Exploring the Significance of Cognitive Motor Dissociation on Patient Outcome in Acute Disorders of Consciousness.

Cognitive motor dissociation (CMD) is characterized by a dissociation between volitional brain responses and motor control, detectable only through techniques such as electroencephalography (EEG) and functional magnetic resonance imaging. Hence, it has recently emerged as a major challenge in the assessment of patients with disorders of consciousness. Specifically, this review focuses on the prognostic implications of CMD detection during the acute stage of brain injury. CMD patients were identified in each diagnostic category (coma, unresponsive wakefulness syndrome/vegetative state, minimally conscious state minus) with a relatively similar prevalence of around 20%. Current knowledge tends to indicate that the diagnosis of CMD in the acute phase often predicts a more favorable clinical outcome compared with other unresponsive non-CMD patients. Nevertheless, the review underscores the limited research in this domain, probably at least partially explained by its nascent nature and the lack of uniformity in the nomenclature for CMD-related disorders, hindering the impact of the literature in the field.

A Scoping Review on the Use of Non-Invasive Brain Stimulation Techniques for Persistent Post-Concussive Symptoms.

BACKGROUND: In the context of managing persistent post-concussive symptoms (PPCS), existing treatments like pharmacotherapy, cognitive behavioral therapy, and physical rehabilitation show only moderate effectiveness. The emergence of neuromodulation techniques in PPCS management has led to debates regarding optimal stimulation parameters and their overall efficacy. METHODS: this scoping review involved a comprehensive search of PubMed and ScienceDirect databases, focusing on controlled studies examining the therapeutic potential of non-invasive brain stimulation (NIBS) techniques in adults with PPCS. RESULTS: Among the 940 abstracts screened, only five studies, encompassing 103 patients (12 to 29 per study), met the inclusion criteria. These studies assessed the efficacy of transcranial direct current stimulation (tDCS), or repetitive transcranial magnetic stimulation (rTMS), applied to specific brain regions (i.e., the left dorsolateral pre-frontal cortex (DLPFC) or left motor cortex (M1)) for addressing cognitive and psychological symptoms, headaches, and general PPCSs. The results indicated improvements in cognitive functions with tDCS. In contrast, reductions in headache intensity and depression scores were observed with rTMS, while no significant findings were noted for general symptoms with rTMS. CONCLUSION: although these pilot studies suggest promise for rTMS and tDCS in PPCS management, further research with larger-scale investigations and standardized protocols is imperative to enhance treatment outcomes for PPCS patients.

Neuro-orthopaedic assessment and management in patients with prolonged disorders of consciousness: A review.

BACKGROUND: Following a severe acquired brain injury, neuro-orthopaedic disorders are commonplace. While these disorders can impact patients' functional recovery and quality of life, little is known regarding the assessment, management and treatment of neuro-orthopaedic disorders in patients with disorders of consciousness (DoC). OBJECTIVE: To describe neuro-orthopaedic disorders in the context of DoC and provide insights on their management and treatment. METHODS: A review of the literature was conducted focusing on neuro-orthopaedic disorders in patients with prolonged DoC. RESULTS: Few studies have investigated the prevalence of spastic paresis in patients with prolonged DoC, which is extremely high, as well as its correlation with pain. Pilot studies exploring the effects of pharmacological treatments and physical therapy show encouraging results yet have limited efficacy. Other neuro-orthopaedic disorders, such as heterotopic ossification, are still poorly investigated. CONCLUSION: The literature of neuro-orthopaedic disorders in patients with prolonged DoC remains scarce, mainly focusing on spastic paresis. We recommend treating neuro-orthopaedic disorders in their early phases to prevent complications such as pain and improve patients' recovery. Additionally, this approach could enhance patients' ability to behaviourally demonstrate signs of consciousness, especially in the context of covert awareness.

International survey on the implementation of the European and American guidelines on disorders of consciousness.

Diagnostic, prognostic, and therapeutic procedures for patients with prolonged disorders of consciousness (pDoCs) vary significantly across countries and clinical settings, likely due to organizational factors (e.g., research vs. non-academic hospitals), expertise and availability of resources (e.g., financial and human). Two international guidelines, one from the European Academy of Neurology (EAN) and one from the American Academy of Neurology (AAN) in collaboration with the American Congress of Rehabilitation Medicine (ACRM) and the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR), were developed to facilitate consistent practice among professionals working with this challenging patient population. While the recommendations of both guidelines agree in principle, it remains an open issue how to implement them into clinical practice in the care pathway for patients with pDoCs. We conducted an online survey to explore health professional clinical practices related to the management of patients with pDoCs, and compare said practices with selected recommendations from both the guidelines. The survey revealed that while some recommendations are being followed, others are not and/or may require more honing/specificity to enhance their clinical utility. Particular attention should be given to the implementation of a multimodal assessment of residual consciousness, to the detection and treatment of pain, and to the impact of restrictions imposed by COVID-19 pandemics on the involvement of patients' families/representatives.

A protocol for a multicenter randomized and personalized controlled trial using rTMS in patients with disorders of consciousness.

Background: Improving the functional recovery of patients with DoC remains one of the greatest challenges of the field. Different theories exist about the role of the anterior (prefrontal areas) versus posterior (parietal areas) parts of the brain as hotspots for the recovery of consciousness. Repetitive transcranial magnetic stimulation (rTMS) is a powerful non-invasive brain stimulation technique for the treatment of DoC. However, a direct comparison of the effect of TMS treatment on the front versus the back of the brain has yet to be performed. In this study, we aim to assess the short- and long-term effects of frontal and parietal rTMS on DoC recovery and characterize responders phenotypically. Methods/design: Ninety patients with subacute and prolonged DoC will be included in a two-part multicenter prospective study. In the first phase (randomized controlled trial, RCT), patients will undergo four rTMS sessions in a crossover design over 10 days, targeting (i) the left dorsolateral prefrontal cortex (DLPFC) and (ii) the left angular gyrus (AG), as well as (iii & iv) their sham alternatives. In the second phase (longitudinal personalized trial), patients will receive personalized stimulations for 20 working days targeting the brain area that showed the best results in the RCT and will be randomly assigned to either active or sham intervention. The effects of rTMS on neurobehavioral and neurophysiological functioning in patients with DoC will be evaluated using clinical biomarkers of responsiveness (i.e., the Coma Recovery Scale-Revised; CRS-R), and electrophysiological biomarkers (e.g., power spectra, functional and effective connectivity, perturbational complexity index before and after intervention). Functional long-term outcomes will be assessed at 3 and 6 months post-intervention. Adverse events will be recorded during the treatment phase. Discussion: This study seeks to identify which brain region (front or back) is best to stimulate for the treatment of patients with DoC using rTMS, and to characterize the neural correlates of its action regarding recovery of consciousness and functional outcome. In addition, we will define the responders' profile based on patients' characteristics and functional impairments; and develop biomarkers of responsiveness using EEG analysis according to the clinical responsiveness to the treatment. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04401319, Clinicaltrials.gov, n° NCT04401319.

Sham-controlled randomized multicentre trial of transcranial direct current stimulation for prolonged disorders of consciousness.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (tDCS) has been shown to improve signs of consciousness in a subset of patients with disorders of consciousness (DoC). However, no multicentre study confirmed its efficacy when applied during rehabilitation. In this randomized controlled double-blind study, the effects of tDCS whilst patients were in rehabilitation were tested at the group level and according to their diagnosis and aetiology to better target DoC patients who might repond to tDCS. METHODS: Patients received 2 mA tDCS or sham applied over the left prefrontal cortex for 4 weeks. Behavioural assessments were performed weekly and up to 3 months' follow-up. Analyses were conducted at the group and subgroup levels based on the diagnosis (minimally conscious state [MCS] and unresponsive wakefulness syndrome) and the aetiology (traumatic or non-traumatic). Interim analyses were planned to continue or stop the trial. RESULTS: The trial was stopped for futility when 62 patients from 10 centres were enrolled (44 ± 14 years, 37 ± 24.5 weeks post-injury, 18 women, 32 MCS, 39 non-traumatic). Whilst, at the group level, no treatment effect was found, the subgroup analyses at 3 months' follow-up revealed a significant improvement for patients in MCS and with traumatic aetiology. CONCLUSIONS: Transcranial direct current stimulation during rehabilitation does not seem to enhance patients' recovery. However, diagnosis and aetiology appear to be important factors leading to a response to the treatment. These findings bring novel insights into possible cortical plasticity changes in DoC patients given these differential results according to the subgroups of patients.

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.

Gender Specificities in Sleep Disturbances following Mild Traumatic Brain Injury: A Preliminary Study.

Mild traumatic brain injury (mTBI), or concussion, can lead to persistent cognitive and functional symptoms that impede quality of life to a varying extent. This condition is referred to as post-concussive syndrome (PCS). Sleep disturbances are part of it but their distribution among different genders remains scarcely investigated. This pilot cross-sectional anonymous web-based survey interviewed volunteer 18-55 years old participants with a recent (i.e., less than 5 years) reported history of mTBI. Questionnaires related to persistent post-concussive symptoms (PPCS; Rivermead post-concussion symptoms questionnaire), sleep quality (Pittsburgh Sleep Quality Index) and daytime sleepiness (Epworth Sleepiness Scale) were administered as part of the survey. Ninety-one participants' responses were analysed (61 female; 30 male); 43% of them suffered from post-concussive syndrome, 60% reported poor sleep quality and 34% experienced excessive daytime sleepiness. The proportion of PPCS was significantly higher in female participants as compared to males (female: 57%; male: 13%; Fisher's exact test p < 0.001). Excessive daytime sleepiness was also significantly more present in females (female: 44%; male: 13%; p < 0.001) whereas poor sleep quality was present in similar proportions between females and males (female: 66%; male: 50%; p = 0.176). Even though based on a relatively small sample, these findings highlight important gender differences that should be accounted for in PPCS medical care and management.

High-speed heating of the skin using a contact thermode elicits brain responses comparable to CO2 laser-evoked potentials.

OBJECTIVE: To compare nociceptive event-related brain potentials elicited by a high-speed contact-thermode vs an infrared CO2 laser stimulator. METHODS: Contact heat-evoked potentials (CHEPs) and CO2 laser-evoked potentials (LEPs) were recorded in healthy volunteers using a high-speed contact-thermode (>200 °C/s) and a temperature-controlled CO2 laser. In separate experiments, stimuli were matched in terms of target surface temperature (55 °C) and intensity of perception. A finite-element model of skin heat transfer was used to explain observed differences. RESULTS: For 55 °C stimuli, CHEPs were reduced in amplitude and delayed in latency as compared to LEPs. For perceptually matched stimuli (CHEPs: 62 °C; LEPs: 55 °C), amplitudes were similar, but CHEPs latencies remained delayed. These differences could be explained by skin thermal inertia producing differences in the heating profile of contact vs radiant heat at the dermo-epidermal junction. CONCLUSIONS: Provided that steep heating ramps are used, and that target temperature is matched at the dermo-epidermal junction, contact and radiant laser heat stimulation elicit responses of similar magnitude. CHEPs are delayed compared to LEPs. SIGNIFICANCE: CHEPs could be used as an alternative to LEPs for the diagnosis of neuropathic pain. Dedicated normative values must be used to account for differences in skin thermal transfer.

What names for covert awareness? A systematic review.

Background: With the emergence of Brain Computer Interfaces (BCI), clinicians have been facing a new group of patients with severe acquired brain injury who are unable to show any behavioral sign of consciousness but respond to active neuroimaging or electrophysiological paradigms. However, even though well documented, there is still no consensus regarding the nomenclature for this clinical entity. Objectives: This systematic review aims to 1) identify the terms used to indicate the presence of this entity through the years, and 2) promote an informed discussion regarding the rationale for these names and the best candidates to name this fascinating disorder. Methods: The Disorders of Consciousness Special Interest Group (DoC SIG) of the International Brain Injury Association (IBIA) launched a search on Pubmed and Google scholar following PRISMA guidelines to collect peer-reviewed articles and reviews on human adults (>18 years) published in English between 2006 and 2021. Results: The search launched in January 2021 identified 4,089 potentially relevant titles. After screening, 1,126 abstracts were found relevant. Finally, 161 manuscripts were included in our analyses. Only 58% of the manuscripts used a specific name to discuss this clinical entity, among which 32% used several names interchangeably throughout the text. We found 25 different names given to this entity. The five following names were the ones the most frequently used: covert awareness, cognitive motor dissociation, functional locked-in, non-behavioral MCS (MCS*) and higher-order cortex motor dissociation. Conclusion: Since 2006, there has been no agreement regarding the taxonomy to use for unresponsive patients who are able to respond to active neuroimaging or electrophysiological paradigms. Developing a standard taxonomy is an important goal for future research studies and clinical translation. We recommend a Delphi study in order to build such a consensus.

Neurorehabilitation for people with disorders of consciousness: an international survey of health-care structures and access to treatment, (Part 1).

AIMS: The provision of rehabilitation services for people with disorders of consciousness (DoC) may vary due to geographical, financial, and political factors. The extent of this variability and the implementation of treatment standards across countries is unknown. This study explored international neurorehabilitation systems for people with DoC. METHODS: An online survey (SurveyMonkey®) was disseminated to all members of the International Brain Injury Association (IBIA) DoC Special Interest Group (SIG) examining existing rehabilitation systems and access to them. RESULTS: Respondents (n = 35) were from 14 countries. Specialized neurorehabilitation was available with varying degrees of access and duration. Commencement of specialized neurorehabilitation averaged 3-4 weeks for traumatic brain injury (TBI) and 5-8 weeks for non-traumatic brain injury (nTBI) etiologies. Length of stay in inpatient rehabilitation was 1-3 months for TBI and 4-6 months for nTBI. There were major differences in access to services and funding across countries. The majority of respondents felt there were not enough resources in place to provide appropriate neurorehabilitation. CONCLUSIONS: There exists inter-country differences for DoC neurorehabilitation after severe acquired brain injury. Further work is needed to implement DoC treatment standards at an international level.

Predicting Long-Term Recovery of Consciousness in Prolonged Disorders of Consciousness Based on Coma Recovery Scale-Revised Subscores: Validation of a Machine Learning-Based Prognostic Index.

Prognosis of prolonged Disorders of Consciousness (pDoC) is influenced by patients' clinical diagnosis and Coma Recovery Scale-Revised (CRS-R) total score. We compared the prognostic accuracy of a novel Consciousness Domain Index (CDI) with that of clinical diagnosis and CRS-R total score, for recovery of full consciousness at 6-, 12-, and 24-months post-injury. The CDI was obtained by a combination of the six CRS-R subscales via an unsupervised machine learning technique. We retrospectively analyzed data on 143 patients with pDoC (75 in Minimally Conscious State; 102 males; median age = 53 years; IQR = 35; time post-injury = 1-3 months) due to different etiologies enrolled in an International Brain Injury Association Disorders of Consciousness Special Interest Group (IBIA DoC-SIG) multicenter longitudinal study. Univariate and multivariate analyses were utilized to assess the association between outcomes and the CDI, compared to clinical diagnosis and CRS-R. The CDI, the clinical diagnosis, and the CRS-R total score were significantly associated with a good outcome at 6, 12 and 24 months. The CDI showed the highest univariate prediction accuracy and sensitivity, and regression models including the CDI provided the highest values of explained variance. A combined scoring system of the CRS-R subscales by unsupervised machine learning may improve clinical ability to predict recovery of consciousness in patients with pDoC.

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.

Risk factors for 2-year mortality in patients with prolonged disorders of consciousness: An international multicentre study.

BACKGROUND AND PURPOSE: Patients with prolonged disorders of consciousness (pDoC) have a high mortality rate due to medical complications. Because an accurate prognosis is essential for decision-making on patients' management, we analysed data from an international multicentre prospective cohort study to evaluate 2-year mortality rate and bedside predictors of mortality. METHODS: We enrolled adult patients in prolonged vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) after traumatic and nontraumatic brain injury within 3 months postinjury. At enrolment, we collected demographic (age, sex), anamnestic (aetiology, time postinjury), clinical (Coma Recovery Scale-Revised [CRS-R], Disability Rating Scale, Nociception Coma Scale-Revised), and neurophysiologic (electroencephalogram [EEG], somatosensory evoked and event-related potentials) data. Patients were followed up to gather data on mortality up to 24 months postinjury. RESULTS: Among 143 traumatic (n = 55) and nontraumatic (n = 88) patients (VS/UWS, n = 68, 19 females; MCS, n = 75, 22 females), 41 (28.7%) died within 24 months postinjury. Mortality rate was higher in VS/UWS (42.6%) than in MCS (16%; p < 0.001). Multivariate regression in VS/UWS showed that significant predictors of mortality were older age and lower CRS-R total score, whereas in MCS female sex and absence of alpha rhythm on EEG at study entry were significant predictors. CONCLUSIONS: This study demonstrated that a feasible multimodal assessment in the postacute phase can help clinicians to identify patients with pDoC at higher risk of mortality within 24 months after brain injury. This evidence can help clinicians and patients' families to navigate the complex clinical decision-making process and promote an international standardization of prognostic procedures for patients with pDoC.

Epilepsy in prolonged disorders of consciousness: a systematic review.

To date, no guideline exists for the management of epilepsy in patients with prolonged Disorders of Consciousness (DoC). This review aimed to assess the occurrence of epilepsy and epileptic abnormalities (EA) in these patients, to determine their impact on recovery; and to review the effect of antiepileptic drugs (AED) and therapeutic interventions on seizure occurrence and consciousness recovery. A structured search for studies on prolonged DoC and epilepsy was undertaken following PRISMA guidelines. From an initial search resulting in 5,775 titles, twelve studies met inclusion criteria. The occurrence of epilepsy and EA in DoC was poorly and inconsistently reported across studies. The results estimated a seizure prevalence of 27% in DoC. No conclusive data were found for the effects of AED on recovery nor on the influence of any therapeutic interventions on seizure occurrence. Given the scarcity of data, it is premature to make evidence-based recommendations on epilepsy in prolonged DoC. Based on this review and current clinical practices the following are recommended: (1) repeated standard EEG for detecting seizures and EA; (2) treating epilepsy while avoiding AEDs with sedating or cognitive side-effects. Future research should use standardized classification systems for seizures and EA.

Neurophysiological Biomarkers of Persistent Post-concussive Symptoms: A Scoping Review.

Background and Objectives: Persistent post-concussive symptoms (PCS) consist of neurologic and psychological complaints persisting after a mild traumatic brain injury (mTBI). It affects up to 50% of mTBI patients, may cause long-term disability, and reduce patients' quality of life. The aim of this review was to examine the possible use of different neuroimaging modalities in PCS. Methods: Articles from Pubmed database were screened to extract studies that investigated the relationship between any neuroimaging features and symptoms of PCS. Descriptive statistics were applied to report the results. Results: A total of 80 out of 939 papers were included in the final review. Ten examined conventional MRI (30% positive finding), 24 examined diffusion weighted imaging (54.17% positive finding), 23 examined functional MRI (82.61% positive finding), nine examined electro(magneto)encephalography (77.78% positive finding), and 14 examined other techniques (71% positive finding). Conclusion: MRI was the most widely used technique, while functional techniques seem to be the most sensitive tools to evaluate PCS. The common functional patterns associated with symptoms of PCS were a decreased anti-correlation between the default mode network and the task positive network and reduced brain activity in specific areas (most often in the prefrontal cortex). Significance: Our findings highlight the importance to use functional approaches which demonstrated a functional alteration in brain connectivity and activity in most studies assessing PCS.

The Brief Evaluation of Receptive Aphasia test for the detection of language impairment in patients with severe brain injury.

PRIMARY OBJECTIVE: The assessment of language in patients post-comatose patients is limited by their reduced behavioral repertoire. We developed the Brief Evaluation of Receptive Aphasia (BERA) tool for assessing phonological, semantic and morphosyntactic abilities in patients with severe brain injury based on visual fixation responses. RESEARCH DESIGN: Prospective cross-sectional study and case reports. METHODS AND PROCEDURE: The BERA and Language Screening Test were first administered to 52 conscious patients with aphasia on two consecutive days in order to determine the validity and reliability of the BERA. Four post-comatose patients were further examined with the BERA, the Coma Recovery Scale-Revised (CRS-R), positron emission tomography and structural magnetic resonance imaging. MAIN OUTCOME AND RESULTS: The BERA showed satisfactory intra- and inter-rater reliability, as well as internal and concurrent validity in patients with aphasia. The BERA scores indicated selective receptive difficulties for phonological, semantic and particularly morphosyntactic abilities in post-comatose patients. These results were in line with the cortical distribution of brain lesions. CONCLUSIONS: The BERA may complement the widely used CRS-R for assessing and diagnosing patients with disorders of consciousness by providing a systematic and detailed characterization of residual language abilities.

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.