Challenges and Pitfalls Associated with Diagnostic and Prognostic Applications of Functional Neuroimaging in Disorders of Consciousness

The diagnostic assessment of patients with disorder of consciousness is currently based on clinical testing at the bedside and prone to a high error rate in the assessment of the degree of conscious awareness. Investigation of more objective assessment strategies, such as the use of functional magnetic resonance imaging (fMRI) to detect conscious awareness, are becoming increasingly popular in the research community. However, inherent challenges to the use of fMRI threaten its validity as a diagnostic tool and will need to be resolved prior to its integration into the clinical setting. These challenges, which range from the heterogeneity of the patient sample to factors influencing data acquisition and biases in interpretation strategies, are discussed below. Recommendations aimed at mitigating some of the limitations are provided

Predictive utility of an adapted Marshall head CT classification scheme after traumatic brain injury

Objective: To study the predictive relationship among persons with traumatic brain injury (TBI) between an objective indicator of injury severity (the adapted Marshall computed tomography [CT] classification scheme) and clinical indicators of injury severity in the acute phase, functional outcomes at inpatient rehabilitation discharge, and functional and participation outcomes at 1 year after injury, including death.Participants: The sample involved 4895 individuals who received inpatient rehabilitation following acute hospitalization for TBI and were enrolled in the Traumatic Brain Injury Model Systems National Database between 1989 and 2014.Design: Head CT variables for each person were fit into adapted Marshall CT classification categories I through IV.Main Measures: Prediction models were developed to determine the amount of variability explained by the CT classification categories compared with commonly used predictors, including a clinical indicator of injury severity.Results: The adapted Marshall classification categories aided only in the prediction of craniotomy or craniectomy during acute hospitalization, otherwise making no meaningful contribution to variance in the multivariable models predicting outcomes at any time point after injury.Conclusion: Results suggest that head CT findings classified in this manner do not inform clinical discussions related to functional prognosis or rehabilitation planning after TBI

Diagnosing Level of Consciousness: Limits of the Glasgow Coma Scale Total Score

In nearly all clinical and research contexts, the initial severity of a traumatic brain injury (TBI) is measured using the Glasgow Coma Scale (GCS) total score. The GCS total score however, may not accurately reflect level of consciousness, a critical indicator of injury severity. We investigated the relationship between GCS total scores and level of consciousness in a consecutive sample of 2455 adult subjects assessed with the GCS 69,487 times as part of the multi-center Transforming Research and Clinical Knowledge in TBI (TRACKTBI) study. We assigned each GCS subscale score combination a level of consciousness rating based on published criteria for the following disorders of consciousness (DoC) diagnoses: coma, vegetative state/ unresponsive wakefulness syndrome, minimally conscious state, and post-traumatic confusional state, and present our findings using summary statistics and four illustrative cases. Participants had the following characteristics: mean (standard deviation) age 41.9 (17.6) years, 69% male, initial GCS 3–8 = 13%; 9–12 = 5%; 13–15 = 82%. All GCS total scores between 4–14 were associated with more than one DoC diagnosis; the greatest variability was observed for scores of 7–11. Further, a wide range of total scores was associated with identical DoC diagnoses. Importantly, a diagnosis of coma was only possible with GCS total scores of 3–6. The GCS total score does not accurately reflect level of consciousness based on published DoC diagnostic criteria. To improve the classification of patients with TBI and to inform the design of future clinical trials, clinicians and investigators should consider individual subscale behaviors and more comprehensive assessments when evaluating TBI severityTRACK-TB

Central curation of Glasgow Outcome Scale-Extended data: lessons learned from TRACK-TBI

The Glasgow Outcome Scale (GOS) in its original or extended (GOSE) form is the most widely used assessment of global disability in traumatic brain injury (TBI) research. Several publications have reported concerns about assessor scoring inconsistencies, but without documentation of contributing factors. We reviewed 6801 GOSE assessments collected longitudinally, across 18 sites in the 5-year, observational Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. We recorded error rates (i.e., corrections to a section or an overall rating) based on site assessor documentation and categorized scoring issues, which then informed further training. In Cohort 1 (n=1261; 2/2014-5/2016), 24% of GOSEs had errors identified by central review. In Cohort 2 (n=1130; 6/2016-7/2018), acquired following curation of Cohort 1 data, feedback, and further training of site assessors, the error rate was reduced to 10%. GOSE sections associated with the most frequent interpretation and scoring difficulties included whether current functioning represented a change from pre-injury (466 corrected ratings in Cohort 1; 62 in Cohort 2), defining dependency in the home and community (163 corrections in Cohort 1; 3 in Cohort 2); and return to work/school (72 corrections in Cohort 1; 35 in Cohort 2). These results highlight the importance of central review in improving consistency across sites and over time. Establishing clear scoring criteria, coupled with ongoing guidance and feedback to data collectors, is essential to avoid scoring errors and resultant misclassification, which carry potential to result in “failure” of clinical trials that rely on the GOSE as their primary outcome measure

The Post-traumatic Confusional State: A Case Definition and Diagnostic Criteria

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury (TBI) and to better describe the characteristics of the condition commonly labeled Post-traumatic Amnesia, a case definition and diagnostic criteria for the Post- traumatic Confusional State (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2,466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and three rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state while upper boundary is marked by significant improvement in the four core and five associated features. Key research goals are establishment of cut-offs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery

Functional MRI Motor Imagery Tasks to Detect Command Following in Traumatic Disorders of Consciousness

Severe traumatic brain injury impairs arousal and awareness, the two components of consciousness. Accurate diagnosis of a patient’s level of consciousness is critical for determining treatment goals, access to rehabilitative services, and prognosis. The bedside behavioral examination, the current clinical standard for diagnosis of disorders of consciousness, is prone to misdiagnosis, a finding that has led to the development of advanced neuroimaging techniques aimed at detection of conscious awareness. Although a variety of paradigms have been used in functional magnetic resonance imaging (fMRI) to reveal covert consciousness, the relative accuracy of these paradigms in the patient population is unknown. Here, we compare the rate of covert consciousness detection by hand squeezing and tennis playing motor imagery paradigms in 10 patients with traumatic disorders of consciousness [six male, six acute, mean ± SD age = 27.9 ± 9.1 years, one coma, four unresponsive wakefulness syndrome, two minimally conscious without language function, and three minimally conscious with language function, per bedside examination with the Coma Recovery Scale-Revised (CRS-R)]. We also tested the same paradigms in 10 healthy subjects (nine male, mean ± SD age = 28.5 ± 9.4 years). In healthy subjects, the hand squeezing paradigm detected covert command following in 7/10 and the tennis playing paradigm in 9/10 subjects. In patients who followed commands on the CRS-R, the hand squeezing paradigm detected covert command following in 2/3 and the tennis playing paradigm in 0/3 subjects. In patients who did not follow commands on the CRS-R, the hand squeezing paradigm detected command following in 1/7 and the tennis playing paradigm in 2/7 subjects. The sensitivity, specificity, and accuracy (ACC) of detecting covert command following in patients who demonstrated this behavior on the CRS-R was 66.7, 85.7, and 80% for the hand squeezing paradigm and 0, 71.4, and 50% for the tennis playing paradigm, respectively. Overall, the tennis paradigm performed better than the hand squeezing paradigm in healthy subjects, but in patients, the hand squeezing paradigm detected command following with greater ACC. These findings indicate that current fMRI motor imagery paradigms frequently fail to detect command following and highlight the need for paradigm optimization to improve the accuracy of covert consciousness detection

Functional MRI Motor Imagery Tasks to Detect Command Following in Traumatic Disorders of Consciousness

Severe traumatic brain injury impairs arousal and awareness, the two components of consciousness. Accurate diagnosis of a patient’s level of consciousness is critical for determining treatment goals, access to rehabilitative services, and prognosis. The bedside behavioral examination, the current clinical standard for diagnosis of disorders of consciousness, is prone to misdiagnosis, a finding that has led to the development of advanced neuroimaging techniques aimed at detection of conscious awareness. Although a variety of paradigms have been used in functional magnetic resonance imaging (fMRI) to reveal covert consciousness, the relative accuracy of these paradigms in the patient population is unknown. Here, we compare the rate of covert consciousness detection by hand squeezing and tennis playing motor imagery paradigms in 10 patients with traumatic disorders of consciousness [six male, six acute, mean ± SD age = 27.9 ± 9.1 years, one coma, four unresponsive wakefulness syndrome, two minimally conscious without language function, and three minimally conscious with language function, per bedside examination with the Coma Recovery Scale-Revised (CRS-R)]. We also tested the same paradigms in 10 healthy subjects (nine male, mean ± SD age = 28.5 ± 9.4 years). In healthy subjects, the hand squeezing paradigm detected covert command following in 7/10 and the tennis playing paradigm in 9/10 subjects. In patients who followed commands on the CRS-R, the hand squeezing paradigm detected covert command following in 2/3 and the tennis playing paradigm in 0/3 subjects. In patients who did not follow commands on the CRS-R, the hand squeezing paradigm detected command following in 1/7 and the tennis playing paradigm in 2/7 subjects. The sensitivity, specificity, and accuracy (ACC) of detecting covert command following in patients who demonstrated this behavior on the CRS-R was 66.7, 85.7, and 80% for the hand squeezing paradigm and 0, 71.4, and 50% for the tennis playing paradigm, respectively. Overall, the tennis paradigm performed better than the hand squeezing paradigm in healthy subjects, but in patients, the hand squeezing paradigm detected command following with greater ACC. These findings indicate that current fMRI motor imagery paradigms frequently fail to detect command following and highlight the need for paradigm optimization to improve the accuracy of covert consciousness detection

Ethical Considerations in Clinical Trials for Disorders of Consciousness

As the clinical trial landscape for patients with disorders of consciousness (DoC) expands, consideration of associated ethical challenges and opportunities is of ever-increasing importance. Responsible conduct of research in the vulnerable population of persons with DoC, including those with coma, vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), covert cortical processing (CCP), and cognitive motor dissociation (CMD), demands proactive deliberation of unique ethical issues that may arise and the adoption of robust protections to safeguard patients, surrogates, and other key stakeholders. Here we identify and critically evaluate four central categories of ethical considerations in clinical trials involving participants with DoC: (1) autonomy, respect for persons and informed consent of individuals with liminal consciousness; (2) balancing unknown benefits and risks, especially considering the epistemological gap between behavior and consciousness that complicates ordinary ascription of subjective states; (3) disclosure to surrogates and clinical teams of investigational results pertaining to consciousness; and (4) justice considerations, including equitable access to clinical trial enrollment across communities and geographies. We outline guiding principles and research opportunities for clinicians, neuroethicists, and researchers engaged in DoC clinical trials to advance ethical study design and deployment in this complex yet crucial area of investigation