Equity in Clinical Care and Research Involving Persons with Disorders of Consciousness.

People with disorders of consciousness (DoC) are characteristically unable to synchronously participate in decision-making about clinical care or research. The inability to self-advocate exacerbates preexisting socioeconomic and geographic disparities, which include the wide variability observed across individuals, hospitals, and countries in access to acute care, expertise, and sophisticated diagnostic, prognostic, and therapeutic interventions. Concerns about equity for people with DoC are particularly notable when they lack a surrogate decision-maker (legally referred to as "unrepresented" or "unbefriended"). Decisions about both short-term and long-term life-sustaining treatment typically rely on neuroprognostication and individual patient preferences that carry additional ethical considerations for people with DoC, as even individuals with well thought out advance directives cannot anticipate every possible situation to guide such decisions. Further challenges exist with the inclusion of people with DoC in research because consent must be completed (in most circumstances) through a surrogate, which excludes those who are unrepresented and may discourage investigators from exploring questions related to this population. In this article, the Curing Coma Campaign Ethics Working Group reviews equity considerations in clinical care and research involving persons with DoC in the following domains: (1) access to acute care and expertise, (2) access to diagnostics and therapeutics, (3) neuroprognostication, (4) medical decision-making for unrepresented people, (5) end-of-life decision-making, (6) access to postacute rehabilitative care, (7) access to research, (8) inclusion of unrepresented people in research, and (9) remuneration and reciprocity for research participation. The goal of this discussion is to advance equitable, harmonized, guideline-directed, and goal-concordant care for people with DoC of all backgrounds worldwide, prioritizing the ethical standards of respect for autonomy, beneficence, and justice. Although the focus of this evaluation is on people with DoC, much of the discussion can be extrapolated to other critically ill persons worldwide.

Applying the IEEE BRAIN neuroethics framework to intra-cortical brain-computer interfaces.

Objective. Brain-computer interfaces (BCIs) are neuroprosthetic devices that allow for direct interaction between brains and machines. These types of neurotechnologies have recently experienced a strong drive in research and development, given, in part, that they promise to restore motor and communication abilities in individuals experiencing severe paralysis. While a rich literature analyzes the ethical, legal, and sociocultural implications (ELSCI) of these novel neurotechnologies, engineers, clinicians and BCI practitioners often do not have enough exposure to these topics.Approach. Here, we present the IEEE Neuroethics Framework, an international, multiyear, iterative initiative aimed at developing a robust, accessible set of considerations for diverse stakeholders.Main results. Using the framework, we provide practical examples of ELSCI considerations for BCI neurotechnologies. We focus on invasive technologies, and in particular, devices that are implanted intra-cortically for medical research applications.Significance. We demonstrate the utility of our framework in exposing a wide range of implications across different intra-cortical BCI technology modalities and conclude with recommendations on how to utilize this knowledge in the development and application of ethical guidelines for BCI neurotechnologies.

Covert cortical processing: a diagnosis in search of a definition.

Historically, clinical evaluation of unresponsive patients following brain injury has relied principally on serial behavioral examination to search for emerging signs of consciousness and track recovery. Advances in neuroimaging and electrophysiologic techniques now enable clinicians to peer into residual brain functions even in the absence of overt behavioral signs. These advances have expanded clinicians' ability to sub-stratify behaviorally unresponsive and seemingly unaware patients following brain injury by querying and classifying covert brain activity made evident through active or passive neuroimaging or electrophysiologic techniques, including functional MRI, electroencephalography (EEG), transcranial magnetic stimulation-EEG, and positron emission tomography. Clinical research has thus reciprocally influenced clinical practice, giving rise to new diagnostic categories including cognitive-motor dissociation (i.e. 'covert consciousness') and covert cortical processing (CCP). While covert consciousness has received extensive attention and study, CCP is relatively less understood. We describe that CCP is an emerging and clinically relevant state of consciousness marked by the presence of intact association cortex responses to environmental stimuli in the absence of behavioral evidence of stimulus processing. CCP is not a monotonic state but rather encapsulates a spectrum of possible association cortex responses from rudimentary to complex and to a range of possible stimuli. In constructing a roadmap for this evolving field, we emphasize that efforts to inform clinicians, philosophers, and researchers of this condition are crucial. Along with strategies to sensitize diagnostic criteria and disorders of consciousness nosology to these vital discoveries, democratizing access to the resources necessary for clinical identification of CCP is an emerging clinical and ethical imperative.

Ethical Considerations in Endovascular Thrombectomy for Stroke.

INTRODUCTION: Stroke is a leading cause of morbidity and mortality globally. Endovascular mechanical thrombectomy is considered for patients with large vessel occlusion stroke presenting up to 24 hours from onset and is being increasingly utilized across diverse clinical contexts. Proactive consideration of distinctive ethical dimensions of endovascular thrombectomy (EVT) can enable stroke care teams to deliver goal-concordant care to appropriately selected patients with stroke but have been underexplored. METHODS: A narrative review with case examples was conducted. RESULTS: We explain and critically evaluate the application of foundational bioethical principles and narrative ethics to the practice of EVT, highlight key ethical issues that may emerge in neuroendovascular practice and develop an ethical framework to aid in the responsible use of EVT for people with large-vessel occlusive ischemic stroke. CONCLUSIONS: EVT for stroke introduces important ethical considerations. Salient challenges include decision-making capacity and informed consent, the telos of EVT, uncertainty, access to care, and resource allocation. An ethical framework focusing on combining patient values and preferences with the best available evidence in the context of a multidisciplinary care team is essential to ensure that the benefits of EVT are responsibly achieved and sustained.

Characterizing coma in large vessel occlusion stroke.

BACKGROUND: Coma is an unresponsive state of disordered consciousness characterized by impaired arousal and awareness. The epidemiology and pathophysiology of coma in ischemic stroke has been underexplored. We sought to characterize the incidence and clinical features of coma as a presentation of large vessel occlusion (LVO) stroke. METHODS: Individuals who presented with LVO were retrospectively identified from July 2018 to December 2020. Coma was defined as an unresponsive state of impaired arousal and awareness, operationalized as a score of 3 on NIHSS item 1a. RESULTS: 28/637 (4.4%) patients with LVO stroke were identified as presenting with coma. The median NIHSS was 32 (IQR 29-34) for those with coma versus 11 (5-18) for those without (p < 0.0001). In coma, occlusion locations included basilar (13), vertebral (2), internal carotid (5), and middle cerebral (9) arteries. 8/28 were treated with endovascular thrombectomy (EVT), and 20/28 died during the admission. 65% of patients not treated with EVT had delayed presentations or large established infarcts. In models accounting for pre-stroke mRS, basilar occlusion location, intravenous thrombolysis, and EVT, coma independently increased the odds of transitioning to comfort care during admission (aOR 6.75; 95% CI 2.87,15.84; p < 0.001) and decreased the odds of 90-day mRS 0-2 (aOR 0.12; 95% CI 0.03,0.55; p = 0.007). CONCLUSIONS: It is not uncommon for patients with LVO to present with coma, and delayed recognition of LVO can lead to poor outcomes, emphasizing the need for maintaining a high index of suspicion. While more commonly thought to result from posterior LVO, coma in our cohort was similarly likely to result from anterior LVO. Efforts to improve early diagnosis and care of patients with LVO presenting with coma are crucial.

Limitation of life sustaining therapy in disorders of consciousness: ethics and practice.

Clinical conversations surrounding the continuation or limitation of life-sustaining therapies (LLST) are both challenging and tragically necessary for patients with disorders of consciousness (DoC) following severe brain injury. Divergent cultural, philosophical and religious perspectives contribute to vast heterogeneity in clinical approaches to LLST-as reflected in regional differences and inter-clinician variability. Here we provide an ethical analysis of factors that inform LLST decisions among patients with DoC. We begin by introducing the clinical and ethical challenge and clarifying the distinction between withdrawing and withholding life-sustaining therapy. We then describe relevant factors that influence LLST decision-making including diagnostic and prognostic uncertainty, perception of pain, defining a 'good' outcome, and the role of clinicians. In concluding sections, we explore global variation in LLST practices as they pertain to patients with DoC and examine the impact of cultural and religious perspectives on approaches to LLST. Understanding and respecting the cultural and religious perspectives of patients and surrogates is essential to protecting patient autonomy and advancing goal-concordant care during critical moments of medical decision-making involving patients with DoC.

Covert consciousness.

Covert consciousness is a state of residual awareness following severe brain injury or neurological disorder that evades routine bedside behavioral detection. Patients with covert consciousness have preserved awareness but are incapable of self-expression through ordinary means of behavior or communication. Growing recognition of the limitations of bedside neurobehavioral examination in reliably detecting consciousness, along with advances in neurotechnologies capable of detecting brain states or subtle signs indicative of consciousness not discernible by routine examination, carry promise to transform approaches to classifying, diagnosing, prognosticating and treating disorders of consciousness. Here we describe and critically evaluate the evolving clinical category of covert consciousness, including approaches to its diagnosis through neuroimaging, electrophysiology, and novel behavioral tools, its prognostic relevance, and open questions pertaining to optimal clinical management of patients with covert consciousness recovering from severe brain injury.

Disclosing Results of Tests for Covert Consciousness: A Framework for Ethical Translation.

The advent of neurotechnologies including advanced functional magnetic resonance imaging and electroencephalography to detect states of awareness not detectable by traditional bedside neurobehavioral techniques (i.e., covert consciousness) promises to transform neuroscience research and clinical practice for patients with brain injury. As these interventions progress from research tools into actionable, guideline-endorsed clinical tests, ethical guidance for clinicians on how to responsibly communicate the sensitive results they yield is crucial yet remains underdeveloped. Drawing on insights from empirical and theoretical neuroethics research and our clinical experience with advanced neurotechnologies to detect consciousness in behaviorally unresponsive patients, we critically evaluate ethical promises and perils associated with disclosing the results of clinical covert consciousness assessments and describe a semistructured approach to responsible data sharing to mitigate potential risks.

Informed consent practices for acute stroke therapy: principles, challenges and emerging opportunities.

IMPORTANCE: Informed consent (IC) plays a crucial yet underexplored role in acute stroke treatment, particularly in the context of intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT). This narrative review examines data on current IC practices in acute ischemic stroke management, specifically for patients treated with IVT or EVT, with the aim of identifying areas for improvement and strategies to enhance the IC process. OBSERVATIONS: IC practices for IVT vary significantly among hospitals and physicians with the frequency of always requiring consent ranging from 21 to 37%. Factors influencing IC for IVT include patient decision-making capacity, standard of care, time sensitive nature of treatments, legal and moral obligations, risk of complications, physician age and speciality, treatment delays, and hospital size. Consent requirements tend to be stricter for patients presenting within the 3-4.5-h window. The content and style of information shared as part of the IC process revealed discrepancies in the disclosure of stroke diagnosis, IVT mechanism, benefits, and risks. Research on IC practices for EVT is scarce, highlighting a concerning gap in the available evidence base. CONCLUSIONS AND RELEVANCE: This review underscores the significant variability and knowledge gaps in IC for EVT and IVT. Challenges related to decision-making capacity assessment and the absence of standardised guidance substantially contributes to these gaps. Future initiatives should focus on simplifying information delivery to patients, developing formal tools for assessing capacity, standardising ethical frameworks to guide physicians when patients lack capacity and harmonizing IC standards across sites. The ultimate goal is to enhance IC practices and uphold patient autonomy, while ensuring timely treatment initiation.

Ethical Considerations in Neuroprognostication Following Acute Brain Injury.

Neuroprognostication following acute brain injury (ABI) is a complex process that involves integrating vast amounts of information to predict a patient's likely trajectory of neurologic recovery. In this setting, critically evaluating salient ethical questions is imperative, and the implications often inform high-stakes conversations about the continuation, limitation, or withdrawal of life-sustaining therapy. While neuroprognostication is central to these clinical "life-or-death" decisions, the ethical underpinnings of neuroprognostication itself have been underexplored for patients with ABI. In this article, we discuss the ethical challenges of individualized neuroprognostication including parsing and communicating its inherent uncertainty to surrogate decision-makers. We also explore the population-based ethical considerations that arise in the context of heterogenous prognostication practices. Finally, we examine the emergence of artificial intelligence-aided neuroprognostication, proposing an ethical framework relevant to both modern and longstanding prognostic tools.

Modified Neuropixels probes for recording human neurophysiology in the operating room.

Neuropixels are silicon-based electrophysiology-recording probes with high channel count and recording-site density. These probes offer a turnkey platform for measuring neural activity with single-cell resolution and at a scale that is beyond the capabilities of current clinically approved devices. Our team demonstrated the first-in-human use of these probes during resection surgery for epilepsy or tumors and deep brain stimulation electrode placement in patients with Parkinson's disease. Here, we provide a better understanding of the capabilities and challenges of using Neuropixels as a research tool to study human neurophysiology, with the hope that this information may inform future efforts toward regulatory approval of Neuropixels probes as research devices. In perioperative procedures, the major concerns are the initial sterility of the device, maintaining a sterile field during surgery, having multiple referencing and grounding schemes available to de-noise recordings (if necessary), protecting the silicon probe from accidental contact before insertion and obtaining high-quality action potential and local field potential recordings. The research team ensures that the device is fully operational while coordinating with the surgical team to remove sources of electrical noise that could otherwise substantially affect the signals recorded by the sensitive hardware. Prior preparation using the equipment and training in human clinical research and working in operating rooms maximize effective communication within and between the teams, ensuring high recording quality and minimizing the time added to the surgery. The perioperative procedure requires ~4 h, and the entire protocol requires multiple weeks.

Navigating the acute to post-acute transition with patients: a first characterization of medical student knowledge gaps in rehabilitation and post-acute care.

PURPOSE: Clinical rehabilitation and post-acute care (PAC) learning experiences are not uniformly required within medical school core curricula in the United States or internationally. This study aims to characterize what medical students might know/need to know to support patients in the transition from acute hospitalization to post-acute rehabilitation settings. MATERIALS/METHODS: The medical student cohort completing required clinical rotations in a United States quaternary care hospital system was provided a voluntary survey prompting reflection on experiences discharging patients to rehabilitation/PAC and related learning needs. Data were analyzed using descriptive statistics and qualitative grounded theory. RESULTS: Response rate was 72% (39/54). All respondents reported at least one gap in rehabilitation/PAC knowledge, falling into 8 themes: daily experience of rehabilitation/PAC; determination of eligibility/screening processes; distinctions among levels of rehabilitation/PAC; insurance coverage/equity; rehabilitation/PAC clinical practice environment; post-rehabilitation/PAC discharge support; medical capabilities within PAC settings; developing rehabilitation goals. CONCLUSIONS: Despite caring for patients discharged to post-acute rehabilitation settings, medical students lack essential knowledge about the process of rehabilitation and recovery, including patient eligibility for and service availability across PAC settings. Explicit rehabilitation/PAC education for medical students could enhance their ability to counsel and advocate for patients with disability and rehabilitation needs through care transitions.Implications for rehabilitationMedical students lack knowledge about rehabilitation and post-acute care that is important for helping patients navigate the acute to post-acute transition.Dedicated rehabilitation/post-acute care education could prepare trainees for counseling and advocating for patients during care transitions.Knowledge gaps identified in this study could inform development of curricular interventions to address medical student learning needs.

Measuring Consciousness in the Intensive Care Unit.

Early reemergence of consciousness predicts long-term functional recovery for patients with severe brain injury. However, tools to reliably detect consciousness in the intensive care unit are lacking. Transcranial magnetic stimulation electroencephalography has the potential to detect consciousness in the intensive care unit, predict recovery, and prevent premature withdrawal of life-sustaining therapy.

Ethics Along the Continuum of Research Involving Persons with Disorders of Consciousness.

Interest in disorders of consciousness (DoC) has grown substantially over the past decade and has illuminated the importance of improving understanding of DoC biology; care needs (use of monitoring, performance of interventions, and provision of emotional support); treatment options to promote recovery; and outcome prediction. Exploration of these topics requires awareness of numerous ethics considerations related to rights and resources. The Curing Coma Campaign Ethics Working Group used its expertise in neurocritical care, neuropalliative care, neuroethics, neuroscience, philosophy, and research to formulate an informal review of ethics considerations along the continuum of research involving persons with DoC related to the following: (1) study design; (2) comparison of risks versus benefits; (3) selection of inclusion and exclusion criteria; (4) screening, recruitment, and enrollment; (5) consent; (6) data protection; (7) disclosure of results to surrogates and/or legally authorized representatives; (8) translation of research into practice; (9) identification and management of conflicts of interest; (10) equity and resource availability; and (11) inclusion of minors with DoC in research. Awareness of these ethics considerations when planning and performing research involving persons with DoC will ensure that the participant rights are respected while maximizing the impact and meaningfulness of the research, interpretation of outcomes, and communication of results.

Toward Uniform Insurer Coverage for Functional MRI Following Severe Brain Injury.

Functional magnetic resonance imaging (fMRI) now promises to improve diagnostic and prognostic accuracy for patients with disorders of consciousness, and accordingly has been endorsed by professional society guidelines, including those of the American Academy of Neurology, American College of Rehabilitation Medicine, National Institute on Disability, Independent Living, and Rehabilitation Research, and the European Academy of Neurology. Despite multiple professional society endorsements of fMRI in evaluating patients with disorders of consciousness following severe brain injury, insurers have yet to issue clear guidance regarding coverage of fMRI for this indication. Lack of insurer coverage may be a rate-limiting barrier to accessing this technique, which could uncover essential diagnostic and prognostic information for patients and their families. The emerging clinical and ethical case for harmonized insurer recognition and reimbursement of fMRI for vulnerable persons following severe brain injury with disorders of consciousness is explained and critically evaluated.

Neuroethics across the Disorders of Consciousness Care Continuum.

This review provides an ethical analysis of disorders of consciousness (DoC) along the care continuum, from preinjury to injury, acute care to subacute care and early rehabilitation, and finally transitioning to chronic rehabilitation and societal reintegration. We provide an actionable, chronological assessment of ethical issues related to DoC care. This expands upon established ethics literature, which focuses almost exclusively on the clinical encounter for DoC. Our goal is to broaden the aperture of ethical analysis to address how social and environmental conditions predispose some persons to brain injury, and how such conditions might also pose barriers to meaningful societal reintegration after recovery.

Ethics Priorities of the Curing Coma Campaign: An Empirical Survey.

BACKGROUND: The Curing Coma Campaign (CCC) is a multidisciplinary global initiative focused on evaluation, diagnosis, treatment, research, and prognostication for patients who are comatose due to any etiology. To support this mission, the CCC Ethics Working Group conducted a survey of CCC collaborators to identify the ethics priorities of the CCC and the variability in priorities based on country of practice. METHODS: An electronic survey on the ethics priorities for the CCC was developed using rank-choice questions and distributed between May and July 2021 to a listserv of the 164 collaborators of the CCC. The median rank for each topic and subtopic was determined. Comparisons were made on the basis of country of practice. RESULTS: The survey was completed by 93 respondents (57% response rate); 67% practiced in the United States. On the basis of respondent ranking of each topic, the prioritization of ethics topics across respondents was as follows: (1) clinical care, (2) diagnostic definitions, (3) clinical research, (4) implementation/innovation, (5) family, (6) data management, (7) public engagement/perceptions, and (8) equity. Respondents who practiced in the United States were particularly concerned about public engagement, the distinction between clinical care and research, disclosure of results from clinical research to families, the definition of "personhood," and the distinction between the self-fulfilling prophecy/nihilism and medical futility. Respondents who practiced in other countries were particularly concerned about diagnostic modalities for clinical care, investigational drugs/devices for clinical research, translation of research into practice, and the definition of "minimally conscious state." CONCLUSIONS: Collaborators of the CCC considered clinical care, diagnostic definitions, and clinical research the top ethics priorities of the CCC. These priorities should be considered as the CCC explores ways to improve evaluation, diagnosis, treatment, research, and prognostication of patients with coma and associated disorders of consciousness. There is some variability in ethics priorities based on country of practice.

Comparative optimization of combinatorial CRISPR screens.

Combinatorial CRISPR technologies have emerged as a transformative approach to systematically probe genetic interactions and dependencies of redundant gene pairs. However, the performance of different functional genomic tools for multiplexing sgRNAs vary widely. Here, we generate and benchmark ten distinct pooled combinatorial CRISPR libraries targeting paralog pairs to optimize digenic knockout screens. Libraries composed of dual Streptococcus pyogenes Cas9 (spCas9), orthogonal spCas9 and Staphylococcus aureus (saCas9), and enhanced Cas12a from Acidaminococcus were evaluated. We demonstrate a combination of alternative tracrRNA sequences from spCas9 consistently show superior effect size and positional balance between the sgRNAs as a robust combinatorial approach to profile genetic interactions of multiple genes.