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International audience; ObjectiveBrain-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*.MethodsBrain 18F-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).Results67% 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.InterpretationMCS* 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

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.

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.

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.

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).

Treatment with apomorphine, a dopamine agonist, has exhibited promising effects on the recovery of patients with disorders of consciousness (DOC) due to traumatic brain injury. This prospective open-label clinical trial aims to confirm its efficacy and investigate its action on brain activity. Patients with chronic DOC were administered subcutaneous apomorphine for 30 days. They were monitored 30 days before initiation, during treatment and 30 days after withdrawal. Outcome measures included Coma Recovery Scale – Revised (CRS-R), actigraphy, positron emission tomography (PET) and electroencephalography-based (EEG) metrics such as network centrality and a multivariate machine-learning classifier.

Aims: Treatment with apomorphine, a dopamine agonist, has exhibited behavioral effects on the recovery of patients with disorders of consciousness (DOC)[1,2], but its action on brain activity remains unknown. We report the preliminary results of a prospective open-label study using multimodal assessment methods, which aims to confirm the efficacy and investigate the mechanism of apomorphine treatment among post-coma patients. Methods: Three patients with chronic DOC (1 female, 2 males; 47, 34 and 23 years old; 1 hemorrhage, 2 traumatic; 3.5, 4.5 and 3 months since onset) were administered subcutaneous apomorphine for 30 days. They were followed 30 days before initiation, during treatment and 30 days after withdrawal. Outcome measures included Coma Recovery Scale – Revised (CRS-R)[3], positron emission tomography (PET)[4,5] and electroencephalography-based (EEG) measures such as functional connectivity[6] and multivariate machine-learning classification[7,8]. Results: At baseline, patients 1 and 2 were diagnosed with the CRS-R as minimally conscious state (MCS) minus[9,10] (language-independent signs of consciousness), and patient 3 as MCS plus (language-related signs of consciousness). After the initiation of apomorphine, patient 1 improved to MCS plus, patient 2 remained in MCS minus but showed a new sign of consciousness and more consistent behaviors, and patient 3 emerged from the MCS. PET revealed an improvement of global brain metabolism after compared to before apomorphine treatment for all three patients (difference of +43%, +26%, and +4% for patient 1, 2 and 3 respectively). Functional connectivity measured by EEG network centrality also increased after treatment for all patients in the alpha frequency bands. EEG multivariate classifier improved after treatment for two patients (difference of +25%, +20%, -1% for patient 1, 2, and 3 respectively) with significant increase in most individual EEG markers. Conclusion: After treatment, patients showed multimodal improvements with more frequent conscious behaviors and increased brain activity measures compared to baseline observations. These results suggest that the action of apomorphine on the recovery of DOC patients may be associated with measurable neuroimaging changes. Additional results from the subsequent placebo-controlled randomized controlled trial[11] will be necessary to confirm the efficacy and further define the neural effects of apomorphine treatment in severely brain-injured patients.