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.

Residual implicit and explicit language abilities in patients with disorders of consciousness: A systematic review.

Language assessment in post-comatose patients is difficult due to their limited behavioral repertoire; yet associated language deficits might lead to an underestimation of consciousness levels in unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS; -/+) diagnoses. We present a systematic review of studies from 2002 assessing residual language abilities with neuroimaging, electrophysiological or behavioral measures in patients with severe brain injury. Eighty-five articles including a total of 2278 patients were assessed for quality. The median percentages of patients showing residual implicit language abilities (i.e., cortical responses to specific words/sentences) were 33 % for UWS, 50 % for MCS- and 78 % for MCS + patients, whereas explicit language abilities (i.e., command-following using brain-computer interfaces) were reported in 20 % of UWS, 33 % of MCS- and 50 % of MCS + patients. Cortical responses to verbal stimuli increased along with consciousness levels and the progressive recovery of consciousness after a coma was paralleled by the reappearance of both implicit and explicit language processing. This review highlights the importance of language assessment in patients with disorders of consciousness.

Behavioral signs of recovery from unresponsive wakefulness syndrome to emergence of minimally conscious state after severe brain injury.

Precise description of behavioral signs denoting transition from unresponsive wakefulness syndrome/vegetative state (UWS/VS) to minimally conscious state (MCS) or emergence from MCS after severe brain injury is crucial for prognostic purposes. A few studies have attempted this goal but involved either non-standardized instruments, limited temporal accuracy or samples, or focused on (sub)acute patients. The objective of this study was to describe the behavioral signs that led to a change of diagnosis, as well as the factors influencing this transition, in a large sample of patients with chronic disorders of consciousness after severe brain injury. In this retrospective cohort study, 185 patients in UWS/VS or MCS were assessed with the Coma Recovery Scale Revised (CRS-R) five times within the two weeks following their admission to a neurorehabilitation center and then weekly until emergence from MCS, discharge or death. Of these 185 patients, 33 patients in UWS/VS and 45 patients in MCS transitioned to another state. Transition to MCS was mostly denoted by one behavioral sign (72%), predominantly visual fixation (57%), followed by localization to noxious stimulation (27%), visual pursuit (21%) and object manipulation (12%), and could be predicted by etiology, time post-injury and age. Emergence from MCS was characterized by one sign in 64% of patients and by two signs (functional communication and objects use) in the remaining cases, and could be predicted by time post-injury and number of behavioral signs at admission. Clinicians should be therefore advised to pay particular attention to visual and motor subscales of the CRS-R to detect behavioral recovery.

Simplified evaluation of CONsciousness disorders (SECONDs) in individuals with severe brain injury: A validation study.

BACKGROUND: The Coma Recovery Scale-Revised (CRS-R) is the gold standard to assess severely brain-injured patients with prolonged disorders of consciousness (DoC). However, the amount of time needed to complete this examination may limit its use in clinical settings. OBJECTIVE: We aimed to validate a new faster tool to assess consciousness in individuals with DoC. METHODS: This prospective validation study introduces the Simplified Evaluation of CONsciousness Disorders (SECONDs), a tool composed of 8 items: arousal, localization to pain, visual fixation, visual pursuit, oriented behaviors, command-following, and communication (both intentional and functional). A total of 57 individuals with DoC were assessed on 2 consecutive days by 3 blinded examiners: one CRS-R and one SECONDs were performed on 1 day, whereas 2 SECONDs were performed on the other day. A Mann-Whitney U test was used to compare the duration of administration of the SECONDs versus the CRS-R, and weighted Fleiss' kappa coefficients were used to assess inter-/intra-rater reliability as well as concurrent validity. RESULTS: In the 57 participants, the SECONDs was about 2.5 times faster to administer than the CRS-R. The comparison of the CRS-R versus the SECONDs on the same day or the best of the 3 SECONDs led to "substantial" or "almost perfect" agreement (kappa coefficients ranging from 0.78 to 0.85). Intra-/inter-rater reliability also showed almost perfect agreement (kappa coefficients from 0.85 to 0.91 and 0.82 to 0.85, respectively). CONCLUSIONS: The SECONDs appears to be a fast, reliable and easy-to-use scale to diagnose DoC and may be a good alternative to other scales in clinical settings where time constraints preclude a more thorough assessment.

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.

An Echo of Consciousness: Brain Function During Preferred Music.

Background: Given its emotional and autobiographical properties, music appears as a potential aid in diagnostic assessment and therapeutics in patients with disorders of consciousness (DOCs). Several studies have shown boosting effects on behavior and brain functioning when patients were exposed to (their preferred) music. Objective: The aim of this study was to investigate if these effects on the brain's spontaneous activity are dependent on the level of consciousness. Methods: Nine postcomatose patients and eight healthy control subjects were assessed using functional magnetic resonance imaging in two conditions: rest (without stimulation) and music. All patients presented at least an auditory startle, thereby suggesting the presence of residual auditory function. A gradient of consciousness (from unresponsive wakefulness syndrome to healthy subjects) was formulated to evaluate consciousness-level-dependent increases in brain activity and connectivity. Network-based functional connectivity assessed auditory, default-mode, frontoparietal, and music-evoked emotion networks. Furthermore, exploratory voxel-to-voxel analyses were performed at the whole brain level using intrinsic connectivity contrast and (fractional) amplitude of low-frequency fluctuations. Results: Stronger consciousness-level-dependent increases within network-to-voxel analysis of connectivity were found in the frontoparietal network with the precuneus during music stimulation compared with rest. Voxel-to-voxel analyses showed stronger increases of intrinsic connectivity in the music condition compared with rest in regions previously related to music processing. There were consistently more regions with increased connectivity during the main effect of music compared with rest. These increases of connectivity during music were observed in brain regions involved in consciousness, language, emotion, and memory processing. Conclusions: Our results show that music seems to trigger more substantial connectivity changes compared with rest, pointing toward the potential ability of music to stimulate patients' brain function. Further research should focus on effects of music in general, its specific acoustical features, and the effects of simple auditory stimuli, as well as the possible therapeutic and diagnostic effects of music in well-controlled clinical trials. Impact statement Due to its emotional and autobiographical properties, music is a particularly salient stimulus. A few studies using musical stimuli have shown promising results in terms of behavioral responsiveness in patients with disorders of consciousness (Magee, 2005; Raglio et al., 2014; Verger et al., 2014). Our study confirms the presence of a beneficial effect of music on brain connectivity in these severely brain-injured patients, which moreover seems to be dependent on the level of consciousness. Our findings therefore strengthen the hypothesis that music could play a role from a diagnostic and therapeutic standpoint in this population, paving the way for future well-controlled clinical trials.

Time-Delay Latency of Resting-State Blood Oxygen Level-Dependent Signal Related to the Level of Consciousness in Patients with Severe Consciousness Impairment.

Recent evidence on resting-state functional magnetic resonance imaging (rs-fMRI) suggests that healthy human brains have a temporal organization represented in a widely complex time-delay structure. This structure seems to underlie brain communication flow, integration/propagation of brain activity, as well as information processing. Therefore, it is probably linked to the emergence of highly coordinated complex brain phenomena, such as consciousness. Nevertheless, possible changes in this structure during an altered state of consciousness remain poorly investigated. In this work, we hypothesized that due to a disruption in high-order functions and alterations of the brain communication flow, patients with disorders of consciousness (DOC) might exhibit changes in their time-delay structure of spontaneous brain activity. We explored this hypothesis by comparing the time-delay projections from fMRI resting-state data acquired in resting state from 48 patients with DOC and 27 healthy controls (HC) subjects. Results suggest that time-delay structure modifies for patients with DOC conditions when compared with HC. Specifically, the average value and the directionality of latency inside the midcingulate cortex (mCC) shift with the level of consciousness. In particular, positive values of latency inside the mCC relate to preserved states of consciousness, whereas negative values change proportionally with the level of consciousness in patients with DOC. These results suggest that the mCC may play a critical role as an integrator of brain activity in HC subjects, but this role vanishes in an altered state of consciousness.

Brain Metabolism but Not Gray Matter Volume Underlies the Presence of Language Function in the Minimally Conscious State (MCS): MCS+ Versus MCS- Neuroimaging Differences.

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

Auditory localization should be considered as a sign of minimally conscious state based on multimodal findings.

Auditory localization (i.e. turning the head and/or the eyes towards an auditory stimulus) is often part of the clinical evaluation of patients recovering from coma. The objective of this study is to determine whether auditory localization could be considered as a new sign of minimally conscious state, using a multimodal approach. The presence of auditory localization and the clinical outcome at 2 years of follow-up were evaluated in 186 patients with severe brain injury, including 64 with unresponsive wakefulness syndrome, 28 in minimally conscious state minus, 71 in minimally conscious state plus and 23 who emerged from the minimally conscious state. Brain metabolism, functional connectivity and graph theory measures were investigated by means of 18F-fluorodeoxyglucose positron emission tomography, functional MRI and high-density electroencephalography in two subgroups of unresponsive patients, with and without auditory localization. These two subgroups were also compared to a subgroup of patients in minimally conscious state minus. Auditory localization was observed in 13% of unresponsive patients, 46% of patients in minimally conscious state minus, 62% of patients in minimally conscious state plus and 78% of patients who emerged from the minimally conscious state. The probability to observe an auditory localization increased along with the level of consciousness, and the presence of auditory localization could predict the level of consciousness. Patients with auditory localization had higher survival rates (at 2-year follow-up) than those without localization. Differences in brain function were found between unresponsive patients with and without auditory localization. Higher connectivity in unresponsive patients with auditory localization was measured between the fronto-parietal network and secondary visual areas, and in the alpha band electroencephalography network. Moreover, patients in minimally conscious state minus significantly differed from unresponsive patients without auditory localization in terms of brain metabolism and alpha network centrality, whereas no difference was found with unresponsive patients who presented auditory localization. Our multimodal findings suggest differences in brain function between unresponsive patients with and without auditory localization, which support our hypothesis that auditory localization should be considered as a new sign of minimally conscious state. Unresponsive patients showing auditory localization should therefore no longer be considered unresponsive but minimally conscious. This would have crucial consequences on these patients' lives as it would directly impact the therapeutic orientation or end-of-life decisions usually taken based on the diagnosis.

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.

Modulation of the spontaneous hemodynamic response function across levels of consciousness.

Functional imaging research has already contributed with several results to the study of neural correlates of consciousness. Apart from task-related activation derived in fMRI, PET based glucose metabolism rate or cerebral blood flow account for a considerable proportion of the study of brain activity under different levels of consciousness. Resting state functional connectivity MRI is playing a crucial role to explore the consciousness related functional integration, successfully complementing PET, another widely used neuroimaging technique. Here, spontaneous hemodynamic response is introduced to characterize resting state brain activity giving information on the local metabolism (neurovascular coupling), and useful to improve the time-resolved activity and connectivity measures based on BOLD fMRI. This voxel-wise measure is then used to investigate the loss of consciousness under Propofol anesthesia and unresponsive wakefulness syndrome. Changes in the hemodynamic response in precuneus and posterior cingulate are found to be a common principle underlying loss of consciousness in both conditions. The thalamus appears to be less obviously modulated by Propofol, compared with frontoparietal regions. However, a significant increase in spontaneous thalamic hemodynamic response was found in patients in unresponsive wakefulness syndrome compared with healthy controls. Our results ultimately show that anesthesia- or pathology-induced neurovascular coupling could be tracked by modulated spontaneous hemodynamic response derived from resting state fMRI.

Reappearance of Command-Following Is Associated With the Recovery of Language and Internal-Awareness Networks: A Longitudinal Multiple-Case Report.

The recovery of patients with disorders of consciousness is a real challenge, especially at the chronic stage. After a severe brain injury, patients can regain some slight signs of consciousness, while not being able to functionally communicate. This entity is called the minimally conscious state (MCS), which has been divided into MCS- and MCS+, respectively based on the absence or presence of language-related signs of consciousness. In this series of cases we aimed to describe retrospectively the longitudinal recovery of specific language-related behaviors using neuroimaging measurement in severely brain-injured patients. Among 209 chronic MCS patients admitted to our center from 2008 to 2018, 19 were assessed at two time points by means of behavioral and neuroimaging assessments. Three of them met our inclusion criteria and were diagnosed as MCS- during their first stay and had recovered command-following when they were reassessed (i.e., MCS+). As compared to their first assessments, when the three patients were in a MCS+, they showed less hypometabolism and/or higher gray matter volume in brain regions such as the precuneus and thalamus, as well as the left caudate and temporal/angular cortices known to be involved in various aspects of semantics. According to these preliminary results, the reappearance of language-related behaviors was concomitant with the recovery of metabolism and gray matter in neural regions that have been associated with self-consciousness and language processing. Prospective studies should be conducted to deepen our understanding of the neural correlates of the recovery of language-related behaviors in chronic MCS.

A Heartbeat Away From Consciousness: Heart Rate Variability Entropy Can Discriminate Disorders of Consciousness and Is Correlated With Resting-State fMRI Brain Connectivity of the Central Autonomic Network.

Background: Disorders of consciousness are challenging to diagnose, with inconsistent behavioral responses, motor and cognitive disabilities, leading to approximately 40% misdiagnoses. Heart rate variability (HRV) reflects the complexity of the heart-brain two-way dynamic interactions. HRV entropy analysis quantifies the unpredictability and complexity of the heart rate beats intervals. We here investigate the complexity index (CI), a score of HRV complexity by aggregating the non-linear multi-scale entropies over a range of time scales, and its discriminative power in chronic patients with unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), and its relation to brain functional connectivity. Methods: We investigated the CI in short (CIs) and long (CIl) time scales in 14 UWS and 16 MCS sedated. CI for MCS and UWS groups were compared using a Mann-Whitney exact test. Spearman's correlation tests were conducted between the Coma Recovery Scale-revised (CRS-R) and both CI. Discriminative power of both CI was assessed with One-R machine learning model. Correlation between CI and brain connectivity (detected with functional magnetic resonance imagery using seed-based and hypothesis-free intrinsic connectivity) was investigated using a linear regression in a subgroup of 10 UWS and 11 MCS patients with sufficient image quality. Results: Higher CIs and CIl values were observed in MCS compared to UWS. Positive correlations were found between CRS-R and both CI. The One-R classifier selected CIl as the best discriminator between UWS and MCS with 90% accuracy, 7% false positive and 13% false negative rates after a 10-fold cross-validation test. Positive correlations were observed between both CI and the recovery of functional connectivity of brain areas belonging to the central autonomic networks (CAN). Conclusion: CI of MCS compared to UWS patients has high discriminative power and low false negative rate at one third of the estimated human assessors' misdiagnosis, providing an easy, inexpensive and non-invasive diagnostic tool. CI reflects functional connectivity changes in the CAN, suggesting that CI can provide an indirect way to screen and monitor connectivity changes in this neural system. Future studies should assess the extent of CI's predictive power in a larger cohort of patients and prognostic power in acute patients.

Brain, Behavior, and Cognitive Interplay in Disorders of Consciousness: A Multiple Case Study.

Patients with prolonged disorders of consciousness (DoC) after severe brain injury may present residual behavioral and cognitive functions. Yet the bedside assessment of these functions is compromised by patients' multiple impairments. Standardized behavioral scales such as the Coma Recovery Scale-Revised (CRS-R) have been developed to diagnose DoC, but there is also a need for neuropsychological measurement in these patients. The Cognitive Assessment by Visual Election (CAVE) was therefore recently created. In this study, we describe five patients in minimally conscious state (MCS) or emerging from the MCS (EMCS). Their cognitive profiles, derived from the CRS-R and CAVE, are presented alongside their neuroimaging results using structural magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Scores on the CAVE decreased along with the CRS-R total score, establishing a consistent behavioral/cognitive profile for each patient. Out of these five cases, the one with highest CRS-R and CAVE performance had the least extended cerebral hypometabolism. All patients showed structural and functional brain impairments that were consistent with their behavioral/cognitive profile as based on previous literature. For instance, the presence of visual and motor residual functions was respectively associated with a relative preservation of occipital and motor cortex/cerebellum metabolism. Moreover, residual language comprehension skills were found in the presence of preserved temporal and angular cortex metabolism. Some patients also presented structural impairment of hippocampus, suggesting the presence of memory impairments. Our results suggest that brain-behavior relationships might be observed even in severely brain-injured patients and they highlight the importance of developing new tools to assess residual cognition and language in MCS and EMCS patients. Indeed, a better characterization of their cognitive profile will be helpful in preparation of rehabilitation programs and daily routines.