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Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.

Memory impairments are common chronic and functionally important consequences of traumatic brain injury (TBI). Among patients with persistent verbal memory impairments due to TBI-related cholinergic deficits, donepezil (an acetylcholinesterase inhibitor) may improve these and related problems. The Multicenter Evaluation of Memory Remediation in TBI with Donepezil (MEMRI-TBI-D) study, a four-site, randomized, parallel-group, double-blind, placebo-controlled, 10-week clinical trial, evaluated the efficacy of donepezil on verbal memory impairments, co-occurring cognitive and noncognitive neuropsychiatric problems, and functional status among persons with severe, persistent, and functionally limiting verbal memory problems at least 6 months after mild, moderate, or severe TBI. Efficacy, safety, and tolerability measures were assessed. Seventy-five participants were randomly assigned to donepezil (N=37) and placebo (N=38) groups. In both modified intent-to-treat and per-protocol analyses, donepezil significantly improved memory (i.e., verbal learning, as measured by the Hopkins Verbal Learning Test-Revised Total Trials 1-3, the primary outcome measure) when compared with placebo. Treatment-responder rates in the donepezil and placebo groups were 42% and 18%, respectively, yielding a number needed to treat of 3.5. Among donepezil responders, delayed recall and processing speed also improved significantly. Treatment-emergent adverse event rates for donepezil and placebo were 46% and 8%, respectively, and mild or moderate (85%); diarrhea and nausea were significantly more common in the donepezil group, yielding a number needed to harm of 6.25 and a likelihood to be helped or harmed ratio of 1.79. These results suggest that donepezil is an efficacious treatment for severe, persistent memory impairments after predominantly severe TBI, with a relatively favorable safety and tolerability profile., Competing Interests: Dr. Giacino has received support via institutional awards from the James S. McDonnell Foundation and the National Football League (NFL). Dr. Hammond serves on the scientific advisory boards of Eli Lilly and Company and Otsuka Pharmaceutical. Dr. Zafonte serves on the scientific advisory boards of Kisbee, Myomo, and Nano Diagnostics, and he evaluates patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors report no financial relationships with commercial interests. Dr. Arciniegas is editor of the Journal of Neuropsychiatry and Clinical Neurosciences; accordingly, Consulting Editor Fred Ovsiew, M.D., served as editor, including refereeing the peer review process and decision making on publication of this article. Dr. Ovsiew has no institutional affiliations or competing obligations with the authors, the authors’ institutions, or the sponsor of this work.

Objectives: To assess the feasibility of the Toolkit for Optimal Recovery after Concussion (TOR-C), the first mind-body program aiming to prevent persistent concussion symptoms among young adults with anxiety, and an active control (Health Enhancement after Concussion [HE-C]). We also tested preliminary improvements in outcome measures and putative mechanistic targets., Design: Single-blind, 2-arm, randomized controlled trial (RCT)., Setting: Academic medical center in the US Northeast., Participants: Fifty young adults (aged 18-35 years) with a recent concussion (3-10 weeks prior) and anxiety (≥5 on the Generalized Anxiety Disorder-7 [GAD-7] questionnaire)., Interventions: Both interventions consisted of four 45-minute 1:1 sessions with a clinician over Zoom. TOR-C (n=25) taught mind-body, cognitive-behavioral, and return-to-activity skills. HE-C (n=25) taught health education (eg, sleep, nutrition) without skills., Main Outcome Measures: Primary: feasibility outcomes (eg, recruitment, credibility, expectancy, acceptability, safety, feasibility of assessments, fidelity, satisfaction, and TOR-C homework adherence) with a-priori-set benchmarks. Secondary: intervention outcomes were concussion symptoms (Post-Concussion Symptom Scale), physical function (World Health Organization Disability Assessment Scale), anxiety (GAD-7/anxiety subscale of the Hospital Anxiety and Depression Scale), depression (depression subscale of the Hospital Anxiety and Depression Scale) and pain (Numerical Rating Scale). TOR-C mechanistic targets were pain catastrophizing (Pain Catastrophizing Scale), mindfulness (Cognitive and Affective Mindfulness Scale-Revised), fear avoidance (Fear Avoidance Behavior after Traumatic Brain Injury), limiting behavior and all-or-nothing behavior (Behavioral Response to Illness Questionnaire)., Results: Both interventions met all feasibility benchmarks and were associated with significant improvements in outcomes (concussion symptoms, physical function, anxiety, depression, and pain; d=0.44-1.21) and TOR-C mechanistic targets (pain catastrophizing, mindfulness, fear-avoidance, and limiting behavior; Cohen's d=0.41-1.24). Improvements in all-or-nothing behavior were only significant in TOR-C (d=0.52). Improvements in all mechanistic targets except all-or-nothing behavior after TOR-C were significantly associated with improvements in at least one outcome., Conclusions: Findings provide strong support for the feasibility of TOR-C and HE-C, and preliminary evidence for improvements in mechanistic targets and outcomes. Findings inform a future fully-powered RCT testing efficacy of TOR-C versus HE-C., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

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 < 0.0001). Median time-to-craniectomy/craniotomy was 1.8 h (interquartile range = 1.1-5.0 h), and 67% underwent intracranial pressure monitoring. Seventy-three percent of subjects with decompressive craniectomy and 58% of subjects with craniotomy had ≥3 intracranial lesion types. Decompressive craniectomy (vs. craniotomy) was associated with intracranial injury severity (median Rotterdam Score = 4 vs. 3, p < 0.0001), intensive care length of stay (median = 13 vs. 4-days, p = 0.0002), and six-month unfavourable outcome (62% vs. 30%; p = 0.0001). Earlier time-to-craniectomy was associated with intracranial injury severity., Interpretation: In a large representative cohort of patients hospitalised with TBI, surgical decision-making and time-to-surgery aligned with intracranial injury severity. Multifocal TBIs predominated in patients with cranial surgery. These findings summarise current TBI surgical practice across US trauma centres and provide the foundation for analyses in targeted subpopulations., Funding: National Institute of Neurological Disorders and Stroke; US Department of Defense; Neurosurgery Research and Education Foundation., Competing Interests: AMD declares: grant funding from the Mercatus Center at George Mason University (not related to the current work). DKM declares: grant funding from United Kingdom National Institute for Health Research (not related to the current work). KKWW declares: is a shareholder of Gryphon Bio, Inc. (not related to the current work). All other authors declare no conflict of interest., (© 2024 The Author(s).)

Disorders of consciousness (DoC) resulting from severe acute brain injuries may prompt clinicians and surrogate decision makers to consider withdrawal of life-sustaining treatment (WLST) if the neurologic prognosis is poor. Recent guidelines suggest, however, that clinicians should avoid definitively concluding a poor prognosis prior to 28 days post injury, as patients may demonstrate neurologic recovery outside the acute time period. This practice may increase the frequency with which clinicians consider the option of delayed WLST (D-WLST), namely, WLST that would occur after hospital discharge, if the patient's recovery trajectory ultimately proves inconsistent with an acceptable quality of life. However acute care clinicians are often uncertain about what D-WLST entails and therefore find it difficult to properly counsel surrogates about this option. Here, we describe practical and theoretical considerations relevant to D-WLST. We first identify post-acute-care facilities to which patients with DoC are likely to be discharged and where D-WLST may be considered. Second, we describe how clinicians and surrogates may determine the appropriate timing of D-WLST. Third, we outline how D-WLST is practically implemented. And finally, we discuss psychosocial barriers to D-WLST, including the regret paradox, in which surrogates of patients who do not recover to meet preestablished goals frequently choose not to ultimately pursue D-WLST. Together, these practical, logistic, and psychosocial factors must be considered when potentially deferring WLST to the post-acute-care setting to optimize neurologic recovery for patients, avoid prolonged undue suffering, and promote informed and shared decision-making between clinicians and surrogates., (© 2024. The Author(s).)

Among patients with severe traumatic brain injury (TBI), there is high prognostic uncertainty but growing evidence that recovery of independence is possible. Nevertheless, families are often asked to make decisions about withdrawal of life-sustaining treatment (WLST) within days of injury. The range of potential outcomes for patients who died after WLST (WLST+) is unknown, posing a challenge for prognostic modeling and clinical counseling. We investigated the potential for survival and recovery of independence after acute TBI in patients who died after WLST. We used Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) data and propensity score matching to pair participants with WLST+ to those with a similar probability of WLST (based on demographic and clinical characteristics), but for whom life-sustaining treatment was not withdrawn (WLST-). To optimize matching, we divided the WLST- cohort into tiers (Tier 1 = 0-11%, Tier 2 = 11-27%, Tier 3 = 27-70% WLST propensity). We estimated the level of recovery that could be expected in WLST+ participants by evaluating 3-, 6-, and 12-month Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale outcomes in matched WLST- participants. Of 90 WLST+ participants (80% male, mean [standard deviation; SD] age = 59.2 [17.9] years, median [IQR] days to WLST = 5.4 [2.2, 11.7]), 80 could be matched to WLST- participants. Of 56 WLST- participants who were followed at 6 months, 31 (55%) died. Among survivors in the overall sample and survivors in Tiers 1 and 2, more than 30% recovered at least partial independence (GOSE ≥4). In Tier 3, recovery to GOSE ≥4 occurred at 12 months, but not 6 months, post-injury. These results suggest a substantial proportion of patients with TBI and WLST may have survived and achieved at least partial independence. However, death or severe disability is a common outcome when the probability of WLST is high. While further validation is needed, our findings support a more cautious clinical approach to WLST and more complete reporting on WLST in TBI studies.

Objective: To determine, in persons with traumatic brain injury (TBI), the association between cognitive change after inpatient rehabilitation discharge and 1-year participation and life satisfaction outcomes., Design: Secondary analysis of prospectively collected TBI Model Systems (TBIMS) data., Setting: Inpatient rehabilitation and community., Participants: 499 individuals with TBI requiring inpatient rehabilitation who completed the Brief Test of Adult Cognition by Telephone (BTACT) at inpatient rehabilitation discharge (ie, baseline) and 1-year postinjury., Main Outcome Measures: Participation Assessment with Recombined Tools-Objective (PART-O) and Satisfaction with Life Scale (SWLS)., Results: Of 2,840 TBIMS participants with baseline BTACT, 499 met inclusion criteria (mean [standard deviation] age = 45 [19] years; 72% male). Change in BTACT executive function (EF) was not associated with 1-year participation (PART-O; β = 0.087, 95% CI [-0.004, 0.178], P = .061) when it was the sole model predictor. Change in BTACT episodic memory (EM) was associated with 1-year participation (β = 0.096, [0.007, 0.184], P = .035), but not after adjusting for demographic, clinical, and functional status covariates (β = 0.067, 95% CI [-0.010, 0.145], P = .089). Change in BTACT EF was not associated with life satisfaction total scores (SWLS) when it was the sole model predictor (β = 0.091, 95% CI [-0.001, 0.182], P = .0503). Change in BTACT EM was associated with 1-year life satisfaction before (β = 0.114, 95% CI [0.025, 0.202], P = .012) and after adjusting for covariates (β = 0.103, [0.014, 0.191], P = .023). In secondary analyses, change in BTACT EF was associated with PART-O Social Relations and Out and About subdomains before (Social Relations: β = 0.127, 95% CI [0.036, 0.217], P = .006; Out and About: β = 0.141, 95% CI [0.051, 0.232], P = .002) and after (Social Relations: β = 0.168, 95% CI [0.072, 0.265], P < .002; Out and About: β = 0.156, 95% CI [0.061, 0.252], P < .002) adjusting for functional status and further adjusting for covariates (Social Relations: β = 0.127, 95% CI [0.040, 0.214], P = .004; Out and About: β = 0.136, 95% CI [0.043, 0.229], P = .004). However, only the models adjusting for functional status remained significant after multiple comparison correction (ie, Bonferroni-adjusted alpha level = 0.002)., Conclusion: EF gains during the first year after TBI were related to 1-year social and community participation. Gains in EM were associated with 1-year life satisfaction. These results highlight the potential benefit of cognitive rehabilitation after inpatient rehabilitation discharge and the need for interventions targeting specific cognitive functions that may contribute to participation and life satisfaction after TBI., Competing Interests: The authors declare no conflicts of interests., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Traumatic brain injury (TBI) represents a major cause of death and disability, significantly impacting the lives of 2.5 million people annually in the United States. Long-term natural history studies have clarified that functional recovery continues for up to a decade, even among those who sustain severe TBI. Despite these findings, nihilistic attitudes regarding prognosis persist among clinicians, highlighting the need for improved understanding of the natural history of recovery from TBI and the factors that influence outcome. Recent advances in neuroimaging technologies and blood-based biomarkers are shedding new light on injury detection, severity classification and the physiologic mechanisms underlying recovery and decline postinjury. Rehabilitation is an essential component of clinical management after moderate to severe TBI and can favorably influence mortality and functional outcome. However, systemic barriers, including healthcare policy, insurance coverage and social determinants of health often limit access to inpatient rehabilitation services. Posttraumatic amnesia and confusion contribute to morbidity after TBI; however, early initiation and sustained provision of rehabilitation interventions optimize long-term outcome. Evidence-based reviews have clearly shown that cognitive rehabilitation strategies can effectively restore or compensate for the cognitive sequelae of TBI when used according to existing practice guidelines. Neurostimulant agents are commonly employed off-label to enhance functional recovery, however, only amantadine hydrochloride has convincingly demonstrated effectiveness when used under tested parameters. Noninvasive brain stimulation procedures, including transcranial direct current stimulation and transcranial magnetic stimulation, have emerged as promising treatments in view of their ability to modulate aberrant neuronal activity and augment adaptive neuroplasticity, but assessment of safety and effectiveness during the acute period has been limited. Understanding the natural history of recovery from TBI and the effectiveness of available therapeutic interventions is essential to ensuring appropriate clinical management of this complex population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with brain injury who are unresponsive to commands may perform cognitive tasks that are detected on functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). This phenomenon, known as cognitive motor dissociation, has not been systematically studied in a large cohort of persons with disorders of consciousness., Methods: In this prospective cohort study conducted at six international centers, we collected clinical, behavioral, and task-based fMRI and EEG data from a convenience sample of 353 adults with disorders of consciousness. We assessed the response to commands on task-based fMRI or EEG in participants without an observable response to verbal commands (i.e., those with a behavioral diagnosis of coma, vegetative state, or minimally conscious state-minus) and in participants with an observable response to verbal commands. The presence or absence of an observable response to commands was assessed with the use of the Coma Recovery Scale-Revised (CRS-R)., Results: Data from fMRI only or EEG only were available for 65% of the participants, and data from both fMRI and EEG were available for 35%. The median age of the participants was 37.9 years, the median time between brain injury and assessment with the CRS-R was 7.9 months (25% of the participants were assessed with the CRS-R within 28 days after injury), and brain trauma was an etiologic factor in 50%. We detected cognitive motor dissociation in 60 of the 241 participants (25%) without an observable response to commands, of whom 11 had been assessed with the use of fMRI only, 13 with the use of EEG only, and 36 with the use of both techniques. Cognitive motor dissociation was associated with younger age, longer time since injury, and brain trauma as an etiologic factor. In contrast, responses on task-based fMRI or EEG occurred in 43 of 112 participants (38%) with an observable response to verbal commands., Conclusions: Approximately one in four participants without an observable response to commands performed a cognitive task on fMRI or EEG as compared with one in three participants with an observable response to commands. (Funded by the James S. McDonnell Foundation and others.)., (Copyright © 2024 Massachusetts Medical Society.)

The purpose of this study was to differentiate clinically meaningful improvement or deterioration from normal fluctuations in patients with disorders of consciousness (DoC) following severe brain injury. We computed indices of responsiveness for the Coma Recovery Scale-Revised (CRS-R) using data from a clinical trial of 180 participants with DoC. We used CRS-R scores from baseline (enrollment in a clinical trial) and a 4-week follow-up assessment period for these calculations. To improve precision, we transformed ordinal CRS-R total scores (0-23 points) to equal-interval measures on a 0-100 unit scale using Rasch Measurement theory. Using the 0-100 unit total Rasch measures, we calculated distribution-based 0.5 standard deviation (SD) minimal clinically important difference, minimal detectable change using 95% confidence intervals, and conditional minimal detectable change using 95% confidence intervals. The distribution-based minimal clinically important difference evaluates group-level changes, whereas the minimal detectable change values evaluate individual-level changes. The minimal clinically important difference and minimal detectable change are derived using the overall variability across total measures at baseline and 4 weeks. The conditional minimal detectable change is generated for each possible pair of CRS-R Rasch person measures and accounts for variation in standard error across the scale. We applied these indices to determine the proportions of participants who made a change beyond measurement error within each of the two subgroups, based on treatment arm (amantadine hydrochloride or placebo) or categorization of baseline Rasch person measure to states of consciousness (i.e., unresponsive wakefulness syndrome and minimally conscious state). We compared the proportion of participants in each treatment arm who made a change according to the minimal detectable change and determined whether they also changed to another state of consciousness. CRS-R indices of responsiveness (using the 0-100 transformed scale) were as follows: 0.5SD minimal clinically important difference = 9 units, minimal detectable change = 11 units, and the conditional minimal detectable change ranged from 11 to 42 units. For the amantadine and placebo groups, 70% and 58% of participants showed change beyond measurement error using the minimal detectable change, respectively. For the unresponsive wakefulness syndrome and minimally conscious state groups, 54% and 69% of participants changed beyond measurement error using the minimal detectable change, respectively. Among 115 participants (64% of the total sample) who made a change beyond measurement error, 29 participants (25%) did not change state of consciousness. CRS-R indices of responsiveness can support clinicians and researchers in discerning when behavioral changes in patients with DoC exceed measurement error. Notably, the minimal detectable change can support the detection of patients who make a "true" change within or across states of consciousness. Our findings highlight that the continued use of ordinal scores may result in incorrect inferences about the degree and relevance of a change score.

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., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose. To characterize societal participation profiles after moderate-severe traumatic brain injury (TBI) along objective (Frequency) and subjective (Satisfaction, Importance, Enfranchisement) dimensions. Materials and Methods. We conducted secondary analyses of a TBI Model Systems sub-study ( N  = 408). Multiaxial assessment of participation included the Participation Assessment with Recombined Tools-Objective and -Subjective questionnaires (Participation Frequency and Importance/Satisfaction, respectively) and the Enfranchisement Scale. Participants provided responses via telephone interview 1-15 years post-injury. Multidimensional participation profiles (classes) were extracted using latent profile analysis. Results. A 4-class solution was identified as providing maximal statistical separation between profiles and being clinically meaningful based on profile demographic features. One profile group (48.5% of the sample) exhibited the "best" participation profile (High Frequency, Satisfaction, Importance, and Enfranchisement) and was also the most advantaged according to socioeconomic indicators. Other profile groups showed appreciable heterogeneity across participation dimensions. Age, race/ethnicity, education level, ability to drive, and urbanicity were features that varied between profiles. Conclusions. Societal participation is a critical, but inherently complex, TBI outcome that may not be adequately captured by a single index. Our data underscore the importance of a multidimensional approach to participation assessment and interpretation using profiles. The use of participation profiles may promote precision health interventions for community integration.Implications for RehabilitationOur study found unidimensional measures of societal participation in traumatic brain injury (TBI) populations that focus exclusively on frequency indicators may be overly simplistic and miss key subjective components of participationTaking a multidimensional perspective, we documented four meaningfully distinct participation subgroups (including both objective and subjective dimensions of societal participation) within the TBI rehabilitation populationMultidimensional profiles of participation may be used to group individuals with TBI into target groups for intervention (e.g., deeper goal assessment for individuals who do not rate standard participation activities as important, but also do not participate and do not feel enfranchised).

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., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Consciousness is composed of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that underlie awareness in the human brain, but knowledge about the subcortical networks that sustain arousal in humans is incomplete. Here, we aimed to map the connectivity of a proposed subcortical arousal network that sustains wakefulness in the human brain, analogous to the cortical default mode network (DMN) that has been shown to contribute to awareness. We integrated data from ex vivo diffusion magnetic resonance imaging (MRI) of three human brains, obtained at autopsy from neurologically normal individuals, with immunohistochemical staining of subcortical brain sections. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain. Deterministic and probabilistic tractography analyses of the ex vivo diffusion MRI data revealed projection, association, and commissural pathways linking dAAN nodes with one another and with DMN nodes. Complementary analyses of in vivo 7-tesla resting-state functional MRI data from the Human Connectome Project identified the dopaminergic ventral tegmental area in the midbrain as a widely connected hub node at the nexus of the subcortical arousal and cortical awareness networks. Our network-based autopsy methods and connectivity data provide a putative neuroanatomic architecture for the integration of arousal and awareness in human consciousness.

Primary Objective: This study aimed to verify the reliability and validity of the Japanese version of the Coma Recovery Scale-Revised (CRS-R)., Methods: Subjects included 59 patients with disorders of consciousness (DOC) due to acquired brain injury. To validate test-retest reliability, Evaluator A assessed the CRS-R twice on the same day (A1, A2). To examine inter-rater reliability, Evaluators A (A2) and B (B) assessed the CRS-R without a time interval. To test concurrent validity, Evaluator A (A1) assessed the CRS-R, Japan Coma Scale (JCS), and the Glasgow Coma Scale (GCS) consecutively. To validate diagnostic accuracy, we evaluated the degree of agreement between A1 and A2 and between A2 and B in their diagnosis of DOC by CRS-R., Results: The test-retest (ρ = 0.92) and inter- (ρ = 0.98) reliability of CRS-R were excellent" and Concurrent validity of CRS-R with JCS (ρ =  -0.82) and GCS (ρ = 0.92) were high. Results of DOC diagnosis were consistent for 48/59 cases (κ = 0.82) for A1 and A2 and for 54/59 cases (κ = 0.92) for A2 and B., Conlcusion: The Japanese version of the CRS-R may be as reliable and valid as the original English and other language versions.

Objective: To conduct a scoping review of models of care for chronic disease management to identify potentially effective components for management of chronic traumatic brain injury (TBI)., Methods: Information sources: Systematic searches of three databases (Ovid MEDLINE, Embase, and Cochrane Database of Systematic Reviews) from January 2010 to May 2021., Eligibility Criteria: Systematic reviews and meta-analyses reporting on the effectiveness of the Chronic Care Model (CCM), collaborative/integrated care, and other chronic disease management models., Data: Target diseases, model components used (n = 11), and six outcomes (disease-specific, generic health-related quality of life and functioning, adherence, health knowledge, patient satisfaction, and cost/health care use)., Synthesis: Narrative synthesis, including proportion of reviews documenting outcome benefits., Results: More than half (55%) of the 186 eligible reviews focused on collaborative/integrated care models, with 25% focusing on CCM and 20% focusing on other chronic disease management models. The most common health conditions were diabetes (n = 22), depression (n = 16), heart disease (n = 12), aging (n = 11), and kidney disease (n = 8). Other single medical conditions were the focus of 22 reviews, multiple medical conditions of 59 reviews, and other or mixed mental health/behavioral conditions of 20 reviews. Some type of quality rating for individual studies was conducted in 126 (68%) of the reviews. Of reviews that assessed particular outcomes, 80% reported disease-specific benefits, and 57% to 72% reported benefits for the other five types of outcomes. Outcomes did not differ by the model category, number or type of components, or target disease., Conclusions: Although there is a paucity of evidence for TBI per se, care model components proven effective for other chronic diseases may be adaptable for chronic TBI care., (© 2023 The Authors. PM&R published by Wiley Periodicals LLC on behalf of American Academy of Physical Medicine and Rehabilitation.)

In this article, we discuss the taxonomy associated with the four major disorders of consciousness (DoC): coma, vegetative state or unresponsive wakefulness syndrome, minimally conscious state, and post-traumatic confusional state. We briefly review the history of each disorder and then provide operational definitions and diagnostic criteria for each one. We rely heavily on recently released practice guidelines and, where appropriate, identify knowledge gaps and discuss future directions to advance DoC research and practice., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Adult patients with mild traumatic brain injury (mTBI) exhibit distinct phenotypes of emotional and cognitive functioning identified by latent profile analysis of clinical neuropsychological assessments. When discerned early after injury, these latent clinical profiles have been found to improve prediction of long-term outcomes from mTBI. The present study hypothesized that white matter (WM) microstructure is better preserved in an emotionally resilient mTBI phenotype compared with a neuropsychiatrically distressed mTBI phenotype., Methods: The present study used diffusion magnetic resonance imaging to investigate and compare WM microstructure in major association, projection, and commissural tracts between the two phenotypes and over time. Diffusion magnetic resonance images from 172 patients with mTBI were analyzed to compute individual diffusion tensor imaging maps at 2 weeks and 6 months after injury., Results: By comparing the diffusion tensor imaging parameters between the two phenotypes at global, regional, and voxel levels, emotionally resilient patients were shown to have higher axial diffusivity compared with neuropsychiatrically distressed patients early after mTBI. Longitudinal analysis revealed greater compromise of WM microstructure in neuropsychiatrically distressed patients, with greater decrease of global axial diffusivity and more widespread decrease of regional axial diffusivity during the first 6 months after injury compared with emotionally resilient patients., Conclusions: These results provide neuroimaging evidence of WM microstructural differences underpinning mTBI phenotypes identified from neuropsychological assessments and show differing longitudinal trajectories of these biological effects. These findings suggest that diffusion magnetic resonance imaging can provide short- and long-term imaging biomarkers of resilience., (Published by Elsevier Inc.)

Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilitate a future consensus-based statement (e.g. via a modified Delphi) and series of recommendations. The panel convened weekly online meetings from October 2021 to December 2022. Research considerations addressed the nosographic status of disorders of consciousness, case ascertainment and verification, selection of dependent variables, choice of covariates and measurement and analysis of outcomes and covariates, aiming to promote more homogeneous designs and practices in future observational studies. The goal of this review is to inform a broad community of professionals with different backgrounds and clinical interests to address the methodological challenges imposed by the transition of care from acute to chronic stages and to streamline data gathering for patients with disorders of consciousness. A coordinated effort will be a key to allow reliable observational data synthesis and epidemiological estimates and ultimately inform condition-modifying clinical trials., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Early prediction of the recovery of consciousness in comatose cardiac arrest patients remains challenging. We prospectively studied task-relevant fMRI responses in 19 comatose cardiac arrest patients and five healthy controls to assess the fMRI's utility for neuroprognostication. Tasks involved instrumental music listening, forward and backward language listening, and motor imagery. Task-specific reference images were created from group-level fMRI responses from the healthy controls. Dice scores measured the overlap of individual subject-level fMRI responses with the reference images. Task-relevant responsiveness index (Rindex) was calculated as the maximum Dice score across the four tasks. Correlation analyses showed that increased Dice scores were significantly associated with arousal recovery ( P < 0.05 ) and emergence from the minimally conscious state (EMCS) by one year ( P < 0.001 ) for all tasks except motor imagery. Greater Rindex was significantly correlated with improved arousal recovery (P = 0.002) and consciousness (P = 0.001). For patients who survived to discharge ( n = 6 ), the Rindex's sensitivity was 75% for predicting EMCS (n = 4). Task-based fMRI holds promise for detecting covert consciousness in comatose cardiac arrest patients, but further studies are needed to confirm these findings. Caution is necessary when interpreting the absence of task-relevant fMRI responses as a surrogate for inevitable poor neurological prognosis., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Mild traumatic brain injury (mTBI) is a heterogenous injury which can be difficult to characterize and manage. Using cross-sectional network analysis (NA) to conceptualize mTBI symptoms offers an innovative solution to identify how mTBI symptoms relate to each other. The centrality hypothesis of network theory posits that certain symptoms in a network are more relevant (central) or have above average influence over the rest of the network. However, no studies have used NA to characterize the interrelationships between symptoms in a cohort of patients who presented with mTBI to a U.S. Level 1 trauma center emergency department and how subacute central symptoms relate to long-term outcomes., Methods: Patients with mTBI (Glasgow Coma Scale = 13-15) evaluated across 18 U.S. Level 1 trauma centers from 2013 to 2019 completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) at 2 weeks (W2) post-injury ( n  = 1,593) and at 3 months (M3), 6 months (M6), and 12 months (M12) post-injury. Network maps were developed from RPQ subscale scores at each timepoint. RPQ scores at W2 were associated with M6 and M12 functional and quality of life outcomes., Results: Network structure did not differ across timepoints, indicating no difference in symptoms/factors influence on the overall symptom network across time. The cognitive factor had the highest expected influence at W2 (1.761), M3 (1.245), and M6 (1.349). Fatigue had the highest expected influence at M12 (1.275). The emotional factor was the only other node with expected influence >1 at any timepoint, indicating disproportionate influence of emotional symptoms on overall symptom burden (M3 = 1.011; M6 = 1.076)., Discussion: Several symptom factors at 2-weeks post-injury were more strongly associated with incomplete recovery and/or poorer injury-related quality of life at 6 and 12 months post-injury than previously validated demographic and clinical covariates. The network analysis suggests that emotional, cognitive, and fatigue symptoms may be useful treatment targets in this population due to high centrality and activating potential of the overall symptom network., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Eagle, Jain, Sun, Preszler, McCrea, Giacino, Manley, Okonkwo, Nelson and The TRACK-TBI Investigators.)

Objective: It is not currently possible to predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Our objective was to fit and externally validate a prediction model for 1-year dependency in patients with DoC ≥ 2 weeks after TBI., Methods: We included adults with TBI enrolled in TBI Model Systems (TBI-MS) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) studies who were not following commands at rehabilitation admission or 2 weeks post-injury, respectively. We fit a logistic regression model in TBI-MS and validated it in TRACK-TBI. The primary outcome was death or dependency at 1 year post-injury, defined using the Disability Rating Scale., Results: In the TBI-MS Discovery Sample, 1,960 participants (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria, and 406 (27%) were dependent 1 year post-injury. In a TBI-MS held out cohort, the dependency prediction model's area under the receiver operating characteristic curve was 0.79 (95% CI 0.74-0.85), positive predictive value was 53% and negative predictive value was 86%. In the TRACK-TBI external validation (n = 124, age 40 [16] years, 77% male, 81% white), the area under the receiver operating characteristic curve was 0.66 (0.53, 0.79), equivalent to the standard IMPACT core + CT score (p = 0.8)., Interpretation: We developed a 1-year dependency prediction model using the largest existing cohort of patients with DoC after TBI. The sensitivity and negative predictive values were greater than specificity and positive predictive values. Accuracy was diminished in an external sample, but equivalent to the IMPACT model. Further research is needed to improve dependency prediction in patients with DoC after TBI. ANN NEUROL 2023;94:1008-1023., (© 2023 American Neurological Association.)

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.ClinicalTrials.gov identifier: NCT02881151 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We developed and validated an abbreviated version of the Coma Recovery Scale-Revised (CRS-R), the CRS-R For Accelerated Standardized Testing (CRSR-FAST), to detect conscious awareness in patients with severe traumatic brain injury in the intensive care unit. In 45 consecutively enrolled patients, CRSR-FAST administration time was approximately one-third of the full-length CRS-R (mean [SD] 6.5 [3.3] vs 20.1 [7.2] minutes, p < 0.0001). Concurrent validity (simple kappa 0.68), test-retest (Mak's ρ = 0.76), and interrater (Mak's ρ = 0.91) reliability were substantial. Sensitivity, specificity, and accuracy for detecting consciousness were 81%, 89%, and 84%, respectively. The CRSR-FAST facilitates serial assessment of consciousness, which is essential for diagnostic and prognostic accuracy. ANN NEUROL 2023;94:919-924., (© 2023 American Neurological Association.)

We previously described five trajectories of insomnia (each defined by a distinct pattern of insomnia severity over 12 months following traumatic brain injury [TBI]). Our objective in the present study was to estimate the association between insomnia trajectory status and trajectories of mental health and neurocognitive outcomes during the 12 months after TBI. In this study, participants included N  = 2022 adults from the Federal Inter-agency Traumatic Brain Injury Repository database and Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. The following outcome measures were assessed serially at 2 weeks, and 3, 6, and 12 months post-injury: Insomnia Severity Index, Patient Health Questionnaire, Post-Traumatic Stress Disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Patient Reported Outcomes Measurement Information System-Pain, and Quality of Life After Brain Injury-Overall Scale. Neurocognitive performance was assessed at 2 weeks, and 6 and 12 months using the Wechsler Adult Intelligence Scales Processing Speed Index and the Trails Making Test Parts A and B. Results indicated that g reater insomnia severity was associated with greater abnormality in mental health, quality of life, and neuropsychological testing outcomes. The pattern of insomnia over time tracked the temporal pattern of all these outcomes for all but a very small number of participants. Notably, severe insomnia at 3 or 6 months post-TBI was a risk factor for poor recovery at 12 months post-injury. In conclusion, in this well-characterized sample of individuals with TBI, insomnia severity generally tracked severity of depression, pain, PTSD, quality of life, and neurocognitive outcomes over 12 months post-injury. More intensive sleep assessment is needed to elucidate the nature of these relationships and to help inform best strategies for intervention.

Importance: One traumatic brain injury (TBI) increases the risk of subsequent TBIs. Research on longitudinal outcomes of civilian repetitive TBIs is limited., Objective: To investigate associations between sustaining 1 or more TBIs (ie, postindex TBIs) after study enrollment (ie, index TBIs) and multidimensional outcomes at 1 year and 3 to 7 years., Design, Setting, and Participants: This cohort study included participants presenting to emergency departments enrolled within 24 hours of TBI in the prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years, February 2014 to July 2020). Participants who completed outcome assessments at 1 year and 3 to 7 years were included. Data were analyzed from September 2022 to August 2023., Exposures: Postindex TBI(s)., Main Outcomes and Measures: Demographic and clinical factors, prior TBI (ie, preindex TBI), and functional (Glasgow Outcome Scale-Extended [GOSE]), postconcussive (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]), psychological distress (Brief Symptom Inventory-18 [BSI-18]), depressive (Patient Health Questionnaire-9 [PHQ-9]), posttraumatic stress disorder (PTSD; PTSD Checklist for DSM-5 [PCL-5]), and health-related quality-of-life (Quality of Life After Brain Injury-Overall Scale [QOLIBRI-OS]) outcomes were assessed. Adjusted mean differences (aMDs) and adjusted relative risks are reported with 95% CIs., Results: Of 2417 TRACK-TBI participants, 1572 completed the outcomes assessment at 1 year (1049 [66.7%] male; mean [SD] age, 41.6 [17.5] years) and 1084 completed the outcomes assessment at 3 to 7 years (714 [65.9%] male; mean [SD] age, 40.6 [17.0] years). At 1 year, a total of 60 participants (4%) were Asian, 255 (16%) were Black, 1213 (77%) were White, 39 (2%) were another race, and 5 (0.3%) had unknown race. At 3 to 7 years, 39 (4%) were Asian, 149 (14%) were Black, 868 (80%) were White, 26 (2%) had another race, and 2 (0.2%) had unknown race. A total of 50 (3.2%) and 132 (12.2%) reported 1 or more postindex TBIs at 1 year and 3 to 7 years, respectively. Risk factors for postindex TBI were psychiatric history, preindex TBI, and extracranial injury severity. At 1 year, compared with those without postindex TBI, participants with postindex TBI had worse functional recovery (GOSE score of 8: adjusted relative risk, 0.57; 95% CI, 0.34-0.96) and health-related quality of life (QOLIBRI-OS: aMD, -15.9; 95% CI, -22.6 to -9.1), and greater postconcussive symptoms (RPQ: aMD, 8.1; 95% CI, 4.2-11.9), psychological distress symptoms (BSI-18: aMD, 5.3; 95% CI, 2.1-8.6), depression symptoms (PHQ-9: aMD, 3.0; 95% CI, 1.5-4.4), and PTSD symptoms (PCL-5: aMD, 7.8; 95% CI, 3.2-12.4). At 3 to 7 years, these associations remained statistically significant. Multiple (2 or more) postindex TBIs were associated with poorer outcomes across all domains., Conclusions and Relevance: In this cohort study of patients with acute TBI, postindex TBI was associated with worse symptomatology across outcome domains at 1 year and 3 to 7 years postinjury, and there was a dose-dependent response with multiple postindex TBIs. These results underscore the critical need to provide TBI prevention, education, counseling, and follow-up care to at-risk patients.

Background and Objectives: Traumatic brain injury (TBI) may be a chronic condition carrying risk of future sequelae; few prospective studies examine long-term postinjury outcomes. We examined the prevalence of functional, cognitive, and psychiatric change outcomes from 1 to 7 years postinjury., Methods: Transforming Research and Clinical Knowledge in TBI LONG (TRACK-TBI LONG) participants were prospectively enrolled within 24 hours of injury and followed up to 1 year postinjury; a subset participated in long-term follow-up from 2 to 7 years postinjury. Reliable change thresholds for the Brief Test of Adult Cognition by Telephone General Composite (cognition) and Brief Symptom Inventory (BSI)-18 (psychiatric) were derived from orthopedic trauma controls (OTCs). Multiple assessments were completed (postinjury baseline assessment and 2 or 3 visits 2-7 years postinjury) within a sample subset. Change was assessed for functional outcome (Glasgow Outcome Scale-Extended [GOSE]) and self-report/informant report of decline. Prevalence ratios for outcomes classified as stable, improved, and declined were reported individually and collectively. The Fisher exact test and log-binomial regression models examined factors associated with decline and improvement., Results: Of the sample (N = 1,264; mild TBI [mTBI], Glasgow Coma Scale [GCS] 13-15, n = 917; moderate-to-severe TBI [msTBI], GCS 3-12, n = 193; or OTC n = 154), "stable" was the most prevalent outcome. Functional outcome showed the highest rates of decline, regardless of TBI severity (mild = 29%; moderate/severe = 23%). When measures were collectively considered, rates of decline included mTBI (21%), msTBI (26%), and OTC (15%). Age and preinjury employment status were associated with functional decline (per 10 years; relative risk [RR] 1.16, 95% CI 1.07-1.25, p < 0.001; higher in retired/disabled/not working vs full-time/part-time; RR 1.81, 95% CI 1.33-2.45, respectively) in the mTBI group. Improvement in functional recovery 2-7 years postinjury was associated with higher BSI scores (per 5 points; RR 1.11, 95% CI 1.04-1.18, p = 0.002) and GOSE score of 5-7 (GOSE = 8 as reference; RR 2.64, 95% CI 1.75-3.97, p < 0.001). Higher BSI scores and identifying as Black (RR 2.28, 95% CI 1.59-3.25, p < 0.001) were associated with a greater likelihood of improved psychiatric symptoms in mTBI (RR 1.21, 95% CI 1.14-1.29, p < 0.001). A greater likelihood of cognitive improvement was observed among those with higher educational attainment in msTBI (per 4 years; RR 2.61, 95% CI 1.43-4.79, p = 0.002)., Discussion: Function across domains at 1-year postinjury, a common recovery benchmark, undergoes change across the subsequent 6 years. Results support consideration of TBI as a chronic evolving condition and suggest continued monitoring, rehabilitation, and support is required to optimize long-term independence and quality of life., (© 2023 American Academy of Neurology.)

Traumatic brain injury (TBI) is a global health priority, associated with substantial burden. Historically conceptualised as an injury event with finite recovery, TBI is now recognised as a chronic condition that can affect multiple domains of health and function, some of which might deteriorate over time. Many people who have had a TBI remain moderately to severely disabled at 5 years, are rehospitalised up to 10 years post-injury, and have a reduced lifespan relative to the general population. Understanding TBI as a chronic disease process can be highly informative for optimising care, which has traditionally focused on acute care. Chronic brain injury care models must be informed by a holistic understanding of long-term outcomes and the factors that can affect how care needs evolve over time. The United States Traumatic Brain Injury Model Systems of Care follows up individuals with moderate-to-severe TBI for over 30 years, allowing characterisation of the chronic (2-30 years or more post injury) functional, cognitive, behavioural, and social sequelae experienced by individuals who have had a moderate-to-severe TBI and the implications for their health and quality of life. Older age, social determinants of health, and lower acute functional status are associated with post-recovery deterioration, while younger age and greater functional independence are associated with risky health behaviours, including substance misuse and re-injury. Systematically collected data on long-term outcomes across multiple domains of health and function are needed worldwide to inform the development of models for chronic disease management, including the proactive surveillance of commonly experienced health and functional challenges., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: The goal of this study is to describe national trends in inpatient rehabilitation facility (IRF) discharges for the most severely disabled cohort of patients with traumatic brain injury (TBI)., Methods: Data from the Uniform Data System for Medical Rehabilitation for patients discharged from an IRF between January 1, 2002, and December 31, 2017, with a diagnosis of TBI and an admission Functional Independence Measure of 18, the lowest possible score, were obtained and analyzed., Results: Of the 252 112 patients with TBI discharged during the study period, 10 098 met the study criteria. From 2002 to 2017, the number of patients with an IRF admission Functional Independence Measure of 18 following TBI discharged from IRFs annually decreased from 649 to 488, modeled by a negative regression (coefficient = -2.97; P = .001), and the mean age (SD) increased from 43.0 (21.0) to 53.7 (21.3) years (coefficient = 0.70; P < .001). During the study period, the number of patients with the most severe disability on admission to IRF who were discharged annually as a proportion of total patients with TBI decreased from 5.5% to 2.5% (odds ratio = 0.95; P < .001) and their mean length of stay decreased from 41.5 (36.2) to 29.3 (24.9) days (coefficient = -0.83; P < .001]., Conclusion: The number and proportion of patients with the most severe disability on IRF admission following TBI who are discharged from IRFs is decreasing over time. This may represent a combination of primary prevention, early mortality due to withdrawal of life-sustaining treatment, alternative discharge dispositions, or changes in admitting and reimbursement practices. Furthermore, there has been a decrease in the duration of IRF level care for these individuals, which could ultimately lead to poorer functional outcomes, particularly given the importance of specialized rehabilitative care in this population., Competing Interests: The authors declare no conflicts of interest, (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Many level I trauma center patients experience clinical sequelae at 1 year following traumatic brain injury (TBI). Longer-term outcome data are needed to develop better monitoring and rehabilitation services., Objective: To examine functional recovery, TBI-related symptoms, and quality of life from 1 to 5 years postinjury., Design, Setting, and Participants: This cohort study enrolled trauma patients across 18 US level I trauma centers between 2014 and 2018. Eligible participants were enrolled within 24 hours of injury and followed up to 5 years postinjury. Data were analyzed January 2023., Exposures: Mild TBI (mTBI), moderate-severe TBI (msTBI), or orthopedic traumatic controls (OTC)., Main Outcomes and Measures: Functional independence (Glasgow Outcome Scale-Extended [GOSE] score 5 or higher), complete functional recovery (GOSE score, 8), better (ie, lower) TBI-related symptom burden (Rivermead Post Concussion Symptoms Questionnaire score of 15 or lower), and better (ie, higher) health-related quality of life (Quality of Life After Brain Injury Scale-Overall Scale score 52 or higher); mortality was analyzed as a secondary outcome., Results: A total 1196 patients were included in analysis (mean [SD] age, 40.8 [16.9] years; 781 [65%] male; 158 [13%] Black, 965 [81%] White). mTBI and OTC groups demonstrated stable, high rates of functional independence (98% to 100% across time). While odds of independence were lower among msTBI survivors, the majority were independent at 1 year (72%), and this proportion increased over time (80% at 5 years; group × year, P = .005; independence per year: odds ratio [OR] for msTBI, 1.28; 95% CI, 1.03-1.58; OR for mTBI, 0.81; 95% CI, 0.64-1.03). For other outcomes, group differences at 1 year remained stable over time (group × year, P ≥ .44). Odds of complete functional recovery remained lower for persons with mTBI vs OTC (OR, 0.39; 95% CI, 0.28-0.56) and lower for msTBI vs mTBI (OR, 0.34; 95% CI, 0.24-0.48). Odds of better TBI-related symptom burden and quality of life were similar for both TBI subgroups and lower than OTCs. Mortality between 1 and 5 years was higher for msTBI (5.5%) than mTBI (1.5%) and OTC (0.7%; P = .02)., Conclusions and Relevance: In this cohort study, patients with previous msTBI displayed increased independence over 5 years; msTBI was also associated with increased mortality. These findings, in combination with the persistently elevated rates of unfavorable outcomes in mTBI vs controls imply that more monitoring and rehabilitation are needed for TBI.

The effects of traumatic brain injury (TBI) are difficult to measure in longitudinal cohort studies, because disparate pre-injury characteristics and injury mechanisms produce variable impairment profiles and recovery trajectories. In preparation for the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, which followed patients with injuries ranging from uncomplicated mild TBI to coma, we designed a multi-dimensional Flexible outcome Assessment Battery (FAB). The FAB relies on a decision-making algorithm that assigns participants to a Comprehensive (CAB) or Abbreviated Assessment Battery (AAB) and guides test selection across all phases of recovery. To assess feasibility of the FAB, we calculated the proportion of participants followed at 2 weeks (2w) and at 3, 6, and 12 months (3m, 6m, 12m) post-injury who completed the FAB and received valid scores. We evaluated utility of the FAB by examining differences in 6m and 12m Glasgow Outcome Scale-Extended (GOSE) scores between participant subgroups derived from the FAB-enabled versus traditional approach to outcome assessment applied at 2w. Among participants followed at 2w ( n  = 2094), 3m ( n  = 1871), 6m ( n  = 1736), and 12m ( n  = 1607) post-injury, 95-99% received valid completion scores on the FAB, in full or in part, either in person or by telephone. Level of function assessed by the FAB-enabled approach at 2w was associated with 6m and 12m GOSE scores (proportional odds p  < 0.001). These findings suggest that the participant classification methodology afforded by the FAB may enable more effective data collection to improve detection of natural history changes and TBI treatment effects.

Objective: The aim of the study was to predict suicidal ideation 1 yr after moderate to severe traumatic brain injury., Design: This study used a cross-sectional design with data collected through the prospective, longitudinal Traumatic Brain Injury Model Systems network at hospitalization and 1 yr after injury. Participants who completed the Patient Health Questionnaire-9 suicide item at year 1 follow-up ( N = 4328) were included., Results: A gradient boosting machine algorithm demonstrated the best performance in predicting suicidal ideation 1 yr after traumatic brain injury. Predictors were Patient Health Questionnaire-9 items (except suicidality), Generalized Anxiety Disorder-7 items, and a measure of heavy drinking. Results of the 10-fold cross-validation gradient boosting machine analysis indicated excellent classification performance with an area under the curve of 0.882. Sensitivity was 0.85 and specificity was 0.77. Accuracy was 0.78 (95% confidence interval, 0.77-0.79). Feature importance analyses revealed that depressed mood and guilt were the most important predictors of suicidal ideation, followed by anhedonia, concentration difficulties, and psychomotor disturbance., Conclusions: Overall, depression symptoms were most predictive of suicidal ideation. Despite the limited clinical impact of the present findings, machine learning has potential to improve prediction of suicidal behavior, leveraging electronic health record data, to identify individuals at greatest risk, thereby facilitating intervention and optimization of long-term outcomes after traumatic brain injury., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2022 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Many patients with mild traumatic brain injury (mTBI) are at risk for mental health problems such as posttraumatic stress disorder (PTSD). The objective of this study was to determine whether the polygenic risk for PTSD (or for related mental health disorders or traits including major depressive disorder [MDD] and neuroticism [NEU]) was associated with an increased likelihood of PTSD in the aftermath of mTBI. We used data from individuals of European ancestry with mTBI enrolled in TRACK-TBI (n = 714), a prospective longitudinal study of level 1 trauma center patients. One hundred and sixteen mTBI patients (16.3%) had probable PTSD (PCL-5 score ≥33) at 6 months post-injury. We used summary statistics from recent GWAS studies of PTSD, MDD, and NEU to generate polygenic risk scores (PRS) for individuals in our sample. A multivariable model that included age, sex, pre-injury history of mental disorder, and cause of injury explained 7% of the variance in the PTSD outcome; the addition of the PTSD-PRS (and five ancestral principal components) significantly increased the variance explained to 11%. The adjusted odds of PTSD in the uppermost PTSD-PRS quintile was nearly four times higher (aOR = 3.71, 95% CI 1.80-7.65) than in the lowest PTSD-PRS quintile. There was no evidence of a statistically significant interaction between PTSD-PRS and prior history of mental disorder, indicating that PTSD-PRS had similar predictive utility among those with and without pre-injury psychiatric illness. When added to the model, neither MDD-PRS nor NEU-PRS were significantly associated with the PTSD outcome. These findings show that the risk for PTSD in the context of mTBI is, in part, genetically influenced. They also raise the possibility that an individual's PRS could be clinically actionable if used-possibly with other non-genetic predictors-to signal the need for enhanced follow-up and early intervention; this precision medicine approach needs to be prospectively studied., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

College-aged individuals with anxiety are vulnerable to developing persistent concussion symptoms, yet evidence-based treatments for this population are limited. Understanding these individuals' perspectives is critical for developing effective interventions. We conducted qualitative interviews with 17 college-aged individuals (18-24 years old) with a recent (≤10 weeks) concussion and at least mild anxiety (≥5 on the GAD-7 questionnaire) to understand the life impact of their concussion. We identified 5 themes: (1) disruption to daily activities (e.g., reduced participation in hobbies and physical activity); (2) disruption to relationships (e.g., reduced social engagement, feeling dismissed by others, stigma, and interpersonal friction); (3) disruptions in school/work (e.g., challenges participating due to light sensitivity, cognitive or sleep disturbance, and related emotional distress); (4) changes in view of the self (e.g., feeling "unlike oneself", duller, or more irritable), and (5) finding "silver linings" after the injury (e.g., increased motivation). Concussions impact the lives of college-aged individuals with co-occurring anxiety in a broad range of domains, many of which remain largely neglected in standard concussion clinical assessment and treatment. Assessing and addressing these issues has the potential to limit the negative impact of concussion, promote recovery, and potentially help prevent persistent concussion symptoms in this at-risk population.

Several proteins have proven useful as blood-based biomarkers to assist in evaluation and management of traumatic brain injury (TBI). The objective of this study was to determine whether two day-of-injury blood-based biomarkers are predictive of posttraumatic stress disorder (PTSD). We used data from 1143 individuals with mild TBI (mTBI; defined as admission Glasgow Coma Scale [GCS] score 13-15) enrolled in TRACK-TBI, a prospective longitudinal study of level 1 trauma center patients. Plasma glial fibrillary acidic protein (GFAP) and serum high sensitivity C-reactive protein (hsCRP) were measured from blood collected within 24 h of injury. Two hundred and twenty-seven (19.9% of) patients had probable PTSD (PCL-5 score ≥ 33) at 6 months post-injury. GFAP levels were positively associated (Spearman's rho = 0.35, p < 0.001) with duration of posttraumatic amnesia (PTA). There was an inverse association between PTSD and (log)GFAP (adjusted OR = 0.85, 95% CI 0.77-0.95 per log unit increase) levels, but no significant association with (log)hsCRP (adjusted OR = 1.11, 95% CI 0.98-1.25 per log unit increase) levels. Elevated day-of-injury plasma GFAP, a biomarker of glial reactivity, is associated with reduced risk of PTSD after mTBI. This finding merits replication and additional studies to determine a possible neurocognitive basis for this relationship., (© 2022. The Author(s).)

Purpose/objective: Traumatic brain injuries (TBIs) are increasingly common and a major cause of death and long-term disability. Many individuals experience chronic stressors and adverse health outcomes, emphasizing the importance of cultivating resilience , (defined herein as individual, social, and systemic components engaged in response to the stressors that allow individuals to "bounce back," or move forward adaptively after TBI). Patients' perceptions of factors influencing resilience are critical to guide interventions that meet their needs. Here we offer the first metasynthesis of factors influencing resilience after TBI using a Social Ecological model framework. Research Methods/Design: We preregistered our metasynthesis on PROSPERO (CRD42021233975) and followed PRISMA guidelines. We searched 4 electronic databases for qualitative studies from inception up until June 2021. We included qualitative studies detailing perspectives of individuals with a history of moderate-severe TBI. We excluded case studies and systematic reviews. After removal of duplicates, we identified 124 articles for screening. We reviewed 49 articles for full text eligibility and included 38 studies. We extracted study characteristics and data (e.g., author interpretations and relevant quotes) relating to factors influencing resilience., Results: We synthesized findings using a Social Ecological model framework to guide thematic analysis. Persons with TBI identified barriers and facilitators to resilience at individual (e.g., physical and cognitive challenges, coping behaviors), interpersonal, (e.g., stigma and isolation) and systemic (e.g., access to resources, rehabilitation support) levels., Conclusions/implications: Considering multifaceted factors at individual, interpersonal and systemic levels in clinical, research, and policy-setting contexts is important for cultivating resilience and optimizing recovery after TBI. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Diffusion tensor imaging (DTI) literature on single-center studies contains conflicting results regarding acute effects of mild traumatic brain injury (mTBI) on white matter (WM) microstructure and the prognostic significance. This larger-scale multi-center DTI study aimed to determine how acute mTBI affects WM microstructure over time and how early WM changes affect long-term outcome. From Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI), a cohort study at 11 United States level 1 trauma centers, a total of 391 patients with acute mTBI ages 17 to 60 years were included and studied at two weeks and six months post-injury. Demographically matched friends or family of the participants were the control group ( n  = 148). Axial diffusivity (AD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were the measures of WM microstructure. The primary outcome was the Glasgow Outcome Scale Extended (GOSE) score of injury-related functional limitations across broad life domains at six months post-injury. The AD, MD, and RD were higher and FA was lower in mTBI versus friend control (FC) at both two weeks and six months post-injury throughout most major WM tracts of the cerebral hemispheres. In the mTBI group, AD and, to a lesser extent, MD decreased in WM from two weeks to six months post-injury. At two weeks post-injury, global WM AD and MD were both independently associated with six-month incomplete recovery (GOSE <8 vs = 8) even after accounting for demographic, clinical, and other imaging factors. DTI provides reliable imaging biomarkers of dynamic WM microstructural changes after mTBI that have utility for patient selection and treatment response in clinical trials. Continued technological advances in the sensitivity, specificity, and precision of diffusion magnetic resonance imaging hold promise for routine clinical application in mTBI.

This study aimed to empirically evaluate the hierarchical structure of the Coma Recovery Scale-Revised (CRS-R) rating scale categories and their alignment with the Aspen consensus criteria for determining disorders of consciousness (DoC) following a severe brain injury. CRS-R data from 262 patients with DoC following a severe brain injury were analyzed applying the partial credit Rasch Measurement Model. Rasch Analysis produced logit calibrations for each rating scale category. Twenty-eight of the 29 CRS-R rating scale categories were operationalized to the Aspen consensus criteria. We expected the hierarchical order of the calibrations to reflect Aspen consensus criteria. We also examined the association between the CRS-R Rasch person measures (indicative of performance ability) and states of consciousness as determined by the Aspen consensus criteria. Overall, the order of the 29 rating scale category calibrations reflected current literature regarding the continuum of neurobehavioral function: category 6 "Functional Object Use" of the Motor item was hardest for patients to achieve; category 0 "None" of the Oromotor/Verbal item was easiest to achieve. Of the 29 rating scale categories, six were not ordered as expected. Four rating scale categories reflecting the Vegetative State (VS)/Unresponsive Wakefulness Syndrome (UWS) had higher calibrations (reflecting greater neurobehavioral function) than the easiest Minimally Conscious State (MCS) item (category 2 "Fixation" of the Visual item). Two rating scale categories, one reflecting MCS and one not operationalized to the Aspen consensus criteria, had higher calibrations than the easiest eMCS item (category 2 "Functional: Accurate" of the Communication item). CRS-R person measures (indicating amount of neurobehavioral function) and states of consciousness, based on Aspen consensus criteria, showed a strong correlation (r s  = 0.86; p  < 0.01). Our study provides empirical evidence for revising the diagnostic criteria for MCS to also include category 2 "Localization to Sound" of the Auditory item and for Emerged from Minimally Conscious State (eMCS) to include category 4 "Consistent Movement to Command" of the Auditory item.

The epidemiology of coma is unknown because case ascertainment with traditional methods is difficult. Here, we used crowdsourcing methodology to estimate the incidence and prevalence of coma in the UK and the USA. We recruited UK and US laypeople (aged ≥18 years) who were nationally representative (i.e. matched for age, gender and ethnicity according to census data) of the UK and the USA, respectively, utilizing a crowdsourcing platform. We provided a description of coma and asked survey participants if they-'right now' or 'within the last year'-had a family member in coma. These participants (UK n  = 994, USA n  = 977) provided data on 30 387 family members (UK n  = 14 124, USA n  = 16 263). We found more coma cases in the USA ( n  = 47) than in the UK ( n  = 20; P  = 0.009). We identified one coma case in the UK (0.007%, 95% confidence interval 0.00-0.04%) on the day of the survey and 19 new coma cases (0.13%, 95% confidence interval 0.08-0.21%) within the preceding year, resulting in an annual incidence of 135/100 000 (95% confidence interval 81-210) and a point prevalence of 7 cases per 100 000 population (95% confidence interval 0.18-39.44) in the UK. We identified five cases in the USA (0.031%, 95% confidence interval 0.01-0.07%) on the day of the survey and 42 new cases (0.26%, 95% confidence interval 0.19-0.35%) within the preceding year, resulting in an annual incidence of 258/100 000 (95% confidence interval 186-349) and a point prevalence of 31 cases per 100 000 population (95% confidence interval 9.98-71.73) in the USA. The five most common causes were stroke, medically induced coma, COVID-19, traumatic brain injury and cardiac arrest. To summarize, for the first time, we report incidence and prevalence estimates for coma across diagnosis types and settings in the UK and the USA using crowdsourcing methods. Coma may be more prevalent in the USA than in the UK, which requires further investigation. These data are urgently needed to expand the public health perspective on coma and disorders of consciousness., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To determine whether consistent command-following (CCF) should be added to the diagnostic criteria for emergence from the minimally conscious state (eMCS)., Design: Retrospective cohort study., Setting: Inpatient rehabilitation hospital., Participants: Patients (N=214) with acquired brain injury resulting in disorders of consciousness (DoC) admitted to a specialized rehabilitation program., Main Outcome Measures: Difference between time to recovery of CCF and time to recovery of functional object use (FOU) or functional communication (FC), the 2 existing criteria for eMCS as measured by the Coma Recovery Scale-Revised (CRS-R)., Results: Of 214 patients (median age, 53 years [interquartile range {IQR}, 34-66 years], male: 134 [62.6%], traumatic etiology: 115 [53.7%], admission CRS-R total score: 10 [IQR, 7-13]) admitted to rehabilitation without CCF, FOU, or FC, 162 (75.7%) recovered CCF and FOU or FC during the 8-week observation period. On average, recovery of CCF, FOU, and FC was observed within 1 day of one another, approximately 46 days (IQR, 38.25-58 days) post injury. One hundred and sixteen patients (71.6%) recovered FOU or FC prior to or at the same time as CCF., Conclusions: In patients recovering from DoC, CCF reemerges around the same time as FOU and FC. This finding may reflect the shared dependency of these behaviors on cognitive processes (eg, language comprehension, attention, motor control) that are essential for effective interpersonal interaction and social participation. Our results support the addition of CCF to the existing diagnostic criteria for eMCS, but further validation in an independent sample should be conducted., (Copyright © 2022 American Congress of Rehabilitation Medicine. All rights reserved.)

Patients with disorders of consciousness (DoC) after traumatic brain injury (TBI) recover to varying degrees of functional dependency. Dependency is difficult to measure but critical for interpreting clinical trial outcomes and prognostic counseling. In participants with DoC (i.e., not following commands) enrolled in the TBI Model Systems National Database (TBIMS NDB), we used the Functional Independence Measure (FIM ® ) as the reference to evaluate how accurately the Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS) assess dependency. Using the established FIM-dependency cut-point of <80, we measured the classification performance of literature-derived GOSE and DRS cut-points at 1-year post-injury. We compared the area under the receiver operating characteristic curve (AUROC) between the DRS Depend , a DRS-derived marker of dependency, and the data-derived optimal GOSE and DRS cut-points. Of 18,486 TBIMS participants, 1483 met inclusion criteria (mean [standard deviation (SD)] age = 38 [18] years; 76% male). The sensitivity of GOSE cut-points of ≤3 and ≤4 (Lower Severe and Upper Severe Disability, respectively) for identifying FIM-dependency were 97% and 98%, but specificities were 73% and 51%, respectively. The sensitivity of the DRS cut-point of ≥12 (Severe Disability) for identifying FIM-dependency was 60%, but specificity was 100%. The DRS Depend had a sensitivity of 83% and a specificity of 94% for classifying FIM-dependency, with a greater AUROC than the data-derived optimal GOSE (≤3, p  = 0.01) and DRS (≥10, p  = 0.008) cut-points. Commonly used GOSE and DRS cut-points have limited specificity or sensitivity for identifying functional dependency. The DRS Depend identifies FIM-dependency more accurately than the GOSE and DRS cut-points, but requires further validation.

Neuropsychiatric symptoms may persist following acute COVID-19 illness, but the extent to which these symptoms are specific to COVID-19 has not been established. We utilized electronic health records across 6 hospitals in Massachusetts to characterize cohorts of individuals discharged following admission for COVID-19 between March 2020 and May 2021, and compared them to individuals hospitalized for other indications during this period. Natural language processing was applied to narrative clinical notes to identify neuropsychiatric symptom domains up to 150 days following hospitalization, in addition to those reflected in diagnostic codes as measured in prior studies. Among 6619 individuals hospitalized for COVID-19 drawn from a total of 42,961 hospital discharges, the most commonly-documented symptom domains between 31 and 90 days after initial positive test were fatigue (13.4%), mood and anxiety symptoms (11.2%), and impaired cognition (8.0%). In regression models adjusted for sociodemographic features and hospital course, none of these were significantly more common among COVID-19 patients; indeed, mood and anxiety symptoms were less frequent (adjusted OR 0.72 95% CI 0.64-0.92). Between 91 and 150 days after positivity, most commonly-detected symptoms were fatigue (10.9%), mood and anxiety symptoms (8.2%), and sleep disruption (6.8%), with impaired cognition in 5.8%. Frequency was again similar among non-COVID-19 post-hospital patients, with mood and anxiety symptoms less common (aOR 0.63, 95% CI 0.52-0.75). Propensity-score matched analyses yielded similar results. Overall, neuropsychiatric symptoms were common up to 150 days after initial hospitalization, but occurred at generally similar rates among individuals hospitalized for other indications during the same period. Post-acute sequelae of COVID-19 may benefit from standard if less-specific treatments developed for rehabilitation after hospitalization., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)