Toward a coherent structuration of disorders of consciousness expertise at a country scale: A proposal for France.

Probing consciousness and cognitive abilities in non-communicating patients is one of the most challenging diagnostic issues. A fast growing medical and scientific literature explores the various facets of this challenge, often coined under the generic expression of 'Disorders of Consciousness' (DoC). Crucially, a set of independent converging results demonstrated both (1) the diagnostic and prognostic importance of this expertise, and (2) the need to combine behavioural measures with brain structure and activity data to improve diagnostic and prognostication accuracy as well as potential therapeutic intervention. Thus, probing consciousness in DoC patients appears as a crucial activity rich of human, medical, economic and ethical consequences, but this activity needs to be organized in order to offer this expertise to each concerned patient. More precisely, diagnosis of consciousness differs in difficulty across patients: while a minimal set of data can be sufficient to reach a confident result, some patients need a higher level of expertise that relies on additional behavioural and brain activity and brain structure measures. In order to enable this service on a systematic mode, we present two complementary proposals in the present article. First, we sketch a structuration of DoC expertise at a country-scale, namely France. More precisely, we suggest that a 2-tiers network composed of local (Tier-1) and regional (Tier-2) centers backed by distant electronic databases and algorithmic centers could optimally enable the systematic implementation of DoC expertise in France. Second, we propose to create a national common register of DoC patients in order to better monitor this activity, to improve its performance on the basis of nation-wide collected evidence, and to promote rational decision-making.

European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness.

BACKGROUND AND PURPOSE: Patients with acquired brain injury and acute or prolonged disorders of consciousness (DoC) are challenging. Evidence to support diagnostic decisions on coma and other DoC is limited but accumulating. This guideline provides the state-of-the-art evidence regarding the diagnosis of DoC, summarizing data from bedside examination techniques, functional neuroimaging and electroencephalography (EEG). METHODS: Sixteen members of the European Academy of Neurology (EAN) Scientific Panel on Coma and Chronic Disorders of Consciousness, representing 10 European countries, reviewed the scientific evidence for the evaluation of coma and other DoC using standard bibliographic measures. Recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The guideline was endorsed by the EAN. RESULTS: Besides a comprehensive neurological examination, the following suggestions are made: probe for voluntary eye movements using a mirror; repeat clinical assessments in the subacute and chronic setting, using the Coma Recovery Scale - Revised; use the Full Outline of Unresponsiveness score instead of the Glasgow Coma Scale in the acute setting; obtain clinical standard EEG; search for sleep patterns on EEG, particularly rapid eye movement sleep and slow-wave sleep; and, whenever feasible, consider positron emission tomography, resting state functional magnetic resonance imaging (fMRI), active fMRI or EEG paradigms and quantitative analysis of high-density EEG to complement behavioral assessment in patients without command following at the bedside. CONCLUSIONS: Standardized clinical evaluation, EEG-based techniques and functional neuroimaging should be integrated for multimodal evaluation of patients with DoC. The state of consciousness should be classified according to the highest level revealed by any of these three approaches.

Mismatch negativity to predict subsequent awakening in deeply sedated critically ill patients.

BACKGROUND: Mismatch negativity (MMN) is the neurophysiological correlate of cognitive integration of novel stimuli. Although MMN is a well-established predictor of awakening in non-sedated comatose patients, its prognostic value in deeply sedated critically ill patients remains unknown. The aim of this prospective, observational pilot study was to investigate the prognostic value of MMN for subsequent awakening in deeply sedated critically ill patients. METHODS: MMN was recorded in 43 deeply sedated critically ill patients on Day 3 of ICU admission using a classical 'odd-ball' paradigm that delivers rare deviant sounds in a train of frequent standard sounds. Individual visual analyses and a group level analysis of recordings were performed. MMN amplitudes were then analysed according to the neurological status (awake vs not awake) at Day 28. RESULTS: Median (inter-quartile range) Richmond Assessment Sedation Scale (RASS) at the time of recording was -5 (range, from -5 to -4.5). Visual detection of MMN revealed a poor inter-rater agreement [kappa=0.17, 95% confidence interval (0.07-0.26)]. On Day 28, 30 (70%) patients had regained consciousness while 13 (30%) had not. Quantitative group level analysis revealed a significantly greater MMN amplitude for patients who awakened compared with those who had not [mean (standard deviation) = -0.65 (1.4) vs 0.08 (0.17) µV, respectively; P=0.003). CONCLUSIONS: MMN can be observed in deeply sedated critically ill patients and could help predict subsequent awakening. However, visual analysis alone is unreliable and should be systematically completed with individual level statistics.

Disentangling conscious from unconscious cognitive processing with event-related EEG potentials.

By looking for properties of consciousness, cognitive neuroscience studies have dramatically enlarged the scope of unconscious cognitive processing. This emerging knowledge inspired the development of new approaches allowing clinicians to probe and disentangle conscious from unconscious cognitive processes in non-communicating brain-injured patients both in terms of behaviour and brain activity. This information is extremely valuable in order to improve diagnosis and prognosis in such patients both at acute and chronic settings. Reciprocally, the growing observations coming from such patients suffering from disorders of consciousness provide valuable constraints to theoretical models of consciousness. In this review we chose to illustrate these recent developments by focusing on brain signals recorded with EEG at bedside in response to auditory stimuli. More precisely, we present the respective EEG markers of unconscious and conscious processing of two classes of auditory stimuli (sounds and words). We show that in both cases, conscious access to the corresponding representation (e.g.: auditory regularity and verbal semantic content) share a similar neural signature (P3b and P600/LPC) that can be distinguished from unconscious processing occurring during an earlier stage (MMN and N400). We propose a two-stage serial model of processing and discuss how unconscious and conscious signatures can be measured at bedside providing relevant informations for both diagnosis and prognosis of consciousness recovery. These two examples emphasize how fruitful can be the bidirectional approach exploring cognition in healthy subjects and in brain-damaged patients.

Multimodal assessment improves neuroprognosis performance in clinically unresponsive critical-care patients with brain injury.

Accurately predicting functional outcomes for unresponsive patients with acute brain injury is a medical, scientific and ethical challenge. This prospective study assesses how a multimodal approach combining various numbers of behavioral, neuroimaging and electrophysiological markers affects the performance of outcome predictions. We analyzed data from 349 patients admitted to a tertiary neurointensive care unit between 2009 and 2021, categorizing prognoses as good, uncertain or poor, and compared these predictions with observed outcomes using the Glasgow Outcome Scale-Extended (GOS-E, levels ranging from 1 to 8, with higher levels indicating better outcomes). After excluding cases with life-sustaining therapy withdrawal to mitigate the self-fulfilling prophecy bias, our findings reveal that a good prognosis, compared with a poor or uncertain one, is associated with better one-year functional outcomes (common odds ratio (95% CI) for higher GOS-E: OR = 14.57 (5.70-40.32), P < 0.001; and 2.9 (1.56-5.45), P < 0.001, respectively). Moreover, increasing the number of assessment modalities decreased uncertainty (OR = 0.35 (0.21-0.59), P < 0.001) and improved prognostic accuracy (OR = 2.72 (1.18-6.47), P = 0.011). Our results underscore the value of multimodal assessment in refining neuroprognostic precision, thereby offering a robust foundation for clinical decision-making processes for acutely brain-injured patients. ClinicalTrials.gov registration: NCT04534777 .

Single-trial decoding of auditory novelty responses facilitates the detection of residual consciousness.

Detecting residual consciousness in unresponsive patients is a major clinical concern and a challenge for theoretical neuroscience. To tackle this issue, we recently designed a paradigm that dissociates two electro-encephalographic (EEG) responses to auditory novelty. Whereas a local change in pitch automatically elicits a mismatch negativity (MMN), a change in global sound sequence leads to a late P300b response. The latter component is thought to be present only when subjects consciously perceive the global novelty. Unfortunately, it can be difficult to detect because individual variability is high, especially in clinical recordings. Here, we show that multivariate pattern classifiers can extract subject-specific EEG patterns and predict single-trial local or global novelty responses. We first validate our method with 38 high-density EEG, MEG and intracranial EEG recordings. We empirically demonstrate that our approach circumvents the issues associated with multiple comparisons and individual variability while improving the statistics. Moreover, we confirm in control subjects that local responses are robust to distraction whereas global responses depend on attention. We then investigate 104 vegetative state (VS), minimally conscious state (MCS) and conscious state (CS) patients recorded with high-density EEG. For the local response, the proportion of significant decoding scores (M=60%) does not vary with the state of consciousness. By contrast, for the global response, only 14% of the VS patients' EEG recordings presented a significant effect, compared to 31% in MCS patients' and 52% in CS patients'. In conclusion, single-trial multivariate decoding of novelty responses provides valuable information in non-communicating patients and paves the way towards real-time monitoring of the state of consciousness.

Imaging neural signatures of consciousness: 'what', 'when', 'where' and 'how' does it work?

'What' do we call consciousness? 'When' and 'Where' in the brain do conscious states occur, and 'How' conscious processing and conscious access to a given content work? In the present paper, we present a non-exhaustive overview of each of these 4 major issues, we provide the reader with a brief description of the major difficulties related to these issues, we highlight the current theoretical points of debate, and we advocate for the explanatory power of the "global workspace" model of consciousness (Baars 1989; Dehaene and Naccache 2001; Dehaene, Changeux et al. 2006) which can accommodate for a fairly large proportion of current experimental findings, and which can be used to reinterpret apparent contradictory findings within a single theoretical framework. Most notably, we emphasize the crucial importance to distinguish genuine neural signatures of conscious access from neural events correlated with consciousness but occurring either before ('upstream') or after ('downstream').

[Toward a taxonomy of unconscious perceptual visual processes: from the patient to the healthy subject]. / Vers une taxonomie des traitements perceptifs visuels inconscients : de l'homme malade à l'homme sain.

Our conscious perception is not exhaustive of all the processes at work when we face a visual scene. In the light of a recent theoretical model, - the conscious global workspace model -, which states the necessary and sufficient conditions for a perceptual representation to reach conscious content, we propose here a taxonomy, which distinguishes between four types of unconscious visual processes. For each of them, we will draw close links between several neurological syndromes and experimental visual paradigms, which can be used in the laboratory with normal subjects.

Clinical and advanced neurophysiology in the prognostic and diagnostic evaluation of disorders of consciousness: review of an IFCN-endorsed expert group.

The analysis of spontaneous EEG activity and evoked potentialsis a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). Thepast few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury,opening up the prospect that new concepts and tools may be available at the bedside. This paper provides a comprehensive, critical overview of bothconsolidated and investigational electrophysiological techniquesfor the prognostic and diagnostic assessment of DoC.We describe conventional clinical EEG approaches, then focus on evoked and event-related potentials, and finally we analyze the potential of novel research findings. In doing so, we (i) draw a distinction between acute, prolonged and chronic phases of DoC, (ii) attempt to relate both clinical and research findings to the underlying neuronal processes and (iii) discuss technical and conceptual caveats.The primary aim of this narrative review is to bridge the gap between standard and emerging electrophysiological measures for the detection and prediction of recovery of consciousness. The ultimate scope is to provide a reference and common ground for academic researchers active in the field of neurophysiology and clinicians engaged in intensive care unit and rehabilitation.

What multiple sclerosis could bring to cognitive neuroscience?

The relevance of multiple sclerosis for cognitive neuroscience has evolved significantly during the last decades. After a relative and enduring disinterest, the 1980's has been marked by a first wave of studies aiming at characterizing the cognitive dysfunctions associated with this disease. Once identified, and grouped under the relatively vague and nonspecific concept of "subcorticofrontal syndrome", these cognitive symptoms had to wait until the end of the 1990's to give rise to a new and vigorous resurgence of attention. Interestingly, this genuine contemporary revival of interest originates in the promotion of the very same arguments that served until there to explain the weak investment of multiple sclerosis by neuropsychology and cognitive neuroscience. The early disseminated nature of brain lesions, their dynamic and unstable nature, the prevalence of white-matter lesions, and the alteration of non-modular aspects of cognition: all these arguments have discouraged neuropsychologists for a long time. Today, these very same specific properties of multiple sclerosis offer an extremely relevant model to explore cognitive dimensions of brain plasticity, to revivify the concept of disconnection in neuropsychology, and to evaluate some neuroscientific models of consciousness.

Human consciousness is supported by dynamic complex patterns of brain signal coordination.

Adopting the framework of brain dynamics as a cornerstone of human consciousness, we determined whether dynamic signal coordination provides specific and generalizable patterns pertaining to conscious and unconscious states after brain damage. A dynamic pattern of coordinated and anticoordinated functional magnetic resonance imaging signals characterized healthy individuals and minimally conscious patients. The brains of unresponsive patients showed primarily a pattern of low interareal phase coherence mainly mediated by structural connectivity, and had smaller chances to transition between patterns. The complex pattern was further corroborated in patients with covert cognition, who could perform neuroimaging mental imagery tasks, validating this pattern's implication in consciousness. Anesthesia increased the probability of the less complex pattern to equal levels, validating its implication in unconsciousness. Our results establish that consciousness rests on the brain's ability to sustain rich brain dynamics and pave the way for determining specific and generalizable fingerprints of conscious and unconscious states.

Cerebral mechanisms of word masking and unconscious repetition priming.

We used functional magnetic resonance imaging (fMRI) and event-related potentials (ERPs) to visualize the cerebral processing of unseen masked words. Within the areas associated with conscious reading, masked words activated left extrastriate, fusiform and precentral areas. Furthermore, masked words reduced the amount of activation evoked by a subsequent conscious presentation of the same word. In the left fusiform gyrus, this repetition suppression phenomenon was independent of whether the prime and target shared the same case, indicating that case-independent information about letter strings was extracted unconsciously. In comparison to an unmasked situation, however, the activation evoked by masked words was drastically reduced and was undetectable in prefrontal and parietal areas, correlating with participants' inability to report the masked words.

Language and calculation within the parietal lobe: a combined cognitive, anatomical and fMRI study.

We report the case of a patient (ATH) who suffered from aphasia, deep dyslexia, and acalculia, following a lesion in her left perisylvian area. She showed a severe impairment in all tasks involving numbers in a verbal format, such as reading aloud, writing to dictation, or responding verbally to questions of numerical knowledge. In contrast, her ability to manipulate non-verbal representations of numbers, i.e., Arabic numerals and quantities, was comparatively well preserved, as evidenced for instance in number comparison or number bisection tasks. This dissociated impairment of verbal and non-verbal numerical abilities entailed a differential impairment of the four arithmetic operations. ATH performed much better with subtraction and addition, that can be solved on the basis of quantity manipulation, than with multiplication and division problems, that are commonly solved by retrieving stored verbal sequences. The brain lesion affected the classical language areas, but spared a subset of the left inferior parietal lobule that was active during calculation tasks, as demonstrated with functional MRI. Finally, the relative preservation of subtraction versus multiplication may be related to the fact that subtraction activated the intact right parietal lobe, while multiplication activated predominantly left-sided areas.

Towards a cognitive neuroscience of consciousness: basic evidence and a workspace framework.

This introductory chapter attempts to clarify the philosophical, empirical, and theoretical bases on which a cognitive neuroscience approach to consciousness can be founded. We isolate three major empirical observations that any theory of consciousness should incorporate, namely (1) a considerable amount of processing is possible without consciousness, (2) attention is a prerequisite of consciousness, and (3) consciousness is required for some specific cognitive tasks, including those that require durable information maintenance, novel combinations of operations, or the spontaneous generation of intentional behavior. We then propose a theoretical framework that synthesizes those facts: the hypothesis of a global neuronal workspace. This framework postulates that, at any given time, many modular cerebral networks are active in parallel and process information in an unconscious manner. An information becomes conscious, however, if the neural population that represents it is mobilized by top-down attentional amplification into a brain-scale state of coherent activity that involves many neurons distributed throughout the brain. The long-distance connectivity of these 'workspace neurons' can, when they are active for a minimal duration, make the information available to a variety of processes including perceptual categorization, long-term memorization, evaluation, and intentional action. We postulate that this global availability of information through the workspace is what we subjectively experience as a conscious state. A complete theory of consciousness should explain why some cognitive and cerebral representations can be permanently or temporarily inaccessible to consciousness, what is the range of possible conscious contents, how they map onto specific cerebral circuits, and whether a generic neuronal mechanism underlies all of them. We confront the workspace model with those issues and identify novel experimental predictions. Neurophysiological, anatomical, and brain-imaging data strongly argue for a major role of prefrontal cortex, anterior cingulate, and the areas that connect to them, in creating the postulated brain-scale workspace.

Unconscious semantic priming extends to novel unseen stimuli.

Many subliminal priming experiments are thought to demonstrate unconscious access to semantics. However, most of them can be reinterpreted in a non-semantic framework that supposes only that subjects learn to map non-semantic visual features of the subliminal stimuli onto motor responses. In order to clarify this issue, we engaged subjects in a number comparison task in which the target number was preceded by another invisible masked number. We show that unconscious semantic priming occurs even for prime stimuli that are never presented as target stimuli, and for which no stimulus-response learning could conceivably occur. We also report analyses of the impact of the numerical relation between prime and target, and of the impact of learning on priming, all of which confirm that unconscious utilization of semantic information is indeed possible.

Event-related fMRI analysis of the cerebral circuit for number comparison.

Cerebral activity during number comparison was studied with functional magnetic resonance imaging using an event-related design. We identified an extended network of task-related areas that showed a phasic activation following each trial, including anterior cingulate, bilateral sensorimotor areas, inferior occipito-temporal cortices, posterior parietal cortices, inferior and dorsolateral prefrontal cortices, and thalami. We then tested which of these areas were affected by number notation, numerical distance and response side, three variables that specifically target processes of visual identification, quantity manipulation and motor response in a serial-stage model of the number comparison task. Our results confirm the role of the right fusiform gyrus in digit identification processes, and of the inferior parietal lobule in the internal manipulation of numerical quantities.

Further evidence for a central reorganisation of synaptic connectivity in patients with hypoglossal-facial anastomosis in man.

In normal subjects, electrical stimulation of trigeminal mucosal afferents (lingual nerve - V3) can elicit a short latency (12.5+/-0. 3 ms; mean+/-S.D.) reflex response in the ipsilateral genioglossus muscle (Maisonobe et al., Reflexes elicited from cutaneous and mucosal trigeminal afferents in normal human subjects. Brain Res. 1998;810:220-228). In the present study on patients with hypoglossal-facial (XII-VII) nerve anastomoses, we were able to record similar R1-type blink reflex responses in the orbicularis oculi muscles, following stimulation of either supraorbital nerve (V1) or lingual nerve (V3) afferents. However, these responses were not present in normal control subjects. Voluntary swallowing movements produced clear-cut facilitations of the R1 blink reflex response elicited by stimulation of V1 afferents. In a conditioning-test procedure with a variable inter-stimulus interval, the R1 blink reflex response elicited by supraorbital nerve stimulation was facilitated by an ipsilateral mucosal conditioning stimulus in the V3 region. This facilitatory effect was maximal when the two stimuli (conditioning and test) were applied simultaneously. This effect was not observed on the R1 component of the blink reflex in the normal control subjects. These data strongly suggest that in patients with XII-VII anastomoses, but not in normal subjects, both cutaneous (V1) and mucosal (V3) trigeminal afferents project onto the same interneurones in the trigeminal principal sensory nucleus. This clearly supports the idea that peripheral manipulation of the VIIth and the XIIth nerves induces a plastic change within this nucleus.

[The cerebral substrate of visual consciousness: a neurological approach]. / Les bases cérébrales de la conscience phénoménale visuelle: une approche neurologique.

Since the last thirty Years, scientific study of the cerebral substrate of consciousness has been marked by significant achievements, resulting in part from a rich interaction between the exploration of cognition in both brain-damaged patients and healthy subjects. Several neuropsychological syndromes contain spectacular dissociations which permit to identify principles related to the neurophysiology of consciousness. The generality of those principles can then be evaluated in the healthy subject using the combination of experimental psychology paradigms, and functional brain-imaging tools. In this paper, we review some of the recent results relevant to visual phenomenal consciousness, which is the most scientifically investigated aspect of consciousness. We isolate several of those general principles through the exploration of neuropsychological syndromes such as "blindsight", visual agnosias and neglect, and expose how their generality has been demonstrated in the healthy subject using conditions such as visual illusions or subliminal perception. Finally, we describe the bases of a scientific model of consciousness, based on the concept of a "global workspace", which takes into account the data reviewed.

["Boxer's dementia" without motor signs]. / "Démence pugilistique" sans signes moteurs.

BACKGROUND: The neurological complications related to boxing include dementia. Boxer's dementia is generally associated with severe motor impairment. CASE REPORT: A former professional boxer presented dementia with no motor signs. The diagnostic discussion was based on clinical observations, and neuropsychological and supplementary explorations, and eliminated all other etiological hypotheses. DISCUSSION: This case draws attention to the possibility of cognitive disorders without motor impairment in the neurological complications of boxing.