Serum metabolism alteration behind different etiology, diagnosis, and prognosis of disorders of consciousness.

BACKGROUND: Patients with disorders of consciousness (DoC) exhibit varied revival outcomes based on different etiologies and diagnoses, the mechanisms of which remain largely unknown. The fluctuating clinical presentations in DoC pose challenges in accurately assessing consciousness levels and prognoses, often leading to misdiagnoses. There is an urgent need for a deeper understanding of the physiological changes in DoC and the development of objective diagnostic and prognostic biomarkers to improve treatment guidance. METHODS: To explore biomarkers and understand the biological processes, we conducted a comprehensive untargeted metabolomic analysis on serum samples from 48 patients with DoC. Patients were categorized based on etiology (TBI vs. non-TBI), CRS-R scores, and prognosis. Advanced analytical techniques, including PCA and OPLS-DA models, were employed to identify differential metabolites. RESULTS: Our analysis revealed a distinct separation in metabolomic profiles among the different groups. The primary differential metabolites distinguishing patients with varying etiologies were predominantly phospholipids, with a notable decrease in glycerophospholipids observed in the TBI group. Patients with higher CRS-R scores exhibited a pattern of impaired carbohydrate metabolism coupled with enhanced lipid metabolism. Notably, serum concentrations of both LysoPE and PE were reduced in patients with improved outcomes, suggesting their potential as prognostic biomarkers. CONCLUSIONS: Our study underscores the critical role of phospholipid metabolism in the brain's metabolic alterations in patients with DoC. It identifies key biomarkers for diagnosis and prognosis, offering insights that could lead to novel therapeutic targets. These findings highlight the value of metabolomic profiling in understanding and potentially treating DoC.

Temporal and spatial variability of dynamic microstate brain network in disorders of consciousness.

BACKGROUND: Accurately diagnosing patients with the vegetative state (VS) and the minimally conscious state (MCS) reached a misdiagnosis of approximately 40%. METHODS: A method combined microstate and dynamic functional connectivity (dFC) to study the spatiotemporal variability of the brain in disorders of consciousness (DOC) patients was proposed. Resting-state EEG data were obtained from 16 patients with MCS and 16 patients with VS. Mutual information (MI) was used to assess the EEG connectivity in each microstate. MI-based features with statistical differences were selected as the total feature subset (TFS), then the TFS was utilized to feature selection and fed into the classifier, obtaining the optimal feature subsets (OFS) in each microstate. Subsequently, an OFS-based MI functional connectivity network (MIFCN) was constructed in the cortex. RESULTS: The group-average MI connectivity matrix focused on all channels revealed that all five microstates exhibited stronger information interaction in the MCS when comparing with the VS. While OFS-based MIFCN, which only focused on a few channels, revealed greater MI flow in VS patients than in MCS patients under microstates A, B, C, and E, except for microstate D. Additionally, the average classification accuracy of OFS in the five microstates was 96.2%. CONCLUSION: Constructing features based on microstates to distinguish between two categories of DOC patients had effectiveness.

Circ_BLNK is a Unique Molecular Marker in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) patients are characterized by distant metastasis and poor prognosis. Growing evidence has implied that circular RNAs (circRNAs) are involved in multiple tumor progression, including NSCLC. The objective of the present study was to functionally dissect the role and mechanism of circ_BLNK in NSCLC development and progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of circ_BLNK, miR-942-5p, and forkhead box protein O1 (FOXO1) in NSCLC tissues and cells. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay and colony formation assay detected cell proliferation; the protein expression levels were tested by western blot assay; cell apoptosis was measured by flow cytometry, and transwell assay detected cell migration and invasion. The molecular targeting relationship was determined by dual-luciferase reporter assay. The effect of circ_BLNK overexpression on tumor growth was detected by in vivo experiments and immunohistochemistry. Circ_BLNK was dramatically decreased in NSCLC, and overexpression of circ_BLNK inhibited proliferation, migration, and invasion of NSCLC cells and promoted cell apoptosis. Circ_BLNK level was negatively correlated with miR-942-5p expression and positively correlated with FOXO1 expression. Moreover, circ_BLNK acted as a sponge for miR-942-5p, which targeted FOXO1. Rescue assays presented that miR-942-5p reversed the anticancer action of circ_BLNK in NSCLC. Besides that, miR-942-5p inhibition suppressed the oncogenic behaviors, which were attenuated by FOXO1 knockdown. Animal experiments exhibited that circ_BLNK upregulation repressed tumor growth in vivo. Our study demonstrated a novel regulatory mechanism that circ_BLNK/miR-942-5p/FOXO1 axis adjusted non-small cell lung cancer development.

Global Field Time-Frequency Representation-Based Discriminative Similarity Analysis of Passive Auditory ERPs for Diagnosis of Disorders of Consciousness.

Behavioural diagnosis of patients with disorders of consciousness (DOC) is challenging and prone to inaccuracies. Consequently, there have been increased efforts to develop bedside assessment based on EEG and event-related potentials (ERPs) that are more sensitive to the neural factors supporting conscious awareness. However, individual detection of residual consciousness using these techniques is less established. Here, we hypothesize that the cross-state similarity (defined as the similarity between healthy and impaired conscious states) of passive brain responses to auditory stimuli can index the level of awareness in individual DOC patients. To this end, we introduce the global field time-frequency representation-based discriminative similarity analysis (GFTFR-DSA). This method quantifies the average cross-state similarity index between an individual patient and our constructed healthy templates using the GFTFR as an EEG feature. We demonstrate that the proposed GFTFR feature exhibits superior within-group consistency in 34 healthy controls over traditional EEG features such as temporal waveforms. Second, we observed the GFTFR-based similarity index was significantly higher in patients with a minimally conscious state (MCS, 40 patients) than those with unresponsive wakefulness syndrome (UWS, 54 patients), supporting our hypothesis. Finally, applying a linear support vector machine classifier for individual MCS/UWS classification, the model achieved a balanced accuracy and F1 score of 0.77. Overall, our findings indicate that combining discriminative and interpretable markers, along with automatic machine learning algorithms, is effective for the differential diagnosis in patients with DOC. Importantly, this approach can, in principle, be transferred into any ERP of interest to better inform DOC diagnoses.

Combined behavioral and EEG evidence for the 70 Hz frequency selection of short-term spinal cord stimulation in disorders of consciousness.

OBJECTIVES: This study investigated the prognostic effect of electroencephalography (EEG) instant effects of single spinal cord stimulation (SCS) on clinical outcome in disorders of consciousness (DOC) and the time-dependent brain response during the recovery of consciousness prompted by SCS. METHODS: Twenty three patients with DOC underwent short-term SCS (stSCS) implantation operation. Then, all patients received the postoperative EEG test including EEG record before (T1) and after (T2) single SCS session. Subsequently, 2 weeks stSCS treatment was performed and revised coma recovery scale (CRS-R) and EEG data were collected. Finally, they were classified into effective and ineffective groups at 3-month follow-up (T6). RESULTS: The parietal-occipital (PO) connectivity and clustering coefficients (CC) in the beta band of the effective group at the 1 week after the treatment (T5) were found to be higher than preoperative assessment (T0). Correlation analysis showed that the change in beta CC at T1/T2 was correlated with the change in CRS-R at T0/T6. In addition, the change in PO connectivity and CC in the beta at T0/T5 were also correlated with the change in CRS-R at T0/T5. CONCLUSION: SCS may facilitate the recovery of consciousness by enhancing local information interaction in posterior brain regions. And the recovery can be predicted by beta CC in the EEG test.

Clinical neuromodulatory effects of deep brain stimulation in disorder of consciousness: A literature review.

BACKGROUND: The management of patients with disorders of consciousness (DOC) presents substantial challenges in clinical practice. Deep brain stimulation (DBS) has emerged as a potential therapeutic approach, but the lack of standardized regulatory parameters for DBS in DOC hinders definitive conclusions. OBJECTIVE: This comprehensive review aims to provide a detailed summary of the current issues concerning patient selection, target setting, and modulation parameters in clinical studies investigating the application of DBS for DOC patients. METHODS: A meticulous systematic analysis of the literatures was conducted, encompassing articles published from 1968 to April 2023, retrieved from reputable databases (PubMed, Embase, Medline, and Web of Science). RESULTS: The systematic analysis of 21 eligible articles, involving 146 patients with DOC resulting from acquired brain injury or other disorders, revealed significant insights. The most frequently targeted regions were the Centromedian-parafascicular complex (CM-pf) nuclei and central thalamus (CT), both recognized for their role in regulating consciousness. However, other targets have also been explored in different studies. The stimulation frequency was predominantly set at 25 or 100 Hz, with pulse width of 120 µs, and voltages ranged from 0 to 4 V. These parameters were customized based on individual patient responses and evaluations. The overall clinical efficacy rate in all included studies was 39.7%, indicating a positive effect of DBS in a subset of DOC patients. Nonetheless, the assessment methods, follow-up durations, and outcome measures varied across studies, potentially contributing to the variability in reported efficacy rates. CONCLUSION: Despite the challenges arising from the lack of standardized parameters, DBS shows promising potential as a therapeutic option for patients with DOC. However, there still remains the need for standardized protocols and assessment methods, which are crucial to deepen the understanding and optimizing the therapeutic potential of DBS in this specific patient population.

The EEG complexity, information integration and brain network changes in minimally conscious state patients during general anesthesia.

Objective.General anesthesia (GA) can induce reversible loss of consciousness. Nonetheless, the electroencephalography (EEG) characteristics of patients with minimally consciousness state (MCS) during GA are seldom observed.Approach.We recorded EEG data from nine MCS patients during GA. We used the permutation Lempel-Ziv complexity (PLZC), permutation fluctuation complexity (PFC) to quantify the type I and II complexities. Additionally, we used permutation cross mutual information (PCMI) and PCMI-based brain network to investigate functional connectivity and brain networks in sensor and source spaces.Main results.Compared to the preoperative resting state, during the maintenance of surgical anesthesia state, PLZC decreased (p< 0.001), PFC increased (p< 0.001) and PCMI decreased (p< 0.001) in sensor space. The results for these metrics in source space are consistent with sensor space. Additionally, node network indicators nodal clustering coefficient (NCC) (p< 0.001) and nodal efficiency (NE) (p< 0.001) decreased in these two spaces. Global network indicators normalized average path length (Lave/Lr) (p< 0.01) and modularity (Q) (p< 0.05) only decreased in sensor space, while the normalized average clustering coefficient (Cave/Cr) and small-world index (σ) did not change significantly. Moreover, the dominance of hub nodes is reduced in frontal regions in these two spaces. After recovery of consciousness, PFC decreased in the two spaces, while PLZC, PCMI increased. NCC, NE, and frontal region hub node dominance increased only in the sensor space. These indicators did not return to preoperative levels. In contrast, global network indicatorsLave/LrandQwere not significantly different from the preoperative resting state in sensor space.Significance.GA alters the complexity of the EEG, decreases information integration, and is accompanied by a reconfiguration of brain networks in MCS patients. The PLZC, PFC, PCMI and PCMI-based brain network metrics can effectively differentiate the state of consciousness of MCS patients during GA.

EEG Changes during Propofol Anesthesia Induction in Vegetative State Patients Undergoing Spinal Cord Stimulation Implantation Surgery.

OBJECTIVE: To compare the EEG changes in vegetative state (VS) patients and non-craniotomy, non-vegetative state (NVS) patients during general anesthesia with low-dose propofol and to find whether it affects the arousal rate of VS patients. METHODS: Seven vegetative state patients (VS group: five with traumatic brain injury, two with ischemic-hypoxic VS) and five non-craniotomy, non-vegetative state patients (NVS group) treated in the Department of Neurosurgery, Peking University International Hospital from January to May 2022 were selected. All patients were induced with 0.5 mg/kg propofol, and the Bispectral Index (BIS) changes within 5 min after administration were observed. Raw EEG signals and perioperative EEG signals were collected and analyzed using EEGLAB in the MATLAB software environment, time-frequency spectrums were calculated, and EEG changes were analyzed using power spectrums. RESULTS: There was no significant difference in the general data before surgery between the two groups (p > 0.05); the BIS reduction in the VS group was significantly greater than that in the NVS group at 1 min, 2 min, 3 min, 4 min, and 5 min after 0.5 mg/kg propofol induction (p < 0.05). Time-frequency spectrum analysis showed the following: prominent α band energy around 10 Hz and decreased high-frequency energy in the NVS group, decreased high-frequency energy and main energy concentrated below 10 Hz in traumatic brain injury VS patients, higher energy in the 10-20 Hz band in ischemic-hypoxic VS patients. The power spectrum showed that the brain electrical energy of the NVS group was weakened R5 min after anesthesia induction compared with 5 min before induction, mainly concentrated in the small wave peak after 10 Hz, i.e., the α band peak; the energy of traumatic brain injury VS patients was weakened after anesthesia induction, but no α band peak appeared; and in ischemic-hypoxic VS patients, there was no significant change in low-frequency energy after anesthesia induction, high-frequency energy was significantly weakened, and a clear α band peak appeared slightly after 10 Hz. Three months after the operation, follow-up visits were made to the VS group patients who had undergone SCS surgery. One patient with traumatic brain injury VS was diagnosed with MCS-, one patient with ischemic-hypoxic VS had increased their CRS-R score by 1 point, and the remaining five patients had no change in their CRS scores. CONCLUSIONS: Low doses of propofol cause great differences in the EEG of different types of VS patients, which may be the unique response of damaged nerve cell residual function to propofol, and these weak responses may also be the basis of brain recovery.

Electrophysiological characteristics of CM-pf in diagnosis and outcome of patients with disorders of consciousness.

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

Untargeted Metabolomic Analyses of Body Fluids to Differentiate TBI DOC and NTBI DOC.

OBJECTIVE: To investigate the metabolomic differences between Traumatic brain injury (TBI) disorder of consciousness (DOC) patients and non-traumatic brain injury (NTBI) DOC patients by using cerebrospinal fluid (CSF), serum and urine samples beneficial to understand the pathological mechanism differences between the two etiologies, provide potential clues for the subsequent treatment and prognosis, and investigate the metabolome differences and similarities between TBI and NTBI among three different body fluids. METHODS: In total, 24 TBI DOC subjects and 29 NTBI DOC subjects were enrolled. CSF, serum and urine samples from TBI DOC and NTBI DOC patients were collected and analyzed by performing UPLC-MS. The statistical methods and pathway analyses were applied to discover potential biomarkers and altered metabolic functions. RESULTS: When comparing TBI DOC and NTBI DOC, 36, 31 and 52 differential metabolites were obtained in CSF, serum and urine, respectively. The functional analysis of differential metabolites obtained in CSF, serum and urine were all related to amino acid metabolism. Except for amino acid metabolism, metabolic biomarkers in CSF, serum and urine mainly focus on central function, cognitive function, necrosis and apoptosis and neurological function, respectively. In CSF, the highest AUC was 0.864 (Isoproturon) and 0.816 (Proline betaine). Then, the AUC of NFurfurylformamide in serum was 0.941, while the AUC of Dihydronepetalactone and Doxepin N-oxide glucuronide were 1.0 in urine. CONCLUSION: CSF, serum and urine metabolomic analyses could differentiate TBI DOC from NTBI DOC and functional analyses showed a metabolic change difference between TBI DOC and NTBI DOC.

Effects of simultaneous transcutaneous auricular vagus nerve stimulation and high-definition transcranial direct current stimulation on disorders of consciousness: a study protocol.

Background: Non-invasive brain stimulation (NIBS) techniques are now widely used in patients with disorders of consciousness (DOC) for accelerating their recovery of consciousness, especially minimally conscious state (MCS). However, the effectiveness of single NIBS techniques for consciousness rehabilitation needs further improvement. In this regard, we propose to enhance from bottom to top the thalamic-cortical connection by using transcutaneous auricular vagus nerve stimulation (taVNS) and increase from top to bottom cortical-cortical connections using simultaneous high-definition transcranial direct current stimulation (HD-tDCS) to reproduce the network of consciousness. Methods/design: The study will investigate the effect and safety of simultaneous joint stimulation (SJS) of taVNS and HD-tDCS for the recovery of consciousness. We will enroll 84 MCS patients and randomize them into two groups: a single stimulation group (taVNS and HD-tDCS) and a combined stimulation group (SJS and sham stimulation). All patients will undergo a 4-week treatment. The primary outcome will be assessed using the coma recovery scale-revised (CRS-R) at four time points to quantify the effect of treatment: before treatment (T0), after 1 week of treatment (T1), after 2 weeks of treatment (T2), and after 4 weeks of treatment (T3). At the same time, nociception coma scale-revised (NCS-R) and adverse effects (AEs) will be collected to verify the safety of the treatment. The secondary outcome will involve an analysis of electroencephalogram (EEG) microstates to assess the response mechanisms of dynamic brain networks to SJS. Additionally, CRS-R and AEs will continue to be obtained for a 3-month follow-up (T4) after the end of the treatment. Discussion: This study protocol aims to innovatively develop a full-time and multi-brain region combined neuromodulation paradigm based on the mesocircuit model to steadily promote consciousness recovery by restoring thalamocortical and cortical-cortical interconnections.

Altered brain functional connectivity in vegetative state and minimally conscious state.

Objectives: The pathological mechanism for a disorder of consciousness (DoC) is still not fully understood. Based on traditional behavioral scales, there is a high rate of misdiagnosis for subtypes of DoC. We aimed to explore whether topological characterization may explain the pathological mechanisms of DoC and be effective in diagnosing the subtypes of DoC. Methods: Using resting-state functional magnetic resonance imaging data, the weighted brain functional networks for normal control subjects and patients with vegetative state (VS) and minimally conscious state (MCS) were constructed. Global and local network characteristics of each group were analyzed. A support vector machine was employed to identify MCS and VS patients. Results: The average connection strength was reduced in DoC patients and roughly equivalent in MCS and VS groups. Global efficiency, local efficiency, and clustering coefficients were reduced, and characteristic path length was increased in DoC patients (p < 0.05). For patients of both groups, global network measures were not significantly different (p > 0.05). Nodal efficiency, nodal local efficiency, and nodal clustering coefficient were reduced in frontoparietal brain areas, limbic structures, and occipital and temporal brain areas (p < 0.05). The comparison of nodal centrality suggested that DoC causes reorganization of the network structure on a large scale, especially the thalamus. Lobal network measures emphasized that the differences between the two groups of patients mainly involved frontoparietal brain areas. The accuracy, sensitivity, and specificity of the classifier for identifying MCS and VS patients were 89.83, 78.95, and 95%, respectively. Conclusion: There is an association between altered network structures and clinical symptoms of DoC. With the help of network metrics, it is feasible to differentiate MCS and VS patients.

Cerebrospinal fluid metabolite alterations in patients with different etiologies, diagnoses, and prognoses of disorders of consciousness.

INTRODUCTION: Medical management of disorders of consciousness (DoC) is a growing issue imposing a major burden on families and societies. Recovery rates vary widely among patients with DoC, and recovery predictions strongly influence decisions on medical care. However, the specific mechanisms underlying different etiologies, consciousness levels, and prognoses are still unclear. METHODS: We analyzed the comprehensive cerebrospinal fluid (CSF) metabolome through liquid chromatography-mass spectrometry. Metabolomic analyses were used to identify the metabolic differences between patients with different etiologies, diagnoses, and prognoses. RESULTS: We found that the CSF levels of multiple acylcarnitines were lower in patients with traumatic DoC, suggesting mitochondrial function preservation in the CNS, which might contribute to the better consciousness outcomes of these patients. Metabolites related to glutamate and GABA metabolism were altered and showed a good ability to distinguish the patients in the minimally conscious state and the vegetative state. Moreover, we identified 8 phospholipids as potential biomarkers to predict the recovery of consciousness. CONCLUSIONS: Our findings shed light on the differences in physiological activities underlying DoC with different etiologies and identified some potential biomarkers used for DoC diagnosis and prognosis.

The Characteristics of Electroencephalogram Signatures in Minimally Conscious State Patients Induced by General Anesthesia.

OBJECTIVE: General anesthesia (GA) is necessary for surgery, even for patients in a minimally conscious state (MCS). The characteristics of the electroencephalogram (EEG) signatures of the MCS patients under GA are still unclear. METHODS: The EEG during GA were recorded from 10 MCS patients undergoing spinal cord stimulation surgery. The power spectrum, phase-amplitude coupling (PAC), the diversity of connectivity, and the functional network were investigated. Long term recovery was assessed by the Coma Recovery Scale-Revised at one year after the surgery, and the characteristics of the patients with good or bad prognosis status were compared. RESULTS: For the four MCS patients with good prognostic recovery, slow oscillation (0.1-1 Hz) and the alpha band (8-12 Hz) in the frontal areas increased during the maintenance of a surgical state of anesthesia (MOSSA), and "peak-max" and "trough-max" patterns emerged in frontal and parietal areas. During MOSSA, the six MCS patients with bad prognosis demonstrated: increased modulation index, reduced diversity of connectivity (from mean±SD of 0.877 ± 0.003 to 0.776 ± 0.003, p < 0.001), reduced function connectivity significantly in theta band (from mean±SD of 1.032 ± 0.043 to 0.589 ± 0.036, p < 0.001, in prefrontal-frontal; and from mean±SD of 0.989 ± 0.043 to 0.684 ± 0.036, p < 0.001, in frontal-parietal) and reduced local and global efficiency of the network in delta band. CONCLUSIONS: A bad prognosis in MCS patients is associated with signs of impaired thalamocortical and cortico-cortical connectivity - as indicated by inability to produce inter-frequency coupling and phase synchronization. These indices may have a role in predicting the long-term recovery of MCS patients.

EEG microstate changes during hyperbaric oxygen therapy in patients with chronic disorders of consciousness.

Hyperbaric oxygen (HBO) therapy is an effective treatment for patients with disorders of consciousness (DOC). In this study, real-time electroencephalogram (EEG) recordings were obtained from patients with DOC during HBO therapy. EEG microstate indicators including mean microstate duration (MMD), ratio of total time covered (RTT), global explained variance (GEV), transition probability, mean occurrence, and mean global field power (GFP) were compared before and during HBO therapy. The results showed that the duration of microstate C in all patients with DOC increased after 20 min of HBO therapy (p < 0.05). Further statistical analysis found that the duration of microstate C was longer in the higher CRS-R group (≥8, 17 cases) than in the lower group (<8, 24 cases) during HBO treatment. In the higher CRS-R group, the transition probabilities from microstate A to microstate C and from microstate C to microstate A also increased significantly compared with the probability before treatment (p < 0.05). Microstate C is generally considered to be related to a salience network; an increase in the transition probability between microstate A and microstate C indicates increased information exchange between the auditory network and the salience network. The results of this study show that HBO therapy has a specific activating effect on attention and cognitive control in patients and causes increased activity in the primary sensory cortex (temporal lobe and occipital lobe). This study demonstrates that real-time EEG detection and analysis during HBO is a clinically feasible method for assessing brain function in patients with DOC. During HBO therapy, some EEG microstate indicators show significant changes related to the state of consciousness in patients with chronic DOC. This will be complementary to important electrophysiological indicators for assessing consciousness and may also provide an objective foundation for the precise treatment of patients with DOC.

Acute traumatic coma awakening by right median nerve electrical stimulation: a randomised controlled trial.

PURPOSE: Severe traumatic brain injury (TBI) leads to acute coma and may result in prolonged disorder of consciousness (pDOC). We aimed to determine whether right median nerve electrical stimulation is a safe and effective treatment for accelerating emergence from coma after TBI. METHODS: This randomised controlled trial was performed in 22 centres in China. Participants with acute coma at 7-14 days after TBI were randomly assigned (1:1) to either routine therapy and right median nerve electrical stimulation (RMNS group) or routine treatment (control group). The RMNS group received 20 mA, 300 µs, 40 Hz stimulation pulses, lasting 20 s per minutes, 8 h per day, for 2 weeks. The primary outcome was the proportion of patients who regained consciousness 6 months post-injury. The secondary endpoints were Glasgow Coma Scale (GCS), Full Outline of Unresponsiveness scale (FOUR), Coma Recovery Scale-Revised (CRS-R), Disability Rating Scale (DRS) and Glasgow Outcome Scale Extended (GOSE) scores reported as medians on day 28, 3 months and 6 months after injury, and GCS and FOUR scores on day 1 and day 7 during stimulation. Primary analyses were based on the intention-to-treat set. RESULTS: Between March 26, 2016, and October 18, 2020, 329 participants were recruited, of whom 167 were randomised to the RMNS group and 162 to the control group. At 6 months post-injury, a higher proportion of patients in the RMNS group regained consciousness compared with the control group (72.5%, n = 121, 95% confidence interval (CI) 65.2-78.7% vs. 56.8%, n = 92, 95% CI 49.1-64.2%, p = 0.004). GOSE at 3 months and 6 months (5 [interquartile range (IQR) 3-7] vs. 4 [IQR 2-6], p = 0.002; 6 [IQR 3-7] vs. 4 [IQR 2-7], p = 0.0005) and FOUR at 28 days (15 [IQR 13-16] vs. 13 [interquartile range (IQR) 11-16], p = 0.002) were significantly increased in the RMNS group compared with the control group. Trajectory analysis showed that significantly more patients in the RMNS group had faster GCS, CRS-R and DRS improvement (p = 0.01, 0.004 and 0.04, respectively). Adverse events were similar in both groups. No serious adverse events were associated with the stimulation device. CONCLUSION: Right median nerve electrical stimulation is a possible effective treatment for patients with acute traumatic coma, that will require validation in a confirmatory trial.

Evaluation of residual cognition in patients with disorders of consciousness based on functional near-infrared spectroscopy.

Significance: Accurate evaluation of consciousness in patients with prolonged disorders of consciousness (DOC) is critical for designing therapeutic plans, determining rehabilitative services, and predicting prognosis. Effective ways for detecting consciousness in patients with DOC are still needed. Aim: Evaluation of the residual awareness in patients with DOC and investigation of the spatiotemporal differences in the hemodynamic responses between the minimally conscious state (MCS) and the unresponsive wakefulness syndrome (UWS) groups using active command-driven motor imagery (MI) tasks. Approach: In this study, functional near-infrared spectroscopy (fNIRS) was used to measure the changes of hemodynamic responses in 19 patients with DOC (9 MCS and 10 UWS) using active command-driven MI tasks. The characteristics of the hemodynamic responses were extracted to compare the differences between the MCS and UWS groups. Moreover, the correlations between the hemodynamic responses and the clinical behavioral evaluations were also studied. Results: The results showed significant differences in the spatiotemporal distribution of the hemodynamic responses between the MCS and UWS groups. For the patients with MCS, significant increases in task-evoked hemodynamic responses occurred during the "YES" questions of the command-driven MI tasks. Importantly, these changes were significantly correlated with their coma-recovery scale-revised (CRS-R) scores. However, for the patients with UWS, no significant changes of the hemodynamic responses were found. Additionally, the results did not show any statistical correlation between the hemodynamic responses and their CRS-R scores. Conclusions: The fNIRS-based command-driven MI tasks can be used as a promising tool for detecting residual awareness in patients with DOC. We hope that the findings and the active paradigm used in this study will provide useful insights into the diagnosis, therapy, and prognosis of this challenging patient population.

EEG complexity correlates with residual consciousness level of disorders of consciousness.

BACKGROUND AND OBJECTIVE: Electroencephalography (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. METHODS: Resting-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. RESULTS: PLZC 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. CONCLUSION: Neural complexity measured on EEG correlates with residual consciousness levels of DOC patients. PLZC showed higher sensitivity than LZC in the classification of consciousness levels.

Optimizing the modulation paradigm of transcutaneous auricular vagus nerve stimulation in patients with disorders of consciousness: A prospective exploratory pilot study protocol.

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique. Several studies have reported the effectiveness of taVNS in patients with disorders of consciousness (DOC); however, differences in the modulation paradigm have led to inconsistent treatment outcomes. Methods/design: This prospective exploratory trial will include 15 patients with a minimally conscious state (MCS) recruited according to the coma recovery scale-revised (CRS-R). Each patient will receive 5 different frequencies of taVNS (1, 10, 25, 50, and 100 Hz); sham stimulation will be used as a blank control. The order of stimulation will be randomized, and the patients' CRS-R scores and resting electroencephalography (EEG) before and after stimulation will be recorded. Discussion: The overall study of taVNS used in treating patients with DOC is still in the preliminary stage of exploration. Through this experiment, we aim to explore the optimal stimulation frequency parameters of taVNS for the treatment of DOC patients. Furthermore, we expect to achieve a stable improvement of consciousness in DOC patients by continuously optimizing the neuromodulation paradigm of taVNS for the treatment of DOC patients. Clinical trial registration: https://www.chictr.org.cn/index.aspx, identifier ChiCTR 2200063828.

Long-term functional outcomes improved with deep brain stimulation in patients with disorders of consciousness.

BACKGROUND: Deep brain stimulation (DBS) has been preliminarily applied to treat patients with disorders of consciousness (DoCs). The study aimed to determine whether DBS was effective for treating patients with DoC and identify factors related to patients' outcomes. METHODS: Data from 365 patients with DoCs who were consecutively admitted from 15 July 2011 to 31 December 2021 were retrospectively analysed. Multivariate regression and subgroup analysis were performed to adjust for potential confounders. The primary outcome was improvement in consciousness at 1 year. RESULTS: An overall improvement in consciousness at 1 year was achieved in 32.4% (12/37) of the DBS group compared with 4.3% (14/328) of the conservative group. After full adjustment, DBS significantly improved consciousness at 1 year (adjusted OR 11.90, 95% CI 3.65-38.46, p<0.001). There was a significant treatment×follow up interaction (H=14.99, p<0.001). DBS had significantly better effects in patients with minimally conscious state (MCS) compared with patients with vegetative state/unresponsive wakefulness syndrome (p for interaction <0.001). A nomogram based on age, state of consciousness, pathogeny and duration of DoCs indicated excellent predictive performance (c-index=0.882). CONCLUSIONS: DBS was associated with better outcomes in patients with DoC, and the effect was likely to be significantly greater in patients with MCS. DBS should be cautiously evaluated by nomogram preoperatively, and randomised controlled trials are still needed.