Feasibility and Validity of the Coma Recovery Scale-Revised for Accelerated Standardized Testing: A Practical Assessment Tool for Detecting Consciousness in the Intensive Care Unit.

We developed and validated an abbreviated version of the Coma Recovery Scale-Revised (CRS-R), the CRS-R For Accelerated Standardized Testing (CRSR-FAST), to detect conscious awareness in patients with severe traumatic brain injury in the intensive care unit. In 45 consecutively enrolled patients, CRSR-FAST administration time was approximately one-third of the full-length CRS-R (mean [SD] 6.5 [3.3] vs 20.1 [7.2] minutes, p < 0.0001). Concurrent validity (simple kappa 0.68), test-retest (Mak's ρ = 0.76), and interrater (Mak's ρ = 0.91) reliability were substantial. Sensitivity, specificity, and accuracy for detecting consciousness were 81%, 89%, and 84%, respectively. The CRSR-FAST facilitates serial assessment of consciousness, which is essential for diagnostic and prognostic accuracy. ANN NEUROL 2023;94:919-924.

Noninvasive Brain Stimulation Therapies to Promote Recovery of Consciousness: Where We Are and Where We Should Go.

Therapeutic options for patients with disorders of consciousness (DoC) are still underexplored. Noninvasive brain stimulation (NIBS) techniques modulate neural activity of targeted brain areas and hold promise for the treatment of patients with DoC. In this review, we provide a summary of published research using NIBS as therapeutic intervention for DoC patients, with a focus on (but not limited to) randomized controlled trials (RCT). We aim to identify current challenges and knowledge gaps specific to NIBS research in DoC. Furthermore, we propose possible solutions and perspectives for this field. Thus far, the most studied technique remains transcranial electrical stimulation; however, its effect remains moderate. The identified key points that NIBS researchers should focus on in future studies are (1) the lack of large-scale RCTs; (2) the importance of identifying the endotypes of responders; and (3) the optimization of stimulation parameters to maximize the benefits of NIBS.

Transcranial Pulsed-Current Stimulation versus Transcranial Direct Current Stimulation in Patients with Disorders of Consciousness: A Pilot, Sham-Controlled Cross-Over Double-Blind Study.

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

Quantifying arousal and awareness in altered states of consciousness using interpretable deep learning.

Consciousness can be defined by two components: arousal (wakefulness) and awareness (subjective experience). However, neurophysiological consciousness metrics able to disentangle between these components have not been reported. Here, we propose an explainable consciousness indicator (ECI) using deep learning to disentangle the components of consciousness. We employ electroencephalographic (EEG) responses to transcranial magnetic stimulation under various conditions, including sleep (n = 6), general anesthesia (n = 16), and severe brain injury (n = 34). We also test our framework using resting-state EEG under general anesthesia (n = 15) and severe brain injury (n = 34). ECI simultaneously quantifies arousal and awareness under physiological, pharmacological, and pathological conditions. Particularly, ketamine-induced anesthesia and rapid eye movement sleep with low arousal and high awareness are clearly distinguished from other states. In addition, parietal regions appear most relevant for quantifying arousal and awareness. This indicator provides insights into the neural correlates of altered states of consciousness.

Diagnosing Level of Consciousness: The Limits of the Glasgow Coma Scale Total Score.

In nearly all clinical and research contexts, the initial severity of a traumatic brain injury (TBI) is measured using the Glasgow Coma Scale (GCS) total score. The GCS total score however, may not accurately reflect level of consciousness, a critical indicator of injury severity. We investigated the relationship between GCS total scores and level of consciousness in a consecutive sample of 2455 adult subjects assessed with the GCS 69,487 times as part of the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We assigned each GCS subscale score combination a level of consciousness rating based on published criteria for the following disorders of consciousness (DoC) diagnoses: coma, vegetative state/unresponsive wakefulness syndrome, minimally conscious state, and post-traumatic confusional state, and present our findings using summary statistics and four illustrative cases. Participants had the following characteristics: mean (standard deviation) age 41.9 (17.6) years, 69% male, initial GCS 3-8 = 13%; 9-12 = 5%; 13-15 = 82%. All GCS total scores between 4-14 were associated with more than one DoC diagnosis; the greatest variability was observed for scores of 7-11. Further, a wide range of total scores was associated with identical DoC diagnoses. Importantly, a diagnosis of coma was only possible with GCS total scores of 3-6. The GCS total score does not accurately reflect level of consciousness based on published DoC diagnostic criteria. To improve the classification of patients with TBI and to inform the design of future clinical trials, clinicians and investigators should consider individual subscale behaviors and more comprehensive assessments when evaluating TBI severity.

Preservation of Brain Activity in Unresponsive Patients Identifies MCS Star.

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.

A novel closed-loop EEG-tDCS approach to promote responsiveness of patients in minimally conscious state: A study protocol.

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.

SECONDs Administration Guidelines: A Fast Tool to Assess Consciousness in Brain-injured Patients.

Establishing an accurate diagnosis is crucial for patients with disorders of consciousness (DoC) following a severe brain injury. The Coma Recovery Scale-Revised (CRS-R) is the recommended behavioral scale for assessing the level of consciousness among these patients, but its long duration of administration is a major hurdle in clinical settings. The Simplified Evaluation of CONsciousness Disorders (SECONDs) is a shorter scale that was developed to tackle this issue. It consists of six mandatory items, observation, command-following, visual pursuit, visual fixation, oriented behaviors, and arousal, and two conditional items, communication and localization to pain. The score ranges between 0 and 8 and corresponds to a specific diagnosis (i.e., coma, unresponsive wakefulness syndrome, minimally conscious state minus/plus, or emergence from the minimally conscious state). A first validation study on patients with prolonged DoC showed high concurrent validity and intra- and inter-rater reliability. The SECONDs requires less training than the CRS-R and its administration lasts about 7 minutes (interquartile range: 5-9 minutes). An additional index score allows the more precise tracking of a patient's behavioral fluctuation or evolution over time. The SECONDs is therefore a fast and valid tool for assessing the level of consciousness in patients with severe brain injury. It can easily be used by healthcare staff and implemented in time-constrained clinical settings, such as intensive care units, to help decrease misdiagnosis rates and to optimize treatment decisions. These administration guidelines provide detailed instructions for administering the SECONDs in a standardized and reproducible manner, which is an essential requirement for achieving a reliable diagnosis.

Behavioral and electrophysiological effects of network-based frontoparietal tDCS in patients with severe brain injury: A randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) may promote the recovery of severely brain-injured patients with disorders of consciousness (DOC). Prior tDCS studies targeted single brain regions rather than brain networks critical for consciousness recovery. OBJECTIVE: Investigate the behavioral and electrophysiological effects of multifocal tDCS applied over the frontoparietal external awareness network in patients with chronic acquired DOC. METHODS: Forty-six patients were included in this randomized double-blind sham-controlled crossover trial (median [interquartile range]: 46 [35 - 59] years old; 12 [5 - 47] months post injury; 17 unresponsive wakefulness syndrome, 23 minimally conscious state (MCS) and 6 emerged from the MCS). Multifocal tDCS was applied for 20 min using 4 anodes and 4 cathodes with 1 mA per electrode. Coma Recovery Scale-Revised (CRS-R) assessment and 10 min of resting state electroencephalogram (EEG) recordings were acquired before and after the active and sham sessions. RESULTS: At the group level, there was no tDCS behavioral treatment effect. However, following active tDCS, the EEG complexity significantly increased in low frequency bands (1-8 Hz). CRS-R total score improvement was associated with decreased baseline complexity in those bands. At the individual level, after active tDCS, new behaviors consistent with conscious awareness emerged in 5 patients. Conversely, 3 patients lost behaviors consistent with conscious awareness. CONCLUSION: The behavioral effect of multifocal frontoparietal tDCS varies across patients with DOC. Electrophysiological changes were observed in low frequency bands but not translated into behavioral changes at the group level.

Neurophysiological Correlates of a Single Session of Prefrontal tDCS in Patients with Prolonged Disorders of Consciousness: A Pilot Double-Blind Randomized Controlled Study.

Background. Transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) was reported to promote the recovery of signs of consciousness in some patients in a minimally conscious state (MCS), but its electrophysiological effects on brain activity remain poorly understood. Objective. We aimed to assess behavioral (using the Coma Recovery Scale-Revised; CRS-R) and neurophysiological effects (using high density electroencephalography; hdEEG) of lDLPFC-tDCS in patients with prolonged disorders of consciousness (DOC). Methods. In a double-blind, sham-controlled, crossover design, one active and one sham tDCS (2 mA, 20 min) were delivered in a randomized order. Directly before and after tDCS, 10 min of hdEEG were recorded and the CRS-R was administered. Results. Thirteen patients with severe brain injury were enrolled in the study. We found higher relative power at the group level after the active tDCS session in the alpha band in central regions and in the theta band over the frontal and posterior regions (uncorrected results). Higher weighted symbolic mutual information (wSMI) connectivity was found between left and right parietal regions, and higher fronto-parietal weighted phase lag index (wPLI) connectivity was found, both in the alpha band (uncorrected results). At the group level, no significant treatment effect was observed. Three patients showed behavioral improvement after the active session and one patient improved after the sham. Conclusion. We provide preliminary indications that neurophysiological changes can be observed after a single session of tDCS in patients with prolonged DOC, although they are not necessarily paralleled with significant behavioral improvements.

Noninvasive motor cortex stimulation effects on quantitative sensory testing in healthy and chronic pain subjects: a systematic review and meta-analysis.

ABSTRACT: One of the potential mechanisms of motor cortex stimulation by noninvasive brain stimulation (NIBS) effects on pain is through the restoration of the defective endogenous inhibitory pain pathways. However, there are still limited data on quantitative sensory testing (QST), including conditioned pain modulation (CPM), supporting this mechanism. This systematic review and meta-analysis aimed to evaluate the effects of noninvasive motor cortex stimulation on pain perception as indexed by changes in QST outcomes. Database searches were conducted until July 2019 to include randomized controlled trials that performed sham-controlled NIBS on the motor cortex in either the healthy and/or pain population and assessed the QST and CPM. Quality of studies was assessed through the Cochrane tool. We calculated the Hedge's effect sizes of QST and CPM outcomes and their 95% confidence intervals (95% CIs) and performed random-effects meta-analyses. Thirty-eight studies were included (1178 participants). We found significant increases of pain threshold in healthy subjects (ES = 0.16, 95% CI = 0.02-0.31, I2 = 22.2%) and pain populations (ES = 0.48, 95% CI = 0.15-0.80, I2 = 68.8%), and homogeneous higher CPM effect (pain ratings reduction) in healthy subjects (ES = -0.39, 95% CI = -0.64 to -0.14, I2 = 17%) and pain populations (ES = -0.35, 95% CI = -0.60 to -0.11, I2 = 0%) in the active NIBS group compared with sham. These results support the idea of top-down modulation of endogenous pain pathways by motor cortex stimulation as one of the main mechanisms of pain reduction assessed by QST, which could be a useful predictive and prognostic biomarker for chronic pain personalized treatment with NIBS.

Single tDCS session of motor cortex in patients with disorders of consciousness: a pilot study.

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

Diagnostic accuracy of the CRS-R index in patients with disorders of consciousness.

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