Assessing consciousness and cognition in disorders of consciousness.

Detecting willful cognition in these patients is known to be challenging due to the patients' motor disabilities and high vigilance fluctuations but also due to the lack of expertise and use of adequate tools to assess these patients in specific settings. This review will discuss the main disorders of consciousness after severe brain injury, how to assess consciousness and cognition in these patients, as well as the challenges and tools available to overcome these challenges and reach an accurate diagnosis.

Cognitive Motor Dissociation: Gap Analysis and Future Directions.

BACKGROUND: Patients with disorders of consciousness who are behaviorally unresponsive may demonstrate volitional brain responses to motor imagery or motor commands detectable on functional magnetic resonance imaging or electroencephalography. This state of cognitive motor dissociation (CMD) may have prognostic significance. METHODS: The Neurocritical Care Society's Curing Coma Campaign identified an international group of experts who convened in a series of monthly online meetings between September 2021 and April 2023 to examine the science of CMD and identify key knowledge gaps and unmet needs. RESULTS: The group identified major knowledge gaps in CMD research: (1) lack of information about patient experiences and caregiver accounts of CMD, (2) limited epidemiological data on CMD, (3) uncertainty about underlying mechanisms of CMD, (4) methodological variability that limits testing of CMD as a biomarker for prognostication and treatment trials, (5) educational gaps for health care personnel about the incidence and potential prognostic relevance of CMD, and (6) challenges related to identification of patients with CMD who may be able to communicate using brain-computer interfaces. CONCLUSIONS: To improve the management of patients with disorders of consciousness, research efforts should address these mechanistic, epidemiological, bioengineering, and educational gaps to enable large-scale implementation of CMD assessment in clinical practice.

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.

Common Data Element for Disorders of Consciousness: Recommendations from the Working Group on Therapeutic Interventions.

BACKGROUND: Over the past 30 years, there have been significant advances in the understanding of the mechanisms associated with loss and recovery of consciousness following severe brain injury. This work has provided a strong grounding for the development of novel restorative therapeutic interventions. Although all interventions are aimed at modulating and thereby restoring brain function, the landscape of existing interventions encompasses a very wide scope of techniques and protocols. Despite vigorous research efforts, few approaches have been assessed with rigorous, high-quality randomized controlled trials. As a growing number of exploratory interventions emerge, it is paramount to develop standardized approaches to reporting results. The successful evaluation of novel interventions depends on implementation of shared nomenclature and infrastructure. To address this gap, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups and charged them with developing common data elements (CDEs). Here, we report the work of the Therapeutic Interventions Working Group. METHODS: The working group reviewed existing CDEs relevant to therapeutic interventions within the National Institutes of Health National Institute of Neurological Disorders and Stroke database and reviewed the literature for assessing key areas of research in the intervention space. CDEs were then proposed, iteratively discussed and reviewed, classified, and organized in a case report form (CRF). RESULTS: We developed a unified CRF, including CDEs and key design elements (i.e., methodological or protocol parameters), divided into five sections: (1) patient information, (2) general study information, (3) behavioral interventions, (4) pharmacological interventions, and (5) device interventions. CONCLUSIONS: The newly created CRF enhances systematization of future work by proposing a portfolio of measures that should be collected in the development and implementation of studies assessing novel interventions intended to increase the level of consciousness or rate of recovery of consciousness in patients with disorders of consciousness.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Behavioral Phenotyping.

BACKGROUND: The recent publication of practice guidelines for management of patients with disorders of consciousness (DoC) in the United States and Europe was a major step forward in improving the accuracy and consistency of terminology, diagnostic criteria, and prognostication in this population. There remains a pressing need for a more precise brain injury classification system that combines clinical semiology with neuroimaging, electrophysiologic, and other biomarker data. To address this need, the National Institute of Neurological Disorders and Stroke launched the Common Data Elements (CDEs) initiative to facilitate systematic collection of high-quality research data in studies involving patients with neurological disease. The Neurocritical Care Society's Curing Coma Campaign expanded this effort in 2018 to develop CDEs for DoC. Herein, we present CDE recommendations for behavioral phenotyping of patients with DoC. METHODS: The Behavioral Phenotyping Workgroup used a preestablished, five-step process to identify and select candidate CDEs that included review of existing National Institute of Neurological Disorders and Stroke CDEs, nomination and systematic vetting of new CDEs, CDE classification, iterative review, and approval of panel recommendations and development of corresponding case review forms. RESULTS: We identified a slate of existing and newly proposed basic, supplemental, and exploratory CDEs that can be used for behavioral phenotyping of adult and pediatric patients with DoC. CONCLUSIONS: The proposed behavioral phenotyping CDEs will assist with international harmonization of DoC studies and allow for more precise characterization of study cohorts, favorably impacting observational studies and clinical trials aimed at improving outcome in this population.

Sleep Quality Should Be Assessed in Inpatient Rehabilitation Settings: A Preliminary Study.

OBJECTIVES: In this preliminary, longitudinal study, our objective was to assess changes in sleep quality during an inpatient stay in a rehabilitation setting in the United States and to relate changes to patients' demographic and clinical characteristics (i.e., age, gender, BMI, ethnicity, reason for hospitalization, pre-hospital living setting, prior diagnosis of sleep disorders, and mental health status). METHODS: A total of 35 patients participated in this preliminary study (age = 61 ± 16 years old, 50% <65; BMI = 30 ± 7 kg/m2; 51% female; 51% Caucasian). The average length of hospitalization was 18 ± 8 days. Reasons for hospitalization included orthopedic-related issues (28%), spinal cord injury (28%), stroke (20%), and other (23%). In this sample, 23% had prior sleep disorders (mostly sleep apnea), and 60% came from an acute care unit. Patients' sleep quality was assessed using the Pittsburgh sleep quality index (PSQI) at admission and before discharge. Demographic and medical data were collected. Patients' mental health status was also assessed at the same intervals. Nighttime sound levels and the average number of sleep disturbances were also collected throughout the study (6 months). RESULTS: Our data revealed that most patients had poor sleep (PSQI > 5) at admission (86%) and discharge (80%). Using a repeated ANOVA, a significant interaction was obtained between sleep quality and the presence of a diagnosed sleep disorder [F (1, 33) = 12.861, p = 0.001, η2p = 0.280]. The sleep quality of patients with sleep disorders improved over their stay, while the sleep of patients without such disorders did not. The mean nighttime sound collection level averages and peaks were 62.3 ± 5.1 dB and 86.1 ± 4.9 dB, respectively, and the average number of sleep disturbances was 2.6 ± 1.1. CONCLUSION: The improved sleep observed in patients with vs. without sleep disorders might be related to the care received for treating such disorders over the stay. Our findings call for the better detection and management of poor sleep in acute inpatient rehabilitation settings. Furthermore, if our findings are replicated in the future, studies on the implementation of quiet times for medical staff, patients, and family should be performed to improve sleep quality in the inpatient rehabilitation setting.

Validation of the Music Therapy Assessment Tool for Awareness in Disorders of Consciousness With the Coma Recovery Scale-Revised.

OBJECTIVE: To examine (1) the concurrent validity of the Music Therapy Assessment Tool for Awareness in Disorders of Consciousness (MATADOC) with the criterion standard Coma Recovery Scale-Revised (CRS-R) for outcomes of awareness in patients with prolonged disorders of consciousness (PDoC), (2) the relationship between MATADOC items and CRS-R function subscales in similar domains, and (3) determine if items/function subscales measure different constructs. DESIGN: A prospective multicentric blinded study with repeated concurrent measures. SETTING: Three inpatient rehabilitation units. PARTICIPANTS: Convenience sample of 74 adults with PDoC (N=74). MAIN OUTCOME MEASURES: The MATADOC protocol elicits behavioral responsiveness using live music in 5 tasks. A total score ranges 0-10 scoring behaviors across 14-items. The CRS-R uses a language-based protocol and scores observed responses ranging from 0-23 in 6 function subscales. Both measures were delivered at 4 concurrent time points over 2 weeks. RESULTS: Fair (κ=0.238, P=.006) ranging to moderate (κ=0.419, P<.001) significant agreement was found between CRS-R and MATADOC diagnostic outcomes. Fair-borderline moderate significant agreement was found for overall diagnostic outcomes across all diagnostic categories (κ=0.397, P=.001). There was moderate significant agreement between measures for motor scores (0.551≤κ≤0.571, P<.001) and visual outcomes (0.192≤κ≤0.415, .001≤P<.005) but no agreement for item/function subscale outcomes assessing auditory responsiveness. Exploratory factor analysis of all items showed 2 factors, suggesting that MATADOC and CRS-R measure the same underlying latent variable (awareness) in different ways and could complement each other for diagnosis and intervention purposes. This was supported by scale analysis, which showed increased reliability when the 2 scales are used together rather than separately. CONCLUSIONS: Unlike the CRS-R, the music-based MATADOC scores auditory localization for complexity of response and categorizes these behaviors as conscious rather than reflexive. The MATADOC may supplement the CRS-R, having a particular role in interdisciplinary programming for providing a more robust assessment of auditory responsiveness because of using nonverbal musical stimuli.

Needs and Quality of Life of Caregivers of Patients with Prolonged Disorders of Consciousness.

Background. Many patients with severe brain damage may survive and remain in a prolonged disorder of consciousness (PDoC), impacting the quality of life (QoL) and needs of their family caregivers. However, the current literature on the factors influencing these needs is contradictory. We aim to describe the needs, QoL, and emotional distress of caregivers of patients with PDoC. Methods. Questionnaires investigating the importance and satisfaction of six categories of needs (i.e., health information, emotional, instrumental, and professional supports, community support network, and involvement in care), QoL, and emotional distress were completed by the main caregivers of PDoC patients. Results. We analyzed 177 questionnaires. Seventy-nine percent of the needs were considered as important or very important, and 44% were partially met or unmet. The needs for health information and professional support were the most important, while the needs for involvement in care and for health information were the most satisfied. Mean QoL was low and emotional distress high. Variables such as care setting and time since brain injury affected the level of QoL and distress. Conclusion. The needs for health information and professional support should receive particular attention. Given their low QoL and high distress, adequate support structures should be provided to caregivers of PDoC patients.

Language Assessment in Patients with Disorders of Consciousness.

The assessment of residual language abilities in patients with disorders of consciousness (DoC) after severe brain injury is particularly challenging due to their limited behavioral repertoire. Moreover, associated language impairment such as receptive aphasia may lead to an underestimation of actual consciousness levels. In this review, we examine past research on the assessment of residual language processing in DoC patients, and we discuss currently available tools for identifying language-specific abilities and their prognostic value. We first highlight the need for validated and sensitive bedside behavioral assessment tools for residual language abilities in DoC patients. As regards neuroimaging and electrophysiological methods, the tasks involving higher level linguistic commands appear to be the most informative about level of consciousness and have the best prognostic value. Neuroimaging methods should be combined with the most appropriate behavioral tools in multimodal assessment protocols to assess receptive language abilities in DoC patients in the most complete and sensitive manner.

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.

Ultrasonic Deep Brain Neuromodulation in Acute Disorders of Consciousness: A Proof-of-Concept.

The promotion of recovery in patients who have entered a disorder of consciousness (DOC; e.g., coma or vegetative states) following severe brain injury remains an enduring medical challenge despite an ever-growing scientific understanding of these conditions. Indeed, recent work has consistently implicated altered cortical modulation by deep brain structures (e.g., the thalamus and the basal ganglia) following brain damage in the arising of, and recovery from, DOCs. The (re)emergence of low-intensity focused ultrasound (LIFU) neuromodulation may provide a means to selectively modulate the activity of deep brain structures noninvasively for the study and treatment of DOCs. This technique is unique in its combination of relatively high spatial precision and noninvasive implementation. Given the consistent implication of the thalamus in DOCs and prior results inducing behavioral recovery through invasive thalamic stimulation, here we applied ultrasound to the central thalamus in 11 acute DOC patients, measured behavioral responsiveness before and after sonication, and applied functional MRI during sonication. With respect to behavioral responsiveness, we observed significant recovery in the week following thalamic LIFU compared with baseline. With respect to functional imaging, we found decreased BOLD signals in the frontal cortex and basal ganglia during LIFU compared with baseline. In addition, we also found a relationship between altered connectivity of the sonicated thalamus and the degree of recovery observed post-LIFU.

Changes of Spasticity across Time in Prolonged Disorders of Consciousness: A Retrospective Study.

OBJECTIVES: In this retrospective study, we investigated how spasticity developed in patients diagnosed with a prolonged DOC over an almost two-year observation period (21 months), and how it related to the patients' age, gender, time since injury, etiology, level of consciousness, and anti-spastic medications. METHODS: In total, 19 patients with a severe brain injury and prolonged DOC admitted to a long-term care facility were included in this study (14 male, age: 45.8 ± 15.3 years, 10 traumatic brain injury, 1.01 ± 0.99 years after brain injury, 11 minimally conscious state vs. 8 vegetative state). Each patient was assessed at admission and then quarterly, totaling eight assessments over 21 months. Spasticity was measured with the Modified Ashworth Scale (MAS) for both upper and lower limbs. The Western Neuro Sensory Stimulation Profile (WNSSP) was administered to assess the level of consciousness. Any other medical and demographic information of interest was obtained through medical records. Linear mixed models were used to assess each variable's impact on the change of spasticity over time. RESULTS: Significant differences were observed in the evolution of spasticity in patients based on their etiology for the upper limbs [F (7, 107.29) = 2.226; p = 0.038], and on their level of consciousness for the lower limbs [F (7, 107.07) = 3.196; p = 0.004]. CONCLUSION: Our preliminary results suggest that spasticity evolves differently according to the type of brain lesion and the level of consciousness. Spasticity in DOCs might therefore be mediated by different mechanisms and might have to be treated differently among patients. Future longitudinal studies should be performed prospectively in a bigger cohort and with data collection beginning earlier after brain injury to confirm our results and better understand the evolution of spasticity in this population.

A Framework to Advance Biomarker Development in the Diagnosis, Outcome Prediction, and Treatment of Traumatic Brain Injury.

Multi-modal biomarkers (e.g., imaging, blood-based, physiological) of unique traumatic brain injury (TBI) endophenotypes are necessary to guide the development of personalized and targeted therapies for TBI. Optimal biomarkers will be specific, sensitive, rapidly and easily accessed, minimally invasive, cost effective, and bidirectionally translatable for clinical and research use. For both uses, understanding how TBI biomarkers change over time is critical to reliably identify appropriate time windows for an intervention as the injury evolves. Biomarkers that enable researchers and clinicians to identify cellular injury and monitor clinical improvement, inflection, arrest, or deterioration in a patient's clinical trajectory are needed for precision healthcare. Prognostic biomarkers that reliably predict outcomes and recovery windows to assess neurodegenerative change and guide decisions for return to play or duty are also important. TBI biomarkers that fill these needs will transform clinical practice and could reduce the patient's risk for long-term symptoms and lasting deficits. This article summarizes biomarkers currently under investigation and outlines necessary steps to achieve short- and long-term goals, including how biomarkers can advance TBI treatment and improve care for patients with TBI.

Sociodemographic, geographic and clinical factors associated with functional outcome and discharge location in US inpatient rehabilitation settings.

OBJECTIVE: To assess the impact of sociodemographic factors, clinical factors and regional differences on both patients' functional outcome and discharge location in U.S. inpatient rehabilitation settings. METHODS: Using eRehabData, 536,453 admissions was used for functional outcome analyses (based on FIM gain) while 259,308 admissions was used for the discharge location analyses. Regression models were used to look at both outcomes. RESULTS: Having private insurance and being young and male was associated with the higher FIM gains while being African American, widowed, and living in the Midwest was associated with the lower FIM gains. Furthermore, having private insurance, being young, male, married and African American or Hispanic was associated with the lower odds of being discharged to a skilled nursing facility while living in the Midwest was associated with the greatest odds of being discharged to a skilled nursing facility. Clinical factors such as days from onset and length of stay also had a significant effect on both outcomes. CONCLUSION: Our findings suggest that, in the U.S., one of the challenges to successful recovery in the inpatient rehabilitation setting includes insurance status (Medicare/Medicaid), race (African American) but also regional differences (Midwest) and length of stay.

Flowchart for Implementing Advanced Imaging and Electrophysiology in Patients With Disorders of Consciousness: To fMRI or Not to fMRI?

The American Academy of Neurology and the European Academy of Neurology have recognized, for the first time, the value of advanced neuroimaging and electrophysiology techniques (AIEs) in the context of diagnosing patients with a disorder of consciousness (DOC). This recognition is part of an important agenda of promoting evidence-based competency in the management of patients with DOC. Nonetheless, considering that these techniques (and the required knowledge) are seldom available outside of advanced medical centers, it is important to provide physicians with a framework for balancing risks and benefits and deciding, on a single patient basis, whether AIEs are suitable. This issue is all the more urgent considering that family members are increasingly aware of the use of AIEs in patients with DOC, pressure for these assessments is likely to increase in the context of ethical and clinical imperatives to meet standards of care, and pathways for reimbursement for such assessments in DOC are yet to be established. The new guidelines, however, provide no guiding principle for physicians to decide when such assessments are appropriate, a limitation that impedes their wide adoption. We address this important gap by proposing an easy to use algorithmic flowchart that is based on the new guidelines and can be used to determine the appropriateness of AIEs for any given patient with DOC and ensure that evidence-based best practices are being followed. We also provide a brief context for understanding the main categories of AIEs available to clinicians, their advantages, and their limitations.

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.

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.