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Objectives An estimated 14–23% of patients with traumatic brain injury (TBI) incur multiple lifetime TBIs. The relationship between prior TBI and outcomes in patients with moderate to severe TBI (msTBI) is not well delineated. We examined the associations between prior TBI, in-hospital mortality, and outcomes up to 12 months after injury in a prospective US msTBI cohort.Methods Data from hospitalized subjects with Glasgow Coma Scale score of 3–12 were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (enrollment period: 2014–2019). Prior TBI with amnesia or alteration of consciousness was assessed using the Ohio State University TBI Identification Method. Competing risk regressions adjusting for age, sex, psychiatric history, cranial injury and extracranial injury severity examined the associations between prior TBI and in-hospital mortality, with hospital discharged alive as the competing risk. Adjusted HRs (aHR (95% CI)) were reported. Multivariable logistic regressions assessed the associations between prior TBI, mortality, and unfavorable outcome (Glasgow Outcome Scale-Extended score 1–3 (vs. 4–8)) at 3, 6, and 12 months after injury.Results Of 405 acute msTBI subjects, 21.5% had prior TBI, which was associated with male sex (87.4% vs. 77.0%, p=0.037) and psychiatric history (34.5% vs. 20.7%, p=0.010). In-hospital mortality was 10.1% (prior TBI: 17.2%, no prior TBI: 8.2%, p=0.025). Competing risk regressions indicated that prior TBI was associated with likelihood of in-hospital mortality (aHR=2.06 (1.01–4.22)), but not with hospital discharged alive. Prior TBI was not associated with mortality or unfavorable outcomes at 3, 6, and 12 months.Conclusions After acute msTBI, prior TBI history is independently associated with in-hospital mortality but not with mortality or unfavorable outcomes within 12 months after injury. This selective association underscores the importance of collecting standardized prior TBI history data early after acute hospitalization to inform risk stratification. Prospective validation studies are needed.Level of evidence IV.Trial registration number NCT02119182.

Over the last 30 years, there has been a growing trend in clinical trials towards assessing novel interventions not only against the benchmark of statistical significance, but also with respect to whether they lead to clinically meaningful changes for patients. In the context of Disorders of Consciousness (DOC), despite a growing landscape of experimental interventions, there is no agreed standard as to what counts as a minimal clinically important difference (MCID). In part, this issue springs from the fact that, by definition, DOC patients are either unresponsive (i.e., in a Vegetative State; VS) or non-communicative (i.e., in a Minimally Conscious State; MCS), which renders it impossible to assess any subjective perception of benefit, one of the two core aspects of MCIDs. Here, we develop a novel approach that leverages published, international diagnostic guidelines to establish a probability-based minimal clinically important difference (pMCID), and we apply it to the most validated and frequently used scale in DOC: the Coma Recovery Scale-Revised (CRS-R). This novel method is objective (i.e., based on published criteria for patient diagnosis) and easy to recalculate as the field refines its agreed-upon criteria for diagnosis. We believe this new approach can help clinicians determine whether observed changes in patients' behavior are clinically important, even when patients cannot communicate their experiences, and can align the landscape of clinical trials in DOC with the practices in other medical fields.

Summary: Background: Contemporary surgical practices for traumatic brain injury (TBI) remain unclear. We describe the clinical profile of an 18-centre US TBI cohort with cranial surgery. Methods: The prospective, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (2014–2018; ClinicalTrials.gov #NCT02119182) enrolled subjects who presented to trauma centre and received head computed tomography within 24-h (h) post-TBI. We performed a secondary data analysis in subjects aged ≥17-years with hospitalisation. Clinical characteristics, surgery type/timing, hospital and six-month outcomes were reported. Findings: Of 2032 subjects (age: mean = 41.4-years, range = 17–89-years; male = 71% female = 29%), 260 underwent cranial surgery, comprising 65% decompressive craniectomy, 23% craniotomy, 12% other surgery. Subjects with surgery (vs. without surgery) presented with worse neurological injury (median Glasgow Coma Scale = 6 vs. 15; midline shift ≥5 mm: 48% vs. 2%; cisternal effacement: 61% vs. 4%; p

New techniques for individualized assessment of white matter integrity are needed to detect traumatic axonal injury (TAI) and predict outcomes in critically ill patients with acute severe traumatic brain injury (TBI). Diffusion MRI tractography has the potential to quantify white matter microstructure in vivo and has been used to characterize tract-specific changes following TBI. However, tractography is not routinely used in the clinical setting to assess the extent of TAI, in part because focal lesions reduce the robustness of automated methods. Here, we propose a pipeline that combines automated tractography reconstructions of 40 white matter tracts with multivariate analysis of along-tract diffusion metrics to assess the presence of TAI in individual patients with acute severe TBI. We used the Mahalanobis distance to identify abnormal white matter tracts in each of 18 patients with acute severe TBI as compared to 33 healthy subjects. In all patients for which a FreeSurfer anatomical segmentation could be obtained (17 of 18 patients), including 13 with focal lesions, the automated pipeline successfully reconstructed a mean of 37.5 ± 2.1 white matter tracts without the need for manual intervention. A mean of 2.5 ± 2.1 tracts resulted in partial or failed reconstructions and needed to be reinitialized upon visual inspection. The pipeline detected at least one abnormal tract in all patients (mean: 9.1 ± 7.9) and accurately discriminated between patients and controls (AUC: 0.91). The number and neuroanatomic location of abnormal tracts varied across patients and levels of consciousness. The premotor, temporal, and parietal sections of the corpus callosum were the most commonly damaged tracts (in 10, 9, and 8 patients, respectively), consistent with prior histopathological studies of TAI. TAI measures were not associated with concurrent behavioral measures of consciousness. In summary, we provide proof-of-principle evidence that an automated tractography pipeline has translational potential to detect and quantify TAI in individual patients with acute severe TBI.

Over the last 30 years, there has been a growing trend in clinical trials towards assessing novel interventions not only against the benchmark of statistical significance, but also with respect to whether they lead to clinically meaningful changes for patients. In the context of Disorders of Consciousness (DOC), despite a growing landscape of experimental interventions, there is no agreed standard as to what counts as a minimal clinically important difference (MCID). In part, this issue springs from the fact that, by definition, DOC patients are either unresponsive (i.e., in a Vegetative State; VS) or non-communicative (i.e., in a Minimally Conscious State; MCS), which renders it impossible to assess any subjective perception of benefit, one of the two core aspects of MCIDs. Here, we develop a novel approach that leverages published, international diagnostic guidelines to establish a probability-based minimal clinically important difference (pMCID), and we apply it to the most validated and frequently used scale in DOC: the Coma Recovery Scale–Revised (CRS-R). This novel method is objective (i.e., based on published criteria for patient diagnosis) and easy to recalculate as the field refines its agreed-upon criteria for diagnosis. We believe this new approach can help clinicians determine whether observed changes in patients’ behavior are clinically important, even when patients cannot communicate their experiences, and can align the landscape of clinical trials in DOC with the practices in other medical fields.

Transcranial direct-current stimulation (tDCS) over the prefrontal cortex can improve signs of consciousness in patients in a minimally conscious state. Transcranial pulsed-current stimulation (tPCS) over the mastoids can modulate brain activity and connectivity in healthy controls. This study investigated the feasibility of tPCS as a therapeutic tool in patients with disorders of consciousness (DoC) and compared its neurophysiological and behavioral effects with prefrontal tDCS. This pilot study was a randomized, double-blind sham-controlled clinical trial with three sessions: bi-mastoid tPCS, prefrontal tDCS, and sham. Electroencephalography (EEG) and behavioral assessments were collected before and after each stimulation session. Post minus pre differences were compared using Kruskal–Wallis and Wilcoxon signed-rank tests. Twelve patients with DoC were included in the study (eight females, four traumatic brain injury, 50.3 ± 14 y.o., 8.8 ± 10.5 months post-injury). We did not observe any side-effects following tPCS, nor tDCS, and confirmed their feasibility and safety. We did not find a significant effect of the stimulation on EEG nor behavioral outcomes for tPCS. However, consistent with prior findings, our exploratory analyses suggest that tDCS induces behavioral improvements and an increase in theta frontal functional connectivity.

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.

Background: It is not currently possible to predict which patients will develop chronic disorders of consciousness (DoC) after severe traumatic brain injury (TBI). Although the ascending arousal network (AAN) supports human consciousness, it is unknown which AAN pathways must be preserved for patients to recover consciousness. Methods: Sixteen patients with acute traumatic coma and 16 matched healthy controls were scanned with high angular resolution diffusion imaging (HARDI). All patients recovered consciousness (Recovery Cohort). Nine were scanned longitudinally: first in the ICU (Acute), then at ≥5 months post-injury (Follow-up). Six separate patients with post-traumatic DoC were scanned ≥5 months post-injury (Chronic DoC Cohort). For each AAN pathway, we computed the median relative change in Acute-to-Follow-up Connectivity Probability (CP) in the Recovery Cohort. We then used Wilcoxon tests with Bonferroni correction to compare CP in each AAN pathway in the Recovery Cohort at Follow-up versus the Chronic DoC Cohort. In an exploratory analysis, we used principal component analysis (PCA) to determine whether linear combinations of AAN CP values could separate the Chronic DoC Cohort from the Recovery Cohort and the healthy controls. Results: In the Recovery Cohort, the largest relative AAN CP changes were in the brainstem-to-thalamus (median [IQR] = 0.7 [0.09, 0.9]) and forebrain-to-occipital lobe (−0.8 [−0.9, −0.8]) pathways. The AAN connections that differed in the cross-sectional analysis between the Recovery Cohort at Follow-up and the Chronic DoC Cohort included brainstem-to-hypothalamus (W = 53, PBonf = 0.02), brainstem-to-temporal lobe (W = 52, PBonf = 0.04), and thalamus-to-temporal lobe (W = 54, PBonf = 0.009). Plotting the first two principal components of AAN connectivity resulted in a linear separation of Chronic DoC patients from other study groups. Conclusions: We provide evidence for a longitudinal increase in brainstem-thalamic connectivity during recovery of consciousness after traumatic coma. Cross-sectional analyses revealed that brainstem-hypothalamus, brainstem-temporal lobe, and thalamus-temporal lobe connectivity differed between patients who recovered consciousness and those with a chronic DoC. These observations provide the basis for further investigation into AAN connectivity as a biomarker for recovery of consciousness after traumatic coma.

Severe traumatic brain injury (TBI) may result in a disorder of consciousness (DoC) and lead to substantial long-term disability. While level of independence with activities of daily living, especially for persons who recover consciousness during inpatient rehabilitation, generally improves over time, the degree of change in participation remains unknown. We determined level of participation among persons with TBI between 2005 and 2017 who were admitted to inpatient rehabilitation unable to follow commands and subsequently enrolled in the TBI Model Systems National Database. Participation on the Participation Assessment with Recombined Tools-Objective (PART-O) Productivity, Social Relations, and Out and About subscales was evaluated at 1–5 years post-injury. We used a mixed-effects model to longitudinally compare participation between persons who did and did not regain command-following during inpatient rehabilitation. We further explored the level of participation associated with increasing levels of functional independence (FIM). The analysis included 333 persons (229 recovered command-following during rehabilitation, mean age = 35.46 years, 74.9% male). Participation across groups, at all follow-up time points, on all PART-O subscales, was remarkably low (mean range = 0.021–1.91, maximum possible score = 5). Performance was highest on the Social Relations subscale and lowest on the Productivity subscale. Longitudinal analyses revealed no difference in level of participation or change in participation across time for persons who regained command-following during rehabilitation compared to those who did not. While productivity increased over time, social participation did not and participation outside the home increased more for younger than for older persons. Across all three PART-O subscales, FIM Motor scores positively predicted participation. FIM Cognitive scores positively predicted level of participation on the Productivity and Social Relations subscales. Exploratory analyses revealed that even persons who achieved independence on the FIM Motor and Cognitive subscales had low levels of participation across domains and follow-up years. In summary, persons with severe TBI who were admitted to inpatient rehabilitation unable to follow commands were found to be unlikely to participate in productive tasks, social endeavors, or activities outside of the home up to 5 years post-injury, even if functional independence was recovered.

Although comorbidities have a well-known impact on the functional recovery of patients with disorders of consciousness, including coma, vegetative state (VS), and minimally conscious state (MCS), a specific tool for their assessment in this challenging group of patients is lacking. For this aim, a multistep process was used to develop and validate the Comorbidities Coma Scale (CoCoS) in a sample of 162 patients with a diagnosis of coma, VS or MCS admitted to four Acute Inpatient Rehabilitation Units. To establish the psychometric properties of the scale, content validity, and internal consistency were investigated through Exploratory Factor Analysis in the whole sample (n = 162). Interrater reliability, assessed by the weighted Cohen's kappa (Kw), and concurrent validity of the scale as compared to the Greenfield Scale, assessed by ρ Spearman's correlation coefficient, were investigated in a subsample of patients (n = 52) within two of the above units. Our findings provided evidence of a good content validity of the scale, with the identification of a 12-factor structure representing the different comorbid dimensions of the target population. Inter-rater reliability was excellent in both the rehabilitation units where the assessment was made [Kw 0.98 (95% CI 0.96–0.99)]. CoCoS total scores correlated significantly with total scores of the Greenfield Scale (ρ = 0.932, 95% CI 0.89–0.96; P < 0.0001) indicating that CoCoS has concurrent validity while being more informative about the specific pattern of comorbidities of these challenging patients. The CoCos is a new tool which standardizes the approach to assessment of comorbid conditions and reliably identifies the category and severity of each comorbidity detected. It may be used for both clinical and research applications.

Historically, Duret hemorrhages have conferred a devastating prognosis. However, recent case reports suggest that cognitive and functional recovery are possible after Duret hemorrhages. Here, we describe a patient who recovered consciousness, communication, and functional independence after Duret hemorrhages caused by traumatic transtentorial herniation. We performed prospective, standardized behavioral assessments, structural MRI scans and stimulus-based functional MRI (fMRI) scans during the first 2 years of recovery. The multimodal assessments revealed reintegration of neural networks mediating language and consciousness, concurrent with the reemergence of functional independence. These observations provide insights into network-based mechanisms of recovery from coma and add to a growing body of evidence indicating that Duret hemorrhages are not invariably associated with a poor prognosis.

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.