Auditory Steady-State Responses: Multiplexed Amplitude Modulation Frequencies to Reduce Recording Time.

OBJECTIVES: This study investigated the efficiency of a multiplexed amplitude-modulated (AM) stimulus in eliciting auditory steady-state responses. The multiplexed AM stimulus was created by simultaneously modulating speech-shaped noise with three frequencies chosen to elicit different neural generators: 3.1, 40.1, and 102.1 Hz. For comparison, a single AM stimulus was created for each of these frequencies, resulting in three single AM conditions and one multiplex AM condition. DESIGN: Twenty-two bilaterally normal-hearing participants (18 females) listened for 8 minutes to each type of stimuli. The analysis compared the signal to noise ratios (SNRs) and amplitudes of the evoked responses to the single and multiplexed conditions. RESULTS: The results revealed that the SNRs elicited by single AM conditions were, on average, 1.61 dB higher than those evoked by the multiplexed AM condition ( p < 0.05). The single conditions consistently produced a significantly higher SNR when examining various stimulus durations ranging from 1 to 8 minutes. Despite these SNR differences, the frequency spectrum was very similar across and within subjects. In addition, the sensor space patterns across the scalp demonstrated similar trends between the single and multiplexed stimuli for both SNR and amplitudes. Both the single and multiplexed conditions evoked significant auditory steady-state responses within subjects. On average, the multiplexed AM stimulus took 31 minutes for the lower bound of the 95% prediction interval to cross the significance threshold across all three frequencies. In contrast, the single AM stimuli took 45 minutes and 42 seconds. CONCLUSIONS: These findings show that the multiplexed AM stimulus is a promising method to reduce the recording time when simultaneously obtaining information from various neural generators.

Preservation of Brain Activity in Unresponsive Patients Identifies MCS Star.

OBJECTIVE: Brain-injured patients who are unresponsive at the bedside (ie, vegetative state/unresponsive wakefulness syndrome - VS/UWS) may present brain activity similar to patients in minimally conscious state (MCS). This peculiar condition has been termed "non-behavioural MCS" or "MCS*". In the present study we aimed to investigate the proportion and underlying brain characteristics of patients in MCS*. METHODS: Brain 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) was acquired on 135 brain-injured patients diagnosed in prolonged VS/UWS (n = 48) or MCS (n = 87). From an existing database, relative metabolic preservation in the fronto-parietal network (measured with standardized uptake value) was visually inspected by three experts. Patients with hypometabolism of the fronto-parietal network were labelled "VS/UWS", while its (partial) preservation either confirmed the behavioural diagnosis of "MCS" or, in absence of behavioural signs of consciousness, suggested a diagnosis of "MCS*". Clinical outcome at 1-year follow-up, functional connectivity, grey matter atrophy, and regional brain metabolic patterns were investigated in the three groups (VS/UWS, MCS* and MCS). RESULTS: 67% of behavioural VS/UWS presented a partial preservation of brain metabolism (ie, MCS*). Compared to VS/UWS patients, MCS* patients demonstrated a better outcome, global functional connectivity and grey matter preservation more compatible with the diagnosis of MCS. MCS* patients presented lower brain metabolism mostly in the posterior brain regions compared to MCS patients. INTERPRETATION: MCS* is a frequent phenomenon that is associated with better outcome and better brain preservation than the diagnosis of VS/UWS. Complementary exams should be provided to all unresponsive patients before taking medical decisions. ANN NEUROL 2021;90:89-100.

Diagnostic accuracy of the CRS-R index in patients with disorders of consciousness.

Objective: To obtain a CRS-R index suitable for diagnosis of patients with disorders of consciousness (DOC) and compare it to other CRS-R based scores to evaluate its potential for clinics and research. Design: We evaluated the diagnostic accuracy of several CRS-R-based scores in 124 patients with DOC. ROC analysis of the CRS-R total score, the Rasch-based CRS-R score, CRS-R-MS and the CRS-R index evaluated the diagnostic accuracy for patients with the Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS). Correlations were computed between the CRS-R-MS, CRS-R index, the Rasch-based score and the CRS-R total score. Results: Both the CRS-R-MS and CRS-R index ranged from 0 to 100, with a cut-off of 8.315 that perfectly distinguishes between patients with UWS and MCS. The CRS-R total score and Rasch-based score did not provide a cut-off score for patients with UWS and MCS. The proposed CRS-R index correlated with the CRS-R total score, Rasch-based score and the CRS-R-MS. Conclusion: The CRS-R index is reliable to diagnose patients with UWS and MCS and can be used in compliance with the CRS-R scoring guidelines. The obtained index offers the opportunity to improve the interpretation of clinical assessment and can be used in (longitudinal) research protocols. Abbreviations: CRS-R: Coma Recovery Scale-Revised; CRS-R-MS: Coma Recovery Scale-Revised Modified Score; DOC: Disorders of Consciousness; MCS: Minimally Conscious State; UWS: Unresponsive Wakefulness Syndrome; ROC: Receiver Operating Characteristic; AUC: Area Under the Curve; IRT: Item Response Theory.

Assessment and management of pain/nociception in patients with disorders of consciousness or locked-in syndrome: A narrative review.

The assessment and management of pain and nociception is very challenging in patients unable to communicate functionally such as patients with disorders of consciousness (DoC) or in locked-in syndrome (LIS). In a clinical setting, the detection of signs of pain and nociception by the medical staff is therefore essential for the wellbeing and management of these patients. However, there is still a lot unknown and a lack of clear guidelines regarding the assessment, management and treatment of pain and nociception in these populations. The purpose of this narrative review is to examine the current knowledge regarding this issue by covering different topics such as: the neurophysiology of pain and nociception (in healthy subjects and patients), the source and impact of nociception and pain in DoC and LIS and, finally, the assessment and treatment of pain and nociception in these populations. In this review we will also give possible research directions that could help to improve the management of this specific population of severely brain damaged patients.

Cerebral electrometabolic coupling in disordered and normal states of consciousness.

We assess cerebral integrity with cortical and subcortical FDG-PET and cortical electroencephalography (EEG) within the mesocircuit model framework in patients with disorders of consciousness (DoCs). The mesocircuit hypothesis proposes that subcortical activation facilitates cortical function. We find that the metabolic balance of subcortical mesocircuit areas is informative for diagnosis and is associated with four EEG-based power spectral density patterns, cortical metabolism, and α power in healthy controls and patients with a DoC. Last, regional electrometabolic coupling at the cortical level can be identified in the θ and α ranges, showing positive and negative relations with glucose uptake, respectively. This relation is inverted in patients with a DoC, potentially related to altered orchestration of neural activity, and may underlie suboptimal excitability states in patients with a DoC. By understanding the neurobiological basis of the pathophysiology underlying DoCs, we foresee translational value for diagnosis and treatment of patients with a DoC.

French Survey on Pain Perception and Management in Patients with Locked-In Syndrome.

Patients with locked-in syndrome (LIS) may suffer from pain, which can significantly affect their daily life and well-being. In this study, we aim to investigate the presence and the management of pain in LIS patients. Fifty-one participants completed a survey collecting socio-demographic information and detailed reports regarding pain perception and management (type and frequency of pain, daily impact of pain, treatments). Almost half of the LIS patients reported experiencing pain (49%) that affected their quality of life, sleep and cognition. The majority of these patients reported that they did not communicate their pain to clinical staff. Out of the 25 patients reporting pain, 18 (72%) received treatment (60% pharmacological, 12% non-pharmacological) and described the treatment efficacy as 'moderate'. In addition, 14 (56%) patients were willing to try other non-pharmacological treatments, such as hypnosis or meditation. This study provides a comprehensive characterization of pain perception in LIS patients and highlights the lack of guidelines for pain detection and its management. This is especially pertinent given that pain affects diagnoses, by either inducing fatigue or by using pharmacological treatments that modulate the levels of wakefulness and concentration of such patients.

Evaluation of the effect of analgesic treatment on signs of nociception-related behaviors during physiotherapy in patients with disorders of consciousness: a pilot crossover randomized controlled trial.

ABSTRACT: Neuro-orthopedic disorders are common in patients with disorders of consciousness (DOC) and can lead to potential pain. However, the patients' inability to communicate makes pain detection and management very challenging for clinicians. In this crossover randomized double-blind placebo-controlled study, we investigated the effects of an analgesic treatment on the presence of nociception-related behaviors. At baseline, the Nociception Coma Scale-Revised (NCS-R) was performed in 3 conditions: a non-noxious stimulation, a noxious stimulation, and during a physiotherapy session. Patients with a NCS-R total score during physiotherapy equal or above the score observed after the noxious stimulation could participate to the clinical trial, as well as patients with a score above 5. They received an analgesic treatment and a placebo on 2 consecutive days in a randomized order followed by an assessment with the NCS-R. Of the 18 patients, 15 displayed signs of potential pain during physiotherapy. Patients showed higher NCS-R scores during physiotherapy compared with the other conditions, suggesting that mobilizations were potentially painful. Of these 15 patients, 10 met the criteria to participate in the placebo-controlled trial. We did not find any effect of analgesic treatment on the NCS-R scores. This study highlights that physiotherapy may be potentially painful for patients with DOC, while analgesic treatments did not reduced NCS-R scores. Therefore, careful monitoring with appropriate assessment and treatment before and during mobilization should become a priority in clinical settings. Future studies should focus on the development of assessment tools sensitive to analgesic dosage to manage pain in DOC.

SECONDs Administration Guidelines: A Fast Tool to Assess Consciousness in Brain-injured Patients.

Establishing an accurate diagnosis is crucial for patients with disorders of consciousness (DoC) following a severe brain injury. The Coma Recovery Scale-Revised (CRS-R) is the recommended behavioral scale for assessing the level of consciousness among these patients, but its long duration of administration is a major hurdle in clinical settings. The Simplified Evaluation of CONsciousness Disorders (SECONDs) is a shorter scale that was developed to tackle this issue. It consists of six mandatory items, observation, command-following, visual pursuit, visual fixation, oriented behaviors, and arousal, and two conditional items, communication and localization to pain. The score ranges between 0 and 8 and corresponds to a specific diagnosis (i.e., coma, unresponsive wakefulness syndrome, minimally conscious state minus/plus, or emergence from the minimally conscious state). A first validation study on patients with prolonged DoC showed high concurrent validity and intra- and inter-rater reliability. The SECONDs requires less training than the CRS-R and its administration lasts about 7 minutes (interquartile range: 5-9 minutes). An additional index score allows the more precise tracking of a patient's behavioral fluctuation or evolution over time. The SECONDs is therefore a fast and valid tool for assessing the level of consciousness in patients with severe brain injury. It can easily be used by healthcare staff and implemented in time-constrained clinical settings, such as intensive care units, to help decrease misdiagnosis rates and to optimize treatment decisions. These administration guidelines provide detailed instructions for administering the SECONDs in a standardized and reproducible manner, which is an essential requirement for achieving a reliable diagnosis.

Near-Death Experience Memories Include More Episodic Components Than Flashbulb Memories.

Memories of near-death experiences (NDEs) are recalled as "realer" than memories of other real or imagined events. Given their rich phenomenology, emotionality and consequentiality, it was hypothesized that they could meet some aspects of the definition of flashbulb memories. We aimed to identify and compare the episodic and non-episodic information provided in verbal recollections of NDE, flashbulb, and control autobiographical memories. The phenomenological characteristics and centrality of the memories were also compared. Twenty-five participants who had lived a NDE in a life-threatening situation were interviewed and completed the Memory Characteristics Questionnaires as well as the Centrality of Event Scale for their NDE, a flashbulb and another autobiographical memory used as control. Overall, transcribed NDE verbal recollections included a higher overall amount of details and more internal/episodic information than control autobiographical and flashbulb memories. Moreover, flashbulb memories were associated to a lower intensity of feelings while remembering and a lower personal importance, and are less reactivated and less susceptible to be remembered from a first person perspective compared to NDE and control autobiographical memories. Finally, NDE memories are the most central memories to experiencers' identity, followed by control autobiographical and then by flashbulb memories. These findings corroborate previous studies highlighting the impact and uniqueness of NDE memories.

Auditory and Somatosensory P3 Are Complementary for the Assessment of Patients with Disorders of Consciousness.

The evaluation of the level of consciousness in patients with disorders of consciousness (DOC) is primarily based on behavioural assessments. Patients with unresponsive wakefulness syndrome (UWS) do not show any sign of awareness of their environment, while minimally conscious state (MCS) patients show reproducible but fluctuating signs of awareness. Some patients, although with remaining cognitive abilities, are not able to exhibit overt voluntary responses at the bedside and may be misdiagnosed as UWS. Several studies investigated functional neuroimaging and neurophysiology as an additional tool to evaluate the level of consciousness and to detect covert command following in DOC. Most of these studies are based on auditory stimulation, neglecting patients suffering from decreased or absent hearing abilities. In the present study, we aim to assess the response to a P3-based paradigm in 40 patients with DOC and 12 healthy participants using auditory (AEP) and vibrotactile (VTP) stimulation. To this end, an EEG-based brain-computer interface was used at DOC patient's bedside. We compared the significance of the P3 performance (i.e., the interpretation of significance of the evoked P3 response) as obtained by 'direct processing' (i.e., theoretical-based significance threshold) and 'offline processing' (i.e., permutation-based single subject level threshold). We evaluated whether the P3 performances were dependent on clinical variables such as diagnosis (UWS and MCS), aetiology and time since injury. Last we tested the dependency of AEP and VTP performances at the single subject level. Direct processing tends to overestimate P3 performance. We did not find any difference in the presence of a P3 performance according to the level of consciousness (UWS vs. MCS) or the aetiology (traumatic vs. non-traumatic brain injury). The performance achieved at the AEP paradigm was independent from what was achieved at the VTP paradigm, indicating that some patients performed better on the AEP task while others performed better on the VTP task. Our results support the importance of using multimodal approaches in the assessment of DOC patients in order to optimise the evaluation of patient's abilities.

Nociception Coma Scale-Revised Allows to Identify Patients With Preserved Neural Basis for Pain Experience.

The Nociception Coma Scale-Revised (NCS-R) was developed to help assess pain in patients with disorders of consciousness (DOC). Several studies have shown its sensitivity in assessing response to acute noxious stimuli. However, they failed to determine a reliable cut-off score that could be used to infer pain processing in these patients. This retrospective cross-sectional study aimed to determine a NCS-R cut-off score supporting preserved neural basis for pain experience, based on brain metabolism preservation as measured by fluorodeoxyglucose positron emission tomography (FDG-PET). We included patients in unresponsive wakefulness syndrome (UWS) confirmed by the FDG-PET and examined the NCS-R total scores. As the highest score was 4, we defined the cut-off to be 5 and compared the brain metabolism of these patients to matched patients with DOC and a NCS-R cut-off score ≥5 (ie, potential pain), as well as healthy subjects. We found a higher global cerebral metabolism in healthy subjects compared to both patient groups and also in patients with potential pain compared with FDG-PET confirmed UWS. We observed a preserved metabolism in the left insula in patients with potential pain compared with FDG-PET confirmed UWS. PERSPECTIVES: Our data suggest that using the cut-off score of 5 could be helpful to improve pain management in patients with DOC. Future studies should focus on patients showing scores below this cut-off to better characterize their profile and improve care.

Treating Disorders of Consciousness With Apomorphine: Protocol for a Double-Blind Randomized Controlled Trial Using Multimodal Assessments.

Background: There are few available therapeutic options to promote recovery among patients with chronic disorders of consciousness (DOC). Among pharmacological treatments, apomorphine, a dopamine agonist, has exhibited promising behavioral effects and safety of use in small-sample pilot studies. The true efficacy of the drug and its neural mechanism are still unclear. Apomorphine may act through a modulation of the anterior forebrain mesocircuit, but neuroimaging and neurophysiological investigations to test this hypothesis are scarce. This clinical trial aims to (1) assess the treatment effect of subcutaneous apomorphine infusions in patients with DOC, (2) better identify the phenotype of responders to treatment, (3) evaluate tolerance and side effects in this population, and (4) examine the neural networks underlying its modulating action on consciousness. Methods/Design: This study is a prospective double-blind randomized parallel placebo-controlled trial. Forty-eight patients diagnosed with DOC will be randomized to receive a 30-day regimen of either apomorphine hydrochloride or placebo subcutaneous infusions. Patients will be monitored at baseline 30 days before initiation of therapy, during treatment and for 30 days after treatment washout, using standardized behavioral scales (Coma Recovery Scale-Revised, Nociception Coma Scale-Revised), neurophysiological measures (electroencephalography, body temperature, actigraphy) and brain imaging (magnetic resonance imaging, positron emission tomography). Behavioral follow-up will be performed up to 2 years using structured phone interviews. Analyses will look for changes in behavioral status, circadian rhythmicity, brain metabolism, and functional connectivity at the individual level (comparing before and after treatment) and at the group level (comparing apomorphine and placebo arms, and comparing responder and non-responder groups). Discussion: This study investigates the use of apomorphine for the recovery of consciousness in the first randomized placebo-controlled double-blind trial using multimodal assessments. The results will contribute to define the role of dopamine agonists for the treatment of these challenging conditions and identify the neural correlates to their action. Results will bring objective evidence to further assess the modulation of the anterior forebrain mesocircuit by pharmacological agents, which may open new therapeutic perspectives. Clinical Trial Registration: EudraCT n°2018-003144-23; Clinicaltrials.gov n°NCT03623828 (https://clinicaltrials.gov/ct2/show/NCT03623828).