ 2 = 3.846, p = 0.871).ConclusionsSCS is one of the most feasible treatments for patients with DoC, especially for patients with MCS. Younger age is significantly associated with better outcomes and could therefore serve as a basis for preoperative screening. However, more evidence‐based randomized controlled trials are needed to confirm the efficacy of the treatment.

Metabolomic Profiling of the Blood of Patients with Chronic Consciousness Disorders

The main variants of chronic consciousness disorder (CCD) developing in adverse coma outcome are vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimal consciousness state (MCS). The aim of the study was to investigate the main differences in metabolomic abnormalities in patients with VS / UWS and MCS, as well as to identify changes in metabolomics depending on sleep or wakefulness phase. Materials and Methods. Untargeted metabolome analysis of blood plasma of 10 patients in VS / UWS (group 1) and 6 patients in MCS (group 2) was performed using reversed-phase and hydrophilic chromatography methods. The underlying conditions of brain injury were TBI (2 in group 1 and 5 in group 2) and hypoxia (8 in group 1 and 1 in group 2). The internal jugular vein was catheterized in all patients, and blood was collected while awake during the daytime for 2 days. Aliquots of pooled plasma samples were purified from protein components and analyzed by high-performance liquid chromatography in two modes: reversed-phase and hydrophilic ones. Mass-spectrometric detection was performed in full ion current scanning mode: registration of positively charged ions in the m/z range from 50 to 1300 a.u. Data were adjusted and normalized using MS-DIAL software ver. 4.70 software; differences were identified using analysis of variance, discriminant and cluster analysis. The data were analyzed and visualized using MetaboAnalyst 5.0 software (https://www.metaboanalyst.ca). Results. Four major metabolites (at VIP &gt; 0.5), which content was most modulated depending on the study group, were identified including 4 (m/z 124.0867, Rt = 17.67, p &lt; 0.01), 33 (m/z 782.5722, Rt = 17.69, p &lt; 0.01), 6 (m/z 125.0904, Rt = 18.43, p &lt; 0.01) and 1 (m/z 463.2304, Rt = 15.78, p &lt; 0.01), with no significant differences between daytime and nighttime blood samples. Significant quantitative differences were shown for three metabolites in the groups, 14 (m/z 162.1126, Rt = 10.28, p &lt; 0.01), 35 (m/z 780.5483, Rt = 7.65, p &lt; 0.01), and 41 (m/z 806.5649, Rt = 7.58, p &lt; 0.01), and four metabolites when comparing the daytime and nighttime samples: 14 (m/z 162.1126, Rt = 10.28, p = 0.0201), 35 (m/z 780.5483, Rt = 7.65, p &lt; 0.01), 41 (m/z 806.5649, Rt = 7.58, p &lt; 0.01), and 48 (m/z 848.5354, Rt = 7.65, p &lt; 0.01). Conclusion. Untargeted metabolomic analysis confirmed the hypothesis of likely significant quantitative and qualitative differences in metabolite composition depending on the type of CCD and circadian rhythm. The study established a set of metabolites that are potential biomarkers for differential diagnosis of VS/UWS and MCS including 4, 33, 6, 1 (in the experiment on the reversed-phase column) and 14, 35, 41, 48 (in the experiment on the hydrophilic column), based on their significant contribution to intergroup and intragroup differences. Further studies will be aimed to characterize the identified metabolites.

Regional Homogeneity Alterations in Patients with Impaired Consciousness. An Observational Resting-State fMRI Study.

It is always challenging to correctly differentiate between minimally conscious state (MCS) and vegetative state/unresponsive wakefulness syndrome (VS/UWS) among disorders of consciousness (DOC) patients. However, the underlying neural mechanisms of awareness identification remain incompletely understood. Using regional homogeneity (ReHo) analysis, we evaluated how regional connectivity of brain regions is disrupted in MCS and VS/UWS patients. Resting-state functional magnetic resonance imaging was conducted in 14 MCS patients, 25 VS/UWS patients, and 30 age-matched healthy individuals. We found that MCS and VS/UWS patients demonstrated DOC-dependent reduced ReHo within widespread brain regions including posterior cingulate cortices (PCC), medial prefrontal cortices (mPFC), and bilateral fronto-parieto-temporal cortices and showed increased ReHo in limbic structures. Moreover, a positive correlation between Coma Recovery Scale-Revised (CRS-R) total scores and reduced ReHo in the left precuneus was observed in VS/UWS patients, despite the linear trend was not found in MCS patients. In addition, ReHo were also observed reduced in three mainly intrinsic connectivity networks (ICNs), including default mode network (DMN), executive control network (ECN), and salience network (SN). Notably, as the clinical symptoms of consciousness disorders worsen from MCS to VS/UWS, ReHo in dorsal DMN, left ECN, and posterior SN became significantly reduced. These findings make a further understanding of the underlying neural mechanism of regional connectivity among DOC patients and provide additional neuroimaging-based biomarkers for the clinical diagnosis of MCS and VS/UWS patients.

Ethical Considerations in Clinical Trials for Disorders of Consciousness.

As the clinical trial landscape for patients with disorders of consciousness (DoC) expands, consideration of associated ethical challenges and opportunities is of ever-increasing importance. Responsible conduct of research in the vulnerable population of persons with DoC, including those with coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), covert cortical processing (CCP), and cognitive motor dissociation (CMD), demands proactive deliberation of unique ethical issues that may arise and the adoption of robust protections to safeguard patients, surrogates, and other key stakeholders. Here we identify and critically evaluate four central categories of ethical considerations in clinical trials involving participants with DoC: (1) autonomy, respect for persons and informed consent of individuals with liminal consciousness; (2) balancing unknown benefits and risks, especially considering the epistemological gap between behavior and consciousness that complicates ordinary ascription of subjective states; (3) disclosure to surrogates and clinical teams of investigational results pertaining to consciousness; and (4) justice considerations, including equitable access to clinical trial enrollment across communities and geographies. We outline guiding principles and research opportunities for clinicians, neuroethicists, and researchers engaged in DoC clinical trials to advance ethical study design and deployment in this complex yet crucial area of investigation.

Diagnostic Developments in Differentiating Unresponsive Wakefulness Syndrome and the Minimally Conscious State.

When treating patients with a disorder of consciousness (DOC), it is essential to obtain an accurate diagnosis as soon as possible to generate individualized treatment programs. However, accurately diagnosing patients with DOCs is challenging and prone to errors when differentiating patients in a Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) from those in a Minimally Conscious State (MCS). Upwards of ~40% of patients with a DOC can be misdiagnosed when specifically designed behavioral scales are not employed or improperly administered. To improve diagnostic accuracy for these patients, several important neuroimaging and electrophysiological technologies have been proposed. These include Positron Emission Tomography (PET), functional Magnetic Resonance Imaging (fMRI), Electroencephalography (EEG), and Transcranial Magnetic Stimulation (TMS). Here, we review the different ways in which these techniques can improve diagnostic differentiation between VS/UWS and MCS patients. We do so by referring to studies that were conducted within the last 10 years, which were extracted from the PubMed database. In total, 55 studies met our criteria (clinical diagnoses of VS/UWS from MCS as made by PET, fMRI, EEG and TMS- EEG tools) and were included in this review. By summarizing the promising results achieved in understanding and diagnosing these conditions, we aim to emphasize the need for more such tools to be incorporated in standard clinical practice, as well as the importance of data sharing to incentivize the community to meet these goals.

Nociceptive Response Is a Possible Marker of Evolution in the Level of Consciousness in Unresponsive Wakefulness Syndrome Patients.

The Nociception Coma Scale (NCS) and its revised version (NCS-R) were used to evaluate behavioral responses to pain in non-communicative patients. We hypothesized that if patients demonstrate changes to their NCS(-R) scores over time, their evolving behavioral abilities could indicate a forthcoming diagnostic improvement with the Coma Recovery Scale-Revised (CRS-R). Forty-three Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients were enrolled in the study. The patients were assessed weekly using the CRS-R and NCS(-R) for four consecutive weeks. The first assessment was within 10 days after hospitalization. The assessments were performed between 09:30 and 11:30 AM in a room with constant levels of humidity, light and temperature, as well as an absence of transient noise. Noxious stimuli were administered using a Newton-meter, with pressure applied to the fingernail bed for a maximum of 5 s unless interrupted by a behavioral response from subjects. Seventeen patients demonstrated improvements in their level of consciousness, 13 of whom showed significant behavioral changes through the NCS(-R) before being diagnosed with a Minimally Conscious State (MCS) according to the CRS-R. The behavioral changes observed using the NCS(-R) corresponded to a high probability of observing an improvement from VS/UWS to MCS. To characterize the increased likelihood of this transition, our results present threshold scores of ≥5 for the NCS (accuracy 86%, sensitivity 87%, and specificity 86%) and ≥3 for the NCS-R (accuracy 77%, sensitivity 89%, and specificity 73%). In conclusion, a careful evaluation of responses to nociceptive stimuli in DOC patients could constitute an effective procedure in assessing their evolving conscious state.

Risk factors for 2-year mortality in patients with prolonged disorders of consciousness: An international multicentre study.

Patients with prolonged disorders of consciousness (pDoC) have a high mortality rate due to medical complications. Because an accurate prognosis is essential for decision-making on patients' management, we analysed data from an international multicentre prospective cohort study to evaluate 2-year mortality rate and bedside predictors of mortality. We enrolled adult patients in prolonged vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) after traumatic and nontraumatic brain injury within 3months postinjury. At enrolment, we collected demographic (age, sex), anamnestic (aetiology, time postinjury), clinical (Coma Recovery Scale-Revised [CRS-R], Disability Rating Scale, Nociception Coma Scale-Revised), and neurophysiologic (electroencephalogram [EEG], somatosensory evoked and event-related potentials) data. Patients were followed up to gather data on mortality up to 24months postinjury. Among 143 traumatic (n=55) and nontraumatic (n=88) patients (VS/UWS, n=68, 19 females; MCS, n=75, 22 females), 41 (28.7%) died within 24months postinjury. Mortality rate was higher in VS/UWS (42.6%) than in MCS (16%; p<0.001). Multivariate regression in VS/UWS showed that significant predictors of mortality were older age and lower CRS-R total score, whereas in MCS female sex and absence of alpha rhythm on EEG at study entry were significant predictors. This study demonstrated that a feasible multimodal assessment in the postacute phase can help clinicians to identify patients with pDoC at higher risk of mortality within 24months after brain injury. This evidence can help clinicians and patients' families to navigate the complex clinical decision-making process and promote an international standardization of prognostic procedures for patients with pDoC.