Pupil dilation response elicited by violations of auditory regularities is a promising but challenging approach to probe consciousness at the bedside.

Pupil dilation response (PDR) has been proposed as a physiological marker of conscious access to a stimulus or its attributes, such as novelty. In a previous study on healthy volunteers, we adapted the auditory "local global" paradigm and showed that violations of global regularity elicited a PDR. Notably without instructions, this global effect was present only in participants who could consciously report violations of global regularities. In the present study, we used a similar approach in 24 non-communicating patients affected with a Disorder of Consciousness (DoC) and compared PDR to ERPs regarding diagnostic and prognostic performance. At the group level, global effect could not be detected in DoC patients. At the individual level, the only patient with a PDR global effect was in a MCS and recovered consciousness at 6 months. Contrasting the most regular trials to the most irregular ones improved PDR's diagnostic and prognostic power in DoC patients. Pupillometry is a promising tool but requires several methodological improvements to enhance the signal-to-noise ratio and make it more robust for probing consciousness and cognition in DoC patients.

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.

Cortical responses to auditory stimulation predict the prognosis of patients with disorders of consciousness.

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

Classifying Disorders of Consciousness: Past, Present, and Future.

With the advent of advanced analytical methods applied to functional neuroimaging and neurophysiological data, cerebral conditions have been defined that challenge the established classification of disorders of consciousness. A subset of brain-damaged patients has been identified who cannot carry out motor commands, but who exhibit patterns of cerebral activation during mental imagery tasks that are indistinguishable from those in healthy controls. This condition, termed "cognitive motor dissociation," has overturned many assumptions regarding the detection, diagnosis, prognosis, and care of patients with brain injury. Three factors are likely to influence efforts to improve the classification of disorders of consciousness in the near future: the types of data that will become available to characterize brain states, the modeling paradigms utilized for data analysis, and the ability to implement classification schemes in the clinical setting. Here we review past achievements, present states, and future projections for the classification of impaired consciousness and responsiveness.

Delta band activity contributes to the identification of command following in disorder of consciousness.

The overt or covert ability to follow commands in patients with disorders of consciousness is considered a sign of awareness and has recently been defined as cortically mediated behaviour. Despite its clinical relevance, the brain signatures of the perceptual processing supporting command following have been elusive. This multimodal study investigates the temporal spectral pattern of electrical brain activity to identify features that differentiated healthy controls from patients both able and unable to follow commands. We combined evidence from behavioural assessment, functional neuroimaging during mental imagery and high-density electroencephalography collected during auditory prediction, from 21 patients and 10 controls. We used a penalised regression model to identify command following using features from electroencephalography. We identified seven well-defined spatiotemporal signatures in the delta, theta and alpha bands that together contribute to identify DoC subjects with and without the ability to follow command, and further distinguished these groups of patients from controls. A fine-grained analysis of these seven signatures enabled us to determine that increased delta modulation at the frontal sensors was the main feature in command following patients. In contrast, higher frequency theta and alpha modulations differentiated controls from both groups of patients. Our findings highlight a key role of spatiotemporally specific delta modulation in supporting cortically mediated behaviour including the ability to follow command. However, patients able to follow commands nevertheless have marked differences in brain activity in comparison with healthy volunteers.

An action-observation/motor-imagery based approach to differentiate disorders of consciousness: what is beneath the tip of the iceberg?

BACKGROUND: The evaluation of motor imagery in persons with prolonged Disorders of Consciousness (pDOC) is a practical approach to differentiate between patients with Minimally Conscious State (MCS) and Unresponsive Wakefulness Syndrome (UWS) and to identify residual awareness even in individuals with UWS. Investigating the influence of motor observation on motor imagery could be helpful in this regard. OBJECTIVE: In order to corroborate the clinical diagnosis and identify misdiagnosed individuals, we used EEG recordings, to assess the influence of the low-level perceptual and motoric mechanisms on motor observation on motor imagery, taking into account the role of the high-level cognitive mechanisms in patients with pDOC. METHODS: We assessed the influence of motor observation of walking in first-person or third-person view (by a video provision) on motor imagery of walking in the first-person view on the visual N190 (expression of motor observation processing), the readiness potential (RP) (expressing motor preparation), and the P3 component (high-level cognitive processes) in a sample of 10 persons with MCS, 10 with UWS, and 10 healthy controls (CG). Specifically, the video showed a first-view or third-view walk down the street while the participants were asked to imagine a first-view walking down the street. RESULTS: CG showed greater N190 response (low-level sensorimotor processing) in the non-matching than in the matching condition. Conversely, the P3 and RP responses (high-level sensorimotor processing) were greater in the matching than in the non-matching condition. Remarkably, 6 out of 10 patients with MCS showed the preservation of both high- and low-level sensorimotor processing. One UWS patient showed responses similar to those six patients, suggesting a preservation of cognitively-mediated sensorimotor processing despite a detrimental motor preparation process. The remaining patients with MCS did not show diversified EEG responses, suggesting limited cognitive functioning. CONCLUSIONS: Our study suggests that identifying the low-level visual and high-level motor preparation processes in response to a simple influence of motor observation of motor imagery tasks potentially supports the clinical differential diagnosis of with MCS and UWS. This might help identify UWS patients which were misdiagnosed and who deserve more sophisticated diagnoses.

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings.

BACKGROUND: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings. AIMS: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. "set" and "setting"), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings. METHODS: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants. RESULTS: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band. CONCLUSIONS: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Assessing the state of consciousness for individual patients using complex, statistical stimuli.

Patients with prolonged disorders of consciousness (PDOC) are often unable to communicate their state of consciousness. Determining the latter is essential for the patient's care and prospects of recovery. Auditory stimulation in combination with neural recordings is a promising technique towards an objective assessment of conscious awareness. Here, we investigated the potential of complex, acoustic stimuli to elicit EEG responses suitable for classifying multiple subject groups, from unconscious to responding. We presented naturalistic auditory textures with unexpectedly changing statistics to human listeners. Awake, active listeners were asked to indicate the change by button press, while all other groups (awake passive, asleep, minimally conscious state (MCS), and unresponsive wakefulness syndrome (UWS)) listened passively. We quantified the evoked potential at stimulus onset and change in stimulus statistics, as well as the complexity of neural response during the change of stimulus statistics. On the group level, onset and change potentials classified patients and healthy controls successfully but failed to differentiate between the UWS and MCS groups. Conversely, the Lempel-Ziv complexity of the scalp-level potential allowed reliable differentiation between UWS and MCS even for individual subjects, when compared with the clinical assessment aligned to the EEG measurements. The accuracy appears to improve further when taking the latest available clinical diagnosis into account. In summary, EEG signal complexity during onset and changes in complex acoustic stimuli provides an objective criterion for distinguishing states of consciousness in clinical patients. These results suggest EEG-recordings as a cost-effective tool to choose appropriate treatments for non-responsive PDOC patients.

Metabolic encephalopathy caused by nitrous oxide ('laughing gas') induced hyperammonaemia.

A 26-year-old man presented at the emergency department with confusion and decreased consciousness after several days of vomiting. In the preceding 6 months, he had used a 2-litre tank of nitrous oxide (N2O) weekly. His metabolic encephalopathy was caused by hyperammonaemia which probably resulted from interference of N2O-induced vitamin B12 deficiency with ammonia degradation. A catabolic state might have contributed to the hyperammonaemia in this case. After treatment with vitamin B12 and lactulose, both his consciousness and hyperammonaemia improved. He reported no residual complaints after 3 months of follow-up. Since N2O is increasingly used as a recreational drug, we recommend considering hyperammonaemia as a cause of metabolic encephalopathy in cases of N2O use and altered mental status.

A Brain-Computer Interface Based on Three-Dimensional Stereo Stimuli for Assisting Clinical Object Recognition Assessment in Patients With Disorders of Consciousness.

The coma recovery scale-revised (CRS-R) behavioral scale is commonly used for the clinical evaluation of patients with disorders of consciousness (DOC). However, since DOC patients generally cannot supply stable and efficient behavioral responses to external stimulation, evaluation results based on behavioral scales are not sufficiently accurate. In this paper, we proposed a novel brain-computer interface (BCI) based on 3D stereo audiovisual stimuli to supplement object recognition evaluation in the CRS-R. During the experiment, subjects needed to follow the instructions and to focus on the target object on the screen, whereas EEG data were recorded and analyzed in real time to determine the object of focus, and the detection result was output as feedback. Thirteen DOC patients participated in the object recognition assessments using the 3D audiovisual BCI and CRS-R. None of the patients showed object recognition function in the CRS-R assessment before the BCI experiment. However, six of these DOC patients achieved accuracies that were significantly higher than the chance level in the BCI-based assessment, indicating the successful detection of object recognition function in these six patients using our 3D audiovisual BCI system. These results suggest that the BCI method may provide a more sensitive object recognition evaluation compared with CRS-R and may be used to assist clinical CRS-R for DOC patients.

Event-related potentials in the odd-ball paradigm and behavioral scales for the assessment of children and adolescents with disorders of consciousness: A proof of concept study.

OBJECTIVE: Quantification of signatures of conscious processing in children with disorders of consciousness (DoC) using odd-ball paradigms in multiple modalities. METHOD: We review the diagnostic approaches available in the field, from clinical scales to neuroimaging methods, and concentrate upon measures derived from electroencephalographic event related potentials. RESULTS: Evoked potentials were recorded in five procedures, encompassing visual, auditory and tactile modalities, from ten pediatric DoC patients-six in a minimally conscious state (MCS), three in unresponsive wakefulness syndrome (UWS) and one who emerged from MCS (eMCS)-and the control group of 10 healthy children. In almost all the eMCS and MCS patients, higher amplitude of P300 was observed and the effect was statistically significant in at least one out of the five performed procedures. Additionally, signs of conscious information processing were detected in one UWS patient. CONCLUSION: The presented results provide a proof of concept for the possibility of applying ERP-derived electrophysiological measures as an aid in the assessment of children and adolescents in DoC.

Music in the diagnosis, treatment and prognosis of people with prolonged disorders of consciousness.

Using music with people with prolonged disorders of consciousness (PDOC) has progressed considerably in recent years. Using both imaging and behavioural measures has revealed music's potential for enhancing arousal and awareness, boosting cognition and improving behavioural outcomes when compared to non-music conditions. Furthermore, music may have prognostic potential with this population. Explanations for these effects draw on music's potential to simultaneously excite the networks implicated in internal self-referential awareness and external awareness. A music-based protocol and measure for PDOC has been standardised that demonstrates particular sensitivity to assessment of auditory responsiveness, an important factor with a population where visual impairment is prevalent. Such measures can now contribute to interdisciplinary assessment of awareness in people with PDOC. Reviewing the latest research on this topic, priorities for research are identified. These include examining music's potential for prognosis of recovery, as well as its influence on the rate of emergence from PDOC, particularly its capacity to elicit heightened responsiveness across sensory domains when compared to non-music interventions. Research comparing the efficacy of live versus recorded music will help to inform evidence-based protocols. Lastly, its potential as a modality for assessment and treatment with paediatric PDOC populations should also be explored.

Efficacy and safety of electro-acupuncture treatment in improving the consciousness of patients with traumatic brain injury: study protocol for a randomized controlled trial.

BACKGROUND: Traumatic brain injury (TBI) has become a leading cause of death among young people worldwide. Survivors may live with a long-term TBI-related disability or even develop a disorder of consciousness resulting in poor life quality and shortened life expectancy. Thus far, very few approaches have been found to be effective in the consciousness recovery of these patients. Acupuncture has long been used in the treatment of neurological disorders in China. However, its efficacy and safety in consciousness recovery remain to be proved. METHODS: Here, we present a study design and protocol of a randomized, blinded, controlled study to evaluate the efficacy and safety of electro-acupuncture in the consciousness recovery of patients with TBI. A total of 150 patients with initial Glasgow coma scale score of less than 8 points will be recruited in the trial and randomized into acupuncture or control groups. Patients in the control group will receive routine pharmacological treatment alone while patients in the acupuncture group will receive electro-acupuncture treatment for 10 days in addition to routine treatment. The efficacy will be assessed with the changes in Glasgow coma scale score and mismatch negativity of event-related brain potentials before and after treatment. Moreover, Glasgow outcome scale and Barthel index of activities of daily living will be compared between the two groups at 3 months after treatment. The secondary outcome measures are the length of stay in ICU and hospital, expenses in ICU and hospital, as well as the incidence of coma-related complications. The safety of electro-acupuncture will be assessed by monitoring the incidence of adverse events and changes in vital signs during the study. DISCUSSION: Results from this trial will significantly add to the current body of evidence on the role of electro-acupuncture in the consciousness recovery of patients with severe TBI. In addition, a more convenient and consistent electro-acupuncture method can be set up for clinical practice. If found to be effective and safe, electro-acupuncture will be a valuable complementary option for comatose patients with TBI. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-INR-17011674 . Registered on 16 June 2016.

Reducing the rate of misdiagnosis in patients with chronic disorders of consciousness: Is there a place for audiovisual stimulation?

BACKGROUND: The patients with chronic Disorders of Consciousness (DoC) mostly present with extremely challenging differential diagnosis. The advanced analysis of electroencephalographic (EEG) signals induced by brain stimulation paradigms may provide an appropriate approach to differentiate patients with DoC, besides the clinical assessment. OBJECTIVE: This study was performed with an objective of identifying residual brain network perturbations following an innovative, non-invasive audiovisual stimulation protocol, which could be related to behavioral responsiveness in patients with DoC. METHODS: The study comprised of ten healthy controls (HC), seven patients with Minimally Conscious State (MCS), and nine patients with Unresponsive Wakefulness Syndrome (UWS). Both synchronous as well as asynchronous transorbital and transauricolar alternating current were employed as stimuli and their effects were measured in terms of functional and effective connectivity. RESULTS: A more noticeable deterioration of long range connectivity patterns were found in patients with UWS than in those with MCS, with an exception of two patients with UWS, who showed connectivity values similar to those of MCS patients. CONCLUSION: The audiovisual stimulation paradigm used in the present study may be employed as a supportive bedside tool for improving the differential diagnosis in patients with DoC.

Enhancing clinical communication assessments using an audiovisual BCI for patients with disorders of consciousness.

OBJECTIVE: The JFK coma recovery scale-revised (JFK CRS-R), a behavioral observation scale, is widely used in the clinical diagnosis/assessment of patients with disorders of consciousness (DOC). However, the JFK CRS-R is associated with a high rate of misdiagnosis (approximately 40%) because DOC patients cannot provide sufficient behavioral responses. A brain-computer interface (BCI) that detects command/intention-specific changes in electroencephalography (EEG) signals without the need for behavioral expression may provide an alternative method. APPROACH: In this paper, we proposed an audiovisual BCI communication system based on audiovisual 'yes' and 'no' stimuli to supplement the JFK CRS-R for assessing the communication ability of DOC patients. Specifically, patients were given situation-orientation questions as in the JFK CRS-R and instructed to select the answers using the BCI. MAIN RESULTS: Thirteen patients (eight vegetative state (VS) and five minimally conscious state (MCS)) participated in our experiments involving both the BCI- and JFK CRS-R-based assessments. One MCS patient who received a score of 1 in the JFK CRS-R achieved an accuracy of 86.5% in the BCI-based assessment. Seven patients (four VS and three MCS) obtained unresponsive results in the JFK CRS-R-based assessment but responsive results in the BCI-based assessment, and 4 of those later improved scores in the JFK CRS-R-based assessment. Five patients (four VS and one MCS) obtained usresponsive results in both assessments. SIGNIFICANCE: The experimental results indicated that the audiovisual BCI could provide more sensitive results than the JFK CRS-R and therefore supplement the JFK CRS-R.

EEG entropy measures indicate decrease of cortical information processing in Disorders of Consciousness.

OBJECTIVE: Clinical assessments that rely on behavioral responses to differentiate Disorders of Consciousness are at times inapt because of some patients' motor disabilities. To objectify patients' conditions of reduced consciousness the present study evaluated the use of electroencephalography to measure residual brain activity. METHODS: We analyzed entropy values of 18 scalp EEG channels of 15 severely brain-damaged patients with clinically diagnosed Minimally-Conscious-State (MCS) or Unresponsive-Wakefulness-Syndrome (UWS) and compared the results to a sample of 24 control subjects. Permutation entropy (PeEn) and symbolic transfer entropy (STEn), reflecting information processes in the EEG, were calculated for all subjects. Participants were tested on a modified active own-name paradigm to identify correlates of active instruction following. RESULTS: PeEn showed reduced local information content in the EEG in patients, that was most pronounced in UWS. STEn analysis revealed altered directed information flow in the EEG of patients, indicating impaired feed-backward connectivity. Responses to auditory stimulation yielded differences in entropy measures, indicating reduced information processing in MCS and UWS. CONCLUSIONS: Local EEG information content and information flow are affected in Disorders of Consciousness. This suggests local cortical information capacity and feedback information transfer as neural correlates of consciousness. SIGNIFICANCE: The utilized EEG entropy analyses were able to relate to patient groups with different Disorders of Consciousness.

Risk, diagnostic error, and the clinical science of consciousness.

In recent years, a number of new neuroimaging techniques have detected covert awareness in some patients previously thought to be in a vegetative state/unresponsive wakefulness syndrome. This raises worries for patients, families, and physicians, as it indicates that the existing diagnostic error rate in this patient group is higher than assumed. Recent research on a subset of these techniques, called active paradigms, suggests that false positive and false negative findings may result from applying different statistical methods to patient data. Due to the nature of this research, these errors may be unavoidable, and may draw into question the use of active paradigms in the clinical setting. We argue that false positive and false negative findings carry particular moral risks, which may bear on investigators' decisions to use certain methods when independent means for estimating their clinical utility are absent. We review and critically analyze this methodological problem as it relates to both fMRI and EEG active paradigms. We conclude by drawing attention to three common clinical scenarios where the risk of diagnostic error may be most pronounced in this patient group.

Probing ERP correlates of verbal semantic processing in patients with impaired consciousness.

Our ability to identify covert cognitive abilities in non-communicating patients is of prime importance to improve diagnosis, to guide therapeutic decisions and to better predict their cognitive outcome. In the present study, we used a basic and rigorous paradigm contrasting pairs of words orthogonally. This paradigm enables the probing of semantic processing by comparing neural activity elicited by similar words delivered in various combinations. We describe the respective timing, topography and estimated cortical sources of two successive event-related potentials (ERP) components (N400 and late positive component (LPC)) using high-density EEG in conscious controls (N=20) and in minimally conscious (MCS; N=15) and vegetative states (VS; N=15) patients recorded at bedside. Whereas N400-like ERP components could be observed in the VS, MCS and conscious groups, only MCS and conscious groups showed a LPC response, suggesting that this late effect could be a potential specific marker of conscious semantic processing. This result is coherent with recent findings disentangling early and local non-conscious responses (e.g.: MMN in odd-ball paradigms, N400 in semantic violation paradigms) from late, distributed and conscious responses (e.g.: P3b to auditory rule violation) in controls and in patients with disorders of consciousness. However, N400 and LPC responses were not easily observed at the individual level, - even in conscious controls - , with standard ERP analyses, which is a limiting factor for its clinical use. Of potential interest, the only 3 patients presenting both significant N400 and LPC effects were MCS, and 2 of them regained consciousness and functional language abilities.