Pain anticipation is a new behavioural sign of minimally conscious state.

Probing cognition and consciousness in the absence of functional communication remains an extremely challenging task. In this perspective, we imagined a basic clinical procedure to explore pain anticipation at bedside. In a series of 61 patients with a disorder of consciousness, we tested the existence of a nociceptive anticipation response by pairing a somaesthetic stimulation with a noxious stimulation. We then explored how nociceptive anticipation response correlated with (i) clinical status inferred from Coma Recovery Scale-Revised scoring, (ii) with an EEG signature of stimulus anticipation-the contingent negative variation-and (iii) how nociceptive anticipation response could predict consciousness outcome at 6 months. Proportion of nociceptive anticipation response differed significantly according to the state of consciousness: nociceptive anticipation response was present in 5 of 5 emerging from minimally conscious state patients (100%), in 10 of 11 minimally conscious state plus patients (91%), but only in 8 of 17 minimally conscious state minus patients (47%), and only in 1 of 24 vegetative state/unresponsive wakefulness syndrome patients (4%) (χ 2  P < 0.0001). Nociceptive anticipation response correlated with the presence of a contingent negative variation, suggesting that patients with nociceptive anticipation response were more prone to actively expect and anticipate auditory stimuli (Fisher's exact test P = 0.05). However, nociceptive anticipation response presence did not predict consciousness recovery. Nociceptive anticipation response appears as a new additional behavioural sign that can be used to differentiate minimally conscious state from vegetative state/unresponsive wakefulness syndrome patients. As most behavioural signs of minimally conscious state, the nociceptive anticipation response seems to reveal the existence of a cortically mediated state that does not necessarily reflect residual conscious processing.

Cognitive Motor Dissociation in Disorders of Consciousness.

BACKGROUND: Patients with brain injury who are unresponsive to commands may perform cognitive tasks that are detected on functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). This phenomenon, known as cognitive motor dissociation, has not been systematically studied in a large cohort of persons with disorders of consciousness. METHODS: In this prospective cohort study conducted at six international centers, we collected clinical, behavioral, and task-based fMRI and EEG data from a convenience sample of 353 adults with disorders of consciousness. We assessed the response to commands on task-based fMRI or EEG in participants without an observable response to verbal commands (i.e., those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus) and in participants with an observable response to verbal commands. The presence or absence of an observable response to commands was assessed with the use of the Coma Recovery Scale-Revised (CRS-R). RESULTS: Data from fMRI only or EEG only were available for 65% of the participants, and data from both fMRI and EEG were available for 35%. The median age of the participants was 37.9 years, the median time between brain injury and assessment with the CRS-R was 7.9 months (25% of the participants were assessed with the CRS-R within 28 days after injury), and brain trauma was an etiologic factor in 50%. We detected cognitive motor dissociation in 60 of the 241 participants (25%) without an observable response to commands, of whom 11 had been assessed with the use of fMRI only, 13 with the use of EEG only, and 36 with the use of both techniques. Cognitive motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In contrast, responses on task-based fMRI or EEG occurred in 43 of 112 participants (38%) with an observable response to verbal commands. CONCLUSIONS: Approximately one in four participants without an observable response to commands performed a cognitive task on fMRI or EEG as compared with one in three participants with an observable response to commands. (Funded by the James S. McDonnell Foundation and others.).

Content-state dimensions characterize different types of neuronal markers of consciousness.

Identifying the neuronal markers of consciousness is key to supporting the different scientific theories of consciousness. Neuronal markers of consciousness can be defined to reflect either the brain signatures underlying specific conscious content or those supporting different states of consciousness, two aspects traditionally studied separately. In this paper, we introduce a framework to characterize markers according to their dynamics in both the "state" and "content" dimensions. The 2D space is defined by the marker's capacity to distinguish the conscious states from non-conscious states (on the x-axis) and the content (e.g. perceived versus unperceived or different levels of cognitive processing on the y-axis). According to the sign of the x- and y-axis, markers are separated into four quadrants in terms of how they distinguish the state and content dimensions. We implement the framework using three types of electroencephalography markers: markers of connectivity, markers of complexity, and spectral summaries. The neuronal markers of state are represented by the level of consciousness in (i) healthy participants during a nap and (ii) patients with disorders of consciousness. On the other hand, the neuronal markers of content are represented by (i) the conscious content in healthy participants' perception task using a visual awareness paradigm and (ii) conscious processing of hierarchical regularities using an auditory local-global paradigm. In both cases, we see separate clusters of markers with correlated and anticorrelated dynamics, shedding light on the complex relationship between the state and content of consciousness and emphasizing the importance of considering them simultaneously. This work presents an innovative framework for studying consciousness by examining neuronal markers in a 2D space, providing a valuable resource for future research, with potential applications using diverse experimental paradigms, neural recording techniques, and modeling investigations.

Functional and structural brain connectivity in disorders of consciousness.

Brain connectivity, allowing information to be shared between distinct cortical areas and thus to be processed in an integrated way, has long been considered critical for consciousness. However, the relationship between functional intercortical interactions and the structural connections thought to underlie them is poorly understood. In the present work, we explore both functional (with an EEG-based metric: the median weighted symbolic mutual information in the theta band) and structural (with a brain MRI-based metric: fractional anisotropy) connectivities in a cohort of 78 patients with disorders of consciousness. Both metrics could distinguish patients in a vegetative state from patients in minimally conscious state. Crucially, we discovered a significant positive correlation between functional and structural connectivities. Furthermore, we showed that this structure-function relationship is more specifically observed when considering structural connectivity within the intra- and inter-hemispheric long-distance cortico-cortical bundles involved in the Global Neuronal Workspace (GNW) theory of consciousness, thus supporting predictions of this model. Altogether, these results support the interest of multimodal assessments of brain connectivity in refining the diagnostic evaluation of patients with disorders of consciousness.

Cognitive Motor Dissociation: Gap Analysis and Future Directions.

BACKGROUND: Patients with disorders of consciousness who are behaviorally unresponsive may demonstrate volitional brain responses to motor imagery or motor commands detectable on functional magnetic resonance imaging or electroencephalography. This state of cognitive motor dissociation (CMD) may have prognostic significance. METHODS: The Neurocritical Care Society's Curing Coma Campaign identified an international group of experts who convened in a series of monthly online meetings between September 2021 and April 2023 to examine the science of CMD and identify key knowledge gaps and unmet needs. RESULTS: The group identified major knowledge gaps in CMD research: (1) lack of information about patient experiences and caregiver accounts of CMD, (2) limited epidemiological data on CMD, (3) uncertainty about underlying mechanisms of CMD, (4) methodological variability that limits testing of CMD as a biomarker for prognostication and treatment trials, (5) educational gaps for health care personnel about the incidence and potential prognostic relevance of CMD, and (6) challenges related to identification of patients with CMD who may be able to communicate using brain-computer interfaces. CONCLUSIONS: To improve the management of patients with disorders of consciousness, research efforts should address these mechanistic, epidemiological, bioengineering, and educational gaps to enable large-scale implementation of CMD assessment in clinical practice.

A Novel Approach to Screen for Somatosensory Evoked Potentials in Critical Care.

BACKGROUND: Somatosensory evoked potentials (SSEPs) help prognostication, particularly in patients with diffuse brain injury. However, use of SSEP is limited in critical care. We propose a novel, low-cost approach allowing acquisition of screening SSEP using widely available intensive care unit (ICU) equipment, specifically a peripheral "train-of-four" stimulator and standard electroencephalograph. METHODS: The median nerve was stimulated using a train-of-four stimulator, and a standard 21-channel electroencephalograph was recorded to generate the screening SSEP. Generation of the SSEP was supported by visual inspection, univariate event-related potentials statistics, and a multivariate support vector machine (SVM) decoding algorithm. This approach was validated in 15 healthy volunteers and validated against standard SSEPs in 10 ICU patients. The ability of this approach to predict poor neurological outcome, defined as death, vegetative state, or severe disability at 6 months, was tested in an additional set of 39 ICU patients. RESULTS: In each of the healthy volunteers, both the univariate and the SVM methods reliably detected SSEP responses. In patients, when compared against the standard SSEP method, the univariate event-related potentials method matched in nine of ten patients (sensitivity = 94%, specificity = 100%), and the SVM had 100% sensitivity and specificity when compared with the standard method. For the 49 ICU patients, we performed both the univariate and the SVM methods: a bilateral absence of short latency responses (n = 8) predicted poor neurological outcome with 0% FPR (sensitivity = 21%, specificity = 100%). CONCLUSIONS: Somatosensory evoked potentials can reliably be recorded using the proposed approach. Given the very good but slightly lower sensitivity of absent SSEPs in the proposed screening approach, confirmation of absent SSEP responses using standard SSEP recordings is advised.

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.

Heuristics and biases in medical decision-making under uncertainty: The case of neuropronostication for consciousness disorders.

Neuropronostication for consciousness disorders can be very complex and prone to high uncertainty. Despite notable advancements in the development of dedicated scales and physiological markers using innovative paradigms, these technical progressions are often overshadowed by factors intrinsic to the medical environment. Beyond the scarcity of objective data guiding medical decisions, factors like time pressure, fatigue, multitasking, and emotional load can drive clinicians to rely more on heuristic-based clinical reasoning. Such an approach, albeit beneficial under certain circumstances, may lead to systematic error judgments and impair medical decisions, especially in complex and uncertain environments. After a brief review of the main theoretical frameworks, this paper explores the influence of clinicians' cognitive biases on clinical reasoning and decision-making in the challenging context of neuroprognostication for consciousness disorders. The discussion further revolves around developing and implementing various strategies designed to mitigate these biases and their impact, aiming to enhance the quality of care and the patient safety.

Common Data Elements for Disorders of Consciousness: Recommendations from the Electrophysiology Working Group.

BACKGROUND: Electroencephalography (EEG) has long been recognized as an important tool in the investigation of disorders of consciousness (DoC). From inspection of the raw EEG to the implementation of quantitative EEG, and more recently in the use of perturbed EEG, it is paramount to providing accurate diagnostic and prognostic information in the care of patients with DoC. However, a nomenclature for variables that establishes a convention for naming, defining, and structuring data for clinical research variables currently is lacking. As such, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups composed of experts in the field to construct common data elements (CDEs) to provide recommendations for DoC, with the main goal of facilitating data collection and standardization of reporting. This article summarizes the recommendations of the electrophysiology DoC working group. METHODS: After assessing previously published pertinent CDEs, we developed new CDEs and categorized them into "disease core," "basic," "supplemental," and "exploratory." Key EEG design elements, defined as concepts that pertained to a methodological parameter relevant to the acquisition, processing, or analysis of data, were also included but were not classified as CDEs. RESULTS: After identifying existing pertinent CDEs and developing novel CDEs for electrophysiology in DoC, variables were organized into a framework based on the two primary categories of resting state EEG and perturbed EEG. Using this categorical framework, two case report forms were generated by the working group. CONCLUSIONS: Adherence to the recommendations outlined by the electrophysiology working group in the resting state EEG and perturbed EEG case report forms will facilitate data collection and sharing in DoC research on an international level. In turn, this will allow for more informed and reliable comparison of results across studies, facilitating further advancement in the realm of DoC research.

Illusion of knowledge in statistics among clinicians: evaluating the alignment between objective accuracy and subjective confidence, an online survey.

Healthcare professionals' statistical illiteracy can impair medical decision quality and compromise patient safety. Previous studies have documented clinicians' insufficient proficiency in statistics and a tendency in overconfidence. However, an underexplored aspect is clinicians' awareness of their lack of statistical knowledge that precludes any corrective intervention attempt. Here, we investigated physicians', residents' and medical students' alignment between subjective confidence judgments and objective accuracy in basic medical statistics. We also examined how gender, profile of experience and practice of research activity affect this alignment, and the influence of problem framing (conditional probabilities, CP vs. natural frequencies, NF). Eight hundred ninety-eight clinicians completed an online survey assessing skill and confidence on three topics: vaccine efficacy, p value and diagnostic test results interpretation. Results evidenced an overall consistent poor proficiency in statistics often combined with high confidence, even in incorrect answers. We also demonstrate that despite overconfidence bias, clinicians show a degree of metacognitive sensitivity, as their confidence judgments discriminate between their correct and incorrect answers. Finally, we confirm the positive impact of the more intuitive NF framing on accuracy. Together, our results pave the way for the development of teaching recommendations and pedagogical interventions such as promoting metacognition on basic knowledge and statistical reasoning as well as the use of NF to tackle statistical illiteracy in the medical context.

Ethics Along the Continuum of Research Involving Persons with Disorders of Consciousness.

Interest in disorders of consciousness (DoC) has grown substantially over the past decade and has illuminated the importance of improving understanding of DoC biology; care needs (use of monitoring, performance of interventions, and provision of emotional support); treatment options to promote recovery; and outcome prediction. Exploration of these topics requires awareness of numerous ethics considerations related to rights and resources. The Curing Coma Campaign Ethics Working Group used its expertise in neurocritical care, neuropalliative care, neuroethics, neuroscience, philosophy, and research to formulate an informal review of ethics considerations along the continuum of research involving persons with DoC related to the following: (1) study design; (2) comparison of risks versus benefits; (3) selection of inclusion and exclusion criteria; (4) screening, recruitment, and enrollment; (5) consent; (6) data protection; (7) disclosure of results to surrogates and/or legally authorized representatives; (8) translation of research into practice; (9) identification and management of conflicts of interest; (10) equity and resource availability; and (11) inclusion of minors with DoC in research. Awareness of these ethics considerations when planning and performing research involving persons with DoC will ensure that the participant rights are respected while maximizing the impact and meaningfulness of the research, interpretation of outcomes, and communication of results.

EEG lexicality effect predicts clinical outcome in disorders of consciousness.

This study aimed at probing covert language processing in patients with disorders of consciousness. An auditory paradigm contrasting words to pronounceable pseudowords was designed, while recording bedside electroencephalogram and computing the two main correlates of lexicality: N400 and late positive component (LPC). Healthy volunteers and 19 patients, 10 in a minimally conscious state and 9 in a vegetative state (also coined unresponsive wakefulness syndrome), were recorded. N400 was present in all groups, whereas LPC was only present in the healthy volunteers and minimally conscious state groups. At the individual level, an unprecedented detection rate of N400 and LPC was reached, and LPC predicted overt cognitive improvement at 6 months. ANN NEUROL 2023;93:762-767.

Valproic acid as adjuvant treatment for convulsive status epilepticus: a randomised clinical trial.

BACKGROUND: Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20-40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE. METHODS: This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. RESULTS: A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89-1.19); p = 0.58]. There were no between-group differences for secondary outcomes. CONCLUSIONS: VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15. TRIAL REGISTRATION NO: NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.

Description and Outcome of Severe Hypoglycemic Encephalopathy in the Intensive Care Unit.

BACKGROUND: Disorders of consciousness due to severe hypoglycemia are rare but challenging to treat. The aim of this retrospective cohort study was to describe our multimodal neurological assessment of patients with hypoglycemic encephalopathy hospitalized in the intensive care unit and their neurological outcomes. METHODS: Consecutive patients with disorders of consciousness related to hypoglycemia admitted for neuroprognostication from 2010 to 2020 were included. Multimodal neurological assessment included electroencephalography, somatosensory and cognitive event-related potentials, and morphological and quantitative magnetic resonance imaging (MRI) with quantification of fractional anisotropy. Neurological outcomes at 28 days, 3 months, 6 months, 1 year, and 2 years after hypoglycemia were retrieved. RESULTS: Twenty patients were included. After 2 years, 75% of patients had died, 5% remained in a permanent vegetative state, 10% were in a minimally conscious state, and 10% were conscious but with severe disabilities (Glasgow Outcome Scale-Extended scores 3 and 4). All patients showed pathologic electroencephalography findings with heterogenous patterns. Morphological brain MRI revealed abnormalities in 95% of patients, with various localizations including cortical atrophy in 65% of patients. When performed, quantitative MRI showed decreased fractional anisotropy affecting widespread white matter tracts in all patients. CONCLUSIONS: The overall prognosis of patients with severe hypoglycemic encephalopathy was poor, with only a small fraction of patients who slowly improved after intensive care unit discharge. Of note, patients who did not improve during the first 6 months did not recover consciousness. This study suggests that a multimodal approach capitalizing on advanced brain imaging and bedside electrophysiology techniques could improve diagnostic and prognostic performance in severe hypoglycemic encephalopathy.

Older patients with COVID-19 and neuropsychiatric conditions: A study of risk factors for mortality.

BACKGROUND: Little is known about risk factors for mortality in older patients with COVID-19 and neuropsychiatric conditions. METHODS: We conducted a multicentric retrospective observational study at Assistance Publique-Hôpitaux de Paris. We selected inpatients aged 70 years or older, with COVID-19 and preexisting neuropsychiatric comorbidities and/or new neuropsychiatric manifestations. We examined demographics, comorbidities, functional status, and presentation including neuropsychiatric symptoms and disorders, as well as paraclinical data. Cox survival analysis was conducted to determine risk factors for mortality at 40 days after the first symptoms of COVID-19. RESULTS: Out of 191 patients included (median age 80 [interquartile range 74-87]), 135 (71%) had neuropsychiatric comorbidities including cognitive impairment (39%), cerebrovascular disease (22%), Parkinsonism (6%), and brain tumors (6%). A total of 152 (79%) patients presented new-onset neuropsychiatric manifestations including sensory symptoms (6%), motor deficit (11%), behavioral (18%) and cognitive (23%) disturbances, gait impairment (11%), and impaired consciousness (18%). The mortality rate at 40 days was 19.4%. A history of brain tumor or Parkinsonism or the occurrence of impaired consciousness were neurological factors associated with a higher risk of mortality. A lower Activities of Daily Living score (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.58-0.82), a neutrophil-to-lymphocyte ratio ≥ 9.9 (HR 5.69, 95% CI 2.69-12.0), and thrombocytopenia (HR 5.70, 95% CI 2.75-11.8) independently increased the risk of mortality (all p < .001). CONCLUSION: Understanding mortality risk factors in older inpatients with COVID-19 and neuropsychiatric conditions may be helpful to neurologists and geriatricians who manage these patients in clinical practice.

Electroencephalogram in the intensive care unit: a focused look at acute brain injury.

Over the past decades, electroencephalography (EEG) has become a widely applied and highly sophisticated brain monitoring tool in a variety of intensive care unit (ICU) settings. The most common indication for EEG monitoring currently is the management of refractory status epilepticus. In addition, a number of studies have associated frequent seizures, including nonconvulsive status epilepticus (NCSE), with worsening secondary brain injury and with worse outcomes. With the widespread utilization of EEG (spot and continuous EEG), rhythmic and periodic patterns that do not fulfill strict seizure criteria have been identified, epidemiologically quantified, and linked to pathophysiological events across a wide spectrum of critical and acute illnesses, including acute brain injury. Increasingly, EEG is not just qualitatively described, but also quantitatively analyzed together with other modalities to generate innovative measurements with possible clinical relevance. In this review, we discuss the current knowledge and emerging applications of EEG in the ICU, including seizure detection, ischemia monitoring, detection of cortical spreading depolarizations, assessment of consciousness and prognostication. We also review some technical aspects and challenges of using EEG in the ICU including the logistics of setting up ICU EEG monitoring in resource-limited settings.