Twenty-four-hour rhythmicities in disorders of consciousness are associated with a favourable outcome.

Fluctuations of consciousness and their rhythmicities have been rarely studied in patients with a disorder of consciousness after acute brain injuries. 24-h assessment of brain (EEG), behaviour (eye-opening), and circadian (clock-controlled hormones secretion from urine) functions was performed in acute brain-injured patients. The distribution, long-term predictability, and rhythmicity (circadian/ultradian) of various EEG features were compared with the initial clinical status, the functional outcome, and the circadian rhythmicities of behaviour and clock-controlled hormones. Here we show that more physiological and favourable patterns of fluctuations are associated with a higher 24 h predictability and sharp up-and-down shape of EEG switches, reminiscent of the Flip-Flop model of sleep. Multimodal rhythmic analysis shows that patients with simultaneous circadian rhythmicity for brain, behaviour, and hormones had a favourable outcome. Finally, both re-emerging EEG fluctuations and homogeneous 24-h cycles for EEG, eye-opening, and hormones appeared as surrogates for preserved functionality in brainstem and basal forebrain, which are key prognostic factors for later improvement. While the recovery of consciousness has previously been related to a high short-term complexity, we suggest in this exploratory study the importance of the high predictability of the 24 h long-term generation of brain rhythms and highlight the importance of circadian body-brain rhythms in awakening.

Self-processing in coma, unresponsive wakefulness syndrome and minimally conscious state.

Introduction: Behavioral and cerebral dissociation has been now clearly established in some patients with acquired disorders of consciousness (DoC). Altogether, these studies mainly focused on the preservation of high-level cognitive markers in prolonged DoC, but did not specifically investigate lower but key-cognitive functions to consciousness emergence, such as the ability to take a first-person perspective, notably at the acute stage of coma. We made the hypothesis that the preservation of self-recognition (i) is independent of the behavioral impairment of consciousness, and (ii) can reflect the ability to recover consciousness. Methods: Hence, using bedside Electroencephalography (EEG) recordings, we acquired, in a large cohort of 129 severely brain damaged patients, the brain response to the passive listening of the subject's own name (SON) and unfamiliar other first names (OFN). One hundred and twelve of them (mean age ± SD = 46 ± 18.3 years, sex ratio M/F: 71/41) could be analyzed for the detection of an individual and significant discriminative P3 event-related brain response to the SON as compared to OFN ('SON effect', primary endpoint assessed by temporal clustering permutation tests). Results: Patients were either coma (n = 38), unresponsive wakefulness syndrome (UWS, n = 30) or minimally conscious state (MCS, n = 44), according to the revised version of the Coma Recovery Scale (CRS-R). Overall, 33 DoC patients (29%) evoked a 'SON effect'. This electrophysiological index was similar between coma (29%), MCS (23%) and UWS (34%) patients (p = 0.61). MCS patients at the time of enrolment were more likely to emerged from MCS (EMCS) at 6 months than coma and UWS patients (p = 0.013 for comparison between groups). Among the 72 survivors' patients with event-related responses recorded within 3 months after brain injury, 75% of the 16 patients with a SON effect were EMCS at 6 months, while 59% of the 56 patients without a SON effect evolved to this favorable behavioral outcome. Discussion: About 30% of severely brain-damaged patients suffering from DoC are capable to process salient self-referential auditory stimuli, even in case of absence of behavioral detection of self-conscious processing. We suggest that self-recognition covert brain ability could be an index of consciousness recovery, and thus could help to predict good outcome.

Impairment of central language processing in critically ill coronavirus disease 2019 patients with delirium.

Accumulating evidence indicates that coronavirus disease 2019 is a major cause of delirium. Given the global dimension of the current pandemic and the fact that delirium is a strong predictor of cognitive decline for critically ill patients, this raises concerns regarding the neurological cost of coronavirus disease 2019. Currently, there is a major knowledge gap related to the covert yet potentially incapacitating higher-order cognitive impairment underpinning coronavirus disease 2019 related delirium. The aim of the current study was to analyse the electrophysiological signatures of language processing in coronavirus disease 2019 patients with delirium by using a specifically designed multidimensional auditory event-related potential battery to probe hierarchical cognitive processes, including self-processing (P300) and semantic/lexical priming (N400). Clinical variables and electrophysiological data were prospectively collected in controls subjects (n = 14) and in critically ill coronavirus disease 2019 patients with (n = 19) and without (n = 22) delirium. The time from intensive care unit admission to first clinical sign of delirium was of 8 (3.5-20) days, and the delirium lasted for 7 (4.5-9.5) days. Overall, we have specifically identified in coronavirus disease 2019 patients with delirium, both a preservation of low-level central auditory processing (N100 and P200) and a coherent ensemble of covert higher-order cognitive dysfunctions encompassing self-related processing (P300) and sematic/lexical language priming (N400) (spatial-temporal clustering, P-cluster ≤ 0.05). We suggest that our results shed new light on the neuropsychological underpinnings of coronavirus disease 2019 related delirium, and may constitute a valuable method for patient's bedside diagnosis and monitoring in this clinically challenging setting.

The Importance of Material Used in Speech Therapy: Two Case Studies in Minimally Conscious State Patients.

Speech therapy can be part of the care pathway for patients recovering from comas and presenting a disorder of consciousness (DOC). Although there are no official recommendations for speech therapy follow-up, neuroscientific studies suggest that relevant stimuli may have beneficial effects on the behavioral assessment of patients with a DOC. In two case studies, we longitudinally measured (from 4 to 6 weeks) the behavior (observed in a speech therapy session or using items from the Coma Recovery Scale-Revised) of two patients in a minimally conscious state (MCS) when presenting music and/or autobiographical materials. The results highlight the importance of using relevant material during a speech therapy session and suggest that a musical context with a fast tempo could improve behavior evaluation compared to noise. This work supports the importance of adapted speech therapy for MCS patients and encourages larger studies to confirm these initial observations.

Virtually spatialized sounds enhance auditory processing in healthy participants and patients with a disorder of consciousness.

Neuroscientific and clinical studies on auditory perception often use headphones to limit sound interference. In these conditions, sounds are perceived as internalized because they lack the sound-attributes that normally occur with a sound produced from a point in space around the listener. Without the spatial attention mechanisms that occur with localized sounds, auditory functional assessments could thus be underestimated. We hypothesize that adding virtually externalization and localization cues to sounds through headphones enhance sound discrimination in both healthy participants and patients with a disorder of consciousness (DOC). Hd-EEG was analyzed in 14 healthy participants and 18 patients while they listened to self-relevant and irrelevant stimuli in two forms: diotic (classic sound presentation with an "internalized" feeling) and convolved with a binaural room impulse response (to create an "externalized" feeling). Convolution enhanced the brains' discriminative response as well as the processing of irrelevant sounds itself, in both healthy participants and DOC patients. For the healthy participants, these effects could be associated with enhanced activation of both the dorsal (where/how) and ventral (what) auditory streams, suggesting that spatial attributes support speech discrimination. Thus, virtually spatialized sounds might "call attention to the outside world" and improve the sensitivity of assessment of brain function in DOC patients.

Sharing an Open Stimulation System for Auditory EEG Experiments Using Python, Raspberry Pi, and HifiBerry.

In auditory behavioral and EEG experiments, the variability of stimulation solutions, for both software and hardware, adds unnecessary technical constraints. Currently, there is no easy to use, inexpensive, and shareable solution that could improve collaborations and data comparisons across different sites and contexts. This article outlines a system composed by a Raspberry Pi coupled with Python programming and associated with a HifiBerry sound card. We compare its sound performances with those of a wide variety of materials and configurations. This solution achieves the high timing accuracy and sound quality important in auditory cognition experiments, while being simple to use and open source. The present system shows high performances and results along with excellent feedback from users. It is inexpensive, easy to build, share, and improve on. Working with such low-cost, powerful, and collaborative hardware and software tools allows people to create their own specific, adapted, and shareable system that can be standardized across different collaborative sites, while being extremely simple and robust in use.

Personal familiarity of music and its cerebral effect on subsequent speech processing.

Despite the obvious personal relevance of some musical pieces, the cerebral mechanisms associated with listening to personally familiar music and its effects on subsequent brain functioning have not been specifically evaluated yet. We measured cerebral correlates with functional magnetic resonance imaging (fMRI) while composers listened to three types of musical excerpts varying in personal familiarity and self (familiar own/composition, familiar other/favorite or unfamiliar other/unknown music) followed by sequences of names of individuals also varying in personal familiarity and self (familiar own/own name, familiar other/close friend and unfamiliar other/unknown name). Listening to music with autobiographical contents (familiar own and/or other) recruited a fronto-parietal network including mainly the dorsolateral prefrontal cortex, the supramarginal/angular gyri and the precuneus. Additionally, while listening to familiar other music (favorite) was associated with the activation of reward and emotion networks (e.g. the striatum), familiar own music (compositions) engaged brain regions underpinning self-reference (e.g. the medial prefrontal cortex) and visuo-motor imagery. The present findings further suggested that familiar music with self-related reference (compositions) leads to an enhanced activation of the autobiographical network during subsequent familiar name processing (as compared to music without self-related reference); among these structures, the precuneus seems to play a central role in personally familiar processing.

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.

On the externalization of sound sources with headphones without reference to a real source.

Sounds presented over headphones are generally perceived as internalized, i.e., originating from a source inside the head. Prior filtering by binaural room impulse responses (BRIRs) can create externalized sources. Previous studies concluded that these BRIRs need to be listener-specific to produce good externalization; however, listeners were generally facing a loudspeaker and asked to rate externalization relative to that loudspeaker, meaning that the source had to be perceived outside the head and also at the right distance. The present study investigated externalization when there is no visual source to match. Overall, lateral sources were perceived as more externalized than frontal sources. Experiment 1 showed that the perceived externalization obtained with non-individualized BRIRs measured in three different rooms was similar to that obtained with a state-of-the-art simulation using individualized BRIRs. Experiment 2 indicated that when there is no real source spectrum to match, headphone equalization does not improve externalization. Experiment 3 further showed that reverberation improved externalization only when it introduced interaural differences. Correlation analyses finally showed a close correspondence between perceived externalization and binaural cues (especially interaural coherence).

Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients.

Circadian rhythmicity (CR) is involved in the regulation of all integrated functions, from sleep-wake cycle regulation to metabolic function, mood and cognition. However, the interdependence of CR, cognition and consciousness has been poorly addressed. To clarify the state of CR in coma and to determine the chronological relationship between its recovery and consciousness after brain lesions, we conducted a longitudinal observational study investigating how the state of CR was chronologically related with the recovery of behavioural wakefulness, cognition and/or awareness. Among 16 acute comatose patients, we recruited two 37-year-old patients with a persistent disorder of consciousness, presenting diencephalic lesions caused by severe traumatic brain injuries. Two biological urinary markers of CR were explored every 2 hours during 24 hours (6-sulfatoxymelatonin, free cortisol) with a dedicated methodology to extract the endogenous component of rhythmicity (environmental light recording, near-constant-routine protocol, control of beta-blockers). They presented an initial absence of rhythmic secretions and a recovered CR 7-8 months later. This recovery was not associated with the restoration of behavioural wakefulness, but with an improvement of cognition and awareness (up to the minimally conscious state). MRI showed a lesion pattern compatible with the interruption of either the main hypothalamic-sympathetic pathway or the accessory habenular pathway. These results suggest that CR may be a prerequisite for coma recovery with a potential but still unproven favourable effect on brain function of the resorted circadian melatonin secretion and/or the functional recovery of the suprachiasmatic nucleus (SCN). Assessing circadian functions by urinary melatonin should be further explored as a biomarker of cognition reappearance and investigated to prognosticate functional recovery.

Electrodermal reactivity to emotional stimuli in healthy subjects and patients with disorders of consciousness.

OBJECTIVES: After a coma, one major challenge is the detection of awareness in patients with disorders of consciousness. In some patients, the only manifestation indicative of awareness is an appropriate emotional response. Preferred music is a powerful medium to elicit emotions and autobiographical memory. Furthermore, music has been shown to improve cognitive functions both in healthy subjects and patients with neurological impairment. We hypothesized that signs of awareness could be enhanced in some patients with disorders of consciousness under appropriate emotional stimulation such as preferred music and also probably preferred odors. METHODS: To investigate an objective, easily recordable marker of emotions at the patients' bedside, electrodermal activity (skin conductance level, SCL) was assessed with stimulations in auditory and olfactory modalities, notably with preferred music, neutral sound, preferred odors, and neutral odors. The study was conducted in 11 patients with disorders of consciousness (DOC) and 7 healthy participants. RESULTS: In healthy subjects, the mean amplitude of the SCL was increased during exposure to preferred music as compared to neutral sounds (respectively: 0.00037±0.0004 vs. - 0.00004±0.00019µS). No significant difference between conditions was detected in patients. CONCLUSION: The results of this study suggest that electrodermal activity could be a useful marker of emotions induced by music in healthy controls. However, it failed to show any significant difference between conditions in patients with DOC.

Multidimensional cognitive evaluation of patients with disorders of consciousness using EEG: A proof of concept study.

The use of cognitive evoked potentials in EEG is now part of the routine evaluation of non-communicating patients with disorders of consciousness in several specialized medical centers around the world. They typically focus on one or two cognitive markers, such as the mismatch negativity or the P3 to global auditory regularity. However it has become clear that none of these markers in isolation is at the same time sufficiently specific and sufficiently sensitive to be taken as the unique gold standard for diagnosing consciousness. A good way forward would be to combine several cognitive markers within the same test to improve evaluation. Furthermore, given the diversity of lesions leading to disorders of consciousness, it is important not only to probe whether a patient is conscious or not, but also to establish a more general and nuanced profile of the residual cognitive capacities of each patient using a combination of markers. In the present study we built a unique EEG protocol that probed 8 dimensions of cognitive processing in a single 1.5 h session. This protocol probed variants of classical markers together with new markers of spatial attention, which has not yet been studied in these patients. The eight dimensions were: (1) own name recognition, (2) temporal attention, (3) spatial attention, (4) detection of spatial incongruence (5) motor planning, and (6,7,8) modulations of these effects by the global context, reflecting higher-level functions. This protocol was tested in 15 healthy control subjects and in 17 patients with various etiologies, among which 13 could be included in the analysis. The results in the control group allowed a validation and a specific description of the cognitive levels probed by each marker. At the single-subject level, this combined protocol allowed assessing the presence of both classical and newly introduced markers for each patient and control, and revealed that the combination of several markers increased diagnostic sensitivity. The presence of a high-level effect in any of the three tested domains distinguished between minimally conscious and vegetative patients, while the presence of low-level effects was similar in both groups. In summary, this study constitutes a validated proof of concept in favor of probing multiple cognitive dimensions to improve the evaluation of non-communicating patients. At a more conceptual level, this EEG tool can help achieve a better understanding of disorders of consciousness by exploring consciousness in its multiple cognitive facets.

Exploration of Functional Connectivity During Preferred Music Stimulation in Patients with Disorders of Consciousness.

Preferred music is a highly emotional and salient stimulus, which has previously been shown to increase the probability of auditory cognitive event-related responses in patients with disorders of consciousness (DOC). To further investigate whether and how music modifies the functional connectivity of the brain in DOC, five patients were assessed with both a classical functional connectivity scan (control condition), and a scan while they were exposed to their preferred music (music condition). Seed-based functional connectivity (left or right primary auditory cortex), and mean network connectivity of three networks linked to conscious sound perception were assessed. The auditory network showed stronger functional connectivity with the left precentral gyrus and the left dorsolateral prefrontal cortex during music as compared to the control condition. Furthermore, functional connectivity of the external network was enhanced during the music condition in the temporo-parietal junction. Although caution should be taken due to small sample size, these results suggest that preferred music exposure might have effects on patients auditory network (implied in rhythm and music perception) and on cerebral regions linked to autobiographical memory.

Promoting the use of personally relevant stimuli for investigating patients with disorders of consciousness.

Sensory stimuli are used to evaluate and to restore cognitive functions and consciousness in patients with a disorder of consciousness (DOC) following a severe brain injury. Although sophisticated protocols can help assessing higher order cognitive functions and awareness, one major drawback is their lack of sensitivity. The aim of the present review is to show that stimulus selection is crucial for an accurate evaluation of the state of patients with disorders of consciousness as it determines the levels of processing that the patient can have with stimulation from his/her environment. The probability to observe a behavioral response or a cerebral response is increased when her/his personal history and/or her/his personal preferences are taken into account. We show that personally relevant stimuli (i.e., with emotional, autobiographical, or self-related characteristics) are associated with clearer signs of perception than are irrelevant stimuli in patients with DOC. Among personally relevant stimuli, music appears to be a promising clinical tool as it boosts perception and cognition in patients with DOC and could also serve as a prognostic tool. We suggest that the effect of music on cerebral processes in patients might reflect the music's capacity to act both on the external and internal neural networks supporting consciousness.

Boosting Cognition With Music in Patients With Disorders of Consciousness.

BACKGROUND: Music listening conveys beneficial effects on cognitive processes in both normal and pathologic cerebral functioning. Surprisingly, no quantitative study has evaluated the potential effects of music on cognition and consciousness in patients with disorders of consciousness. OBJECTIVE: The aim of the present study was to evaluate the effect of music on cerebral processing in patients with disorders of consciousness. METHODS: Using bedside electroencephalographic recording, we acquired in 13 patients with disorders of consciousness event-related potentials to the patient's first name after either an excerpt of the patient's preferred music (music condition) or a continuous sound (control condition). RESULTS: The cerebral response to the patient's first name was more often observed in the music condition, than in the control condition. Furthermore, the presence or absence of a discriminative response in the music condition seemed to be associated with a favorable or unfavorable outcome, respectively. CONCLUSIONS: These findings demonstrate for the first time that music has a beneficial effect on cognitive processes of patients with disorders of consciousness. The autobiographical characteristics of music, that is, its emotional and personal relevance, probably increase arousal and/or awareness.

Sensorimotor Learning Enhances Expectations During Auditory Perception.

Sounds that have been produced with one's own motor system tend to be remembered better than sounds that have only been perceived, suggesting a role of motor information in memory for auditory stimuli. To address potential contributions of the motor network to the recognition of previously produced sounds, we used event-related potential, electric current density, and behavioral measures to investigate memory for produced and perceived melodies. Musicians performed or listened to novel melodies, and then heard the melodies either in their original version or with single pitch alterations. Production learning enhanced subsequent recognition accuracy and increased amplitudes of N200, P300, and N400 responses to pitch alterations. Premotor and supplementary motor regions showed greater current density during the initial detection of alterations in previously produced melodies than in previously perceived melodies, associated with the N200. Primary motor cortex was more strongly engaged by alterations in previously produced melodies within the P300 and N400 timeframes. Motor memory traces may therefore interface with auditory pitch percepts in premotor regions as early as 200 ms following perceived pitch onsets. Outcomes suggest that auditory-motor interactions contribute to memory benefits conferred by production experience, and support a role of motor prediction mechanisms in the production effect.

Metrical presentation boosts implicit learning of artificial grammar.

The present study investigated whether a temporal hierarchical structure favors implicit learning. An artificial pitch grammar implemented with a set of tones was presented in two different temporal contexts, notably with either a strongly metrical structure or an isochronous structure. According to the Dynamic Attending Theory, external temporal regularities can entrain internal oscillators that guide attention over time, allowing for temporal expectations that influence perception of future events. Based on this framework, it was hypothesized that the metrical structure provides a benefit for artificial grammar learning in comparison to an isochronous presentation. Our study combined behavioral and event-related potential measurements. Behavioral results demonstrated similar learning in both participant groups. By contrast, analyses of event-related potentials showed a larger P300 component and an earlier N2 component for the strongly metrical group during the exposure phase and the test phase, respectively. These findings suggests that the temporal expectations in the strongly metrical condition helped listeners to better process the pitch dimension, leading to improved learning of the artificial grammar.

Similarities in the neural signature for the processing of behaviorally categorized and uncategorized speech sounds.

Recent human behavioral studies have shown semantic and/or lexical processing for stimuli presented below the auditory perception threshold. Here, we investigated electroencephalographic responses to words, pseudo-words and complex sounds, in conditions where phonological and lexical categorizations were behaviorally successful (categorized stimuli) or unsuccessful (uncategorized stimuli). Data showed a greater decrease in low-beta power at left-hemisphere temporal electrodes for categorized non-lexical sounds (complex sounds and pseudo-words) than for categorized lexical sounds (words), consistent with the signature of a failure in lexical access. Similar differences between lexical and non-lexical sounds were observed for uncategorized stimuli, although these stimuli did not yield evoked potentials or theta activity. The results of the present study suggest that behaviorally uncategorized stimuli were processed at the lexical level, and provide evidence of the neural bases of the results observed in previous behavioral studies investigating auditory perception in the absence of stimulus awareness.