Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study.

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 Five participants completed the study and one was withdrawn for protocol non-compliance.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 .

The Roles of Protocols and Protocolization in Improving Outcome From Severe Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Our Phase-I parallel-cohort study suggested that managing severe traumatic brain injury (sTBI) in the absence of intracranial pressure (ICP) monitoring using an ad hoc Imaging and Clinical Examination (ICE) treatment protocol was associated with superior outcome vs nonprotocolized management but could not differentiate the influence of protocolization from that of the specific protocol. Phase II investigates whether adopting the Consensus REVised Imaging and Clinical Examination (CREVICE) protocol improved outcome directly or indirectly via protocolization. METHODS: We performed a Phase-II sequential parallel-cohort study examining adoption of the CREVICE protocol from no protocol vs a previous protocol in patients with sTBI older than 13 years presenting ≤24 hours after injury. Primary outcome was prespecified 6-month recovery. The study was done mostly at public South American centers managing sTBI without ICP monitoring. Fourteen Phase-I nonprotocol centers and 5 Phase-I protocol centers adopted CREVICE. Data were analyzed using generalized estimating equation regression adjusting for demographic imbalances. RESULTS: A total of 501 patients (86% male, mean age 35.4 years) enrolled; 81% had 6 months of follow-up. Adopting CREVICE from no protocol was associated with significantly superior results for overall 6-month extended Glasgow Outcome Score (GOSE) (protocol effect = 0.53 [0.11, 0.95], P = .013), mortality (36% vs 21%, HR = 0.59 [0.46, 0.76], P < .001), and orientation (Galveston Orientation and Amnesia Test discharge protocol effect = 10.9 [6.0, 15.8], P < .001, 6-month protocol effect = 11.4 [4.1, 18.6], P < .005). Adopting CREVICE from ICE was associated with significant benefits to GOSE (protocol effect = 0.51 [0.04, 0.98], P = .033), 6-month mortality (25% vs 18%, HR = 0.55 [0.39, 0.77], P < .001), and orientation (Galveston Orientation and Amnesia Test 6-month protocol effect = 9.2 [3.6, 14.7], P = .004). Comparing both groups using CREVICE, those who had used ICE previously had significantly better GOSE (protocol effect = 1.15 [0.09, 2.20], P = .033). CONCLUSION: Centers managing adult sTBI without ICP monitoring should strongly consider protocolization through adopting/adapting the CREVICE protocol. Protocolization is indirectly supported at sTBI centers regardless of resource availability.

Traumatic Brain Injuries Impact on School One Month and One Year After Injury.

Traumatic brain injury (TBI) is a major cause of death and disability among the American population, but the impact TBIs have on the school experience of high school, and post-secondary students, is poorly understood. In this study, a cohort of 79 students, ages 15-22, with mild-to-severe TBIs, were retrospectively identified from the University of Washington Traumatic Brain Injury Database and Sample Repository. The Sickness Impact Profile (SIP) was used to determine the frequency at which schooling was impacted by a TBI and identify the most common self-reported issues students faced in their return to school. At 1 month post-injury, 70% of students either had not returned to school as a result of their TBI or had returned to school but experienced issues related to their TBI. The most-reported issues at 1 month were a difficulty keeping up with school work as a result of it taking longer to complete assignments, tiring easily, having to take frequent rests, and grades that were not as good as they used to be. At 1 year post-injury, the number of students whose TBIs were affecting their school situation dropped 20 percentage points to 49%. The most reported issues at 1 year were forgetting more quickly what was learned in class and having more difficulty understanding new concepts and material. These findings indicate that TBIs have a profound effect on a student's school experiences up to at least 1 year post-injury.

Testing the Impact of Protocolized Care of Patients With Severe Traumatic Brain Injury Without Intracranial Pressure Monitoring: The Imaging and Clinical Examination Protocol.

BACKGROUND: Most patients with severe traumatic brain injury (sTBI) in low- or-middle-income countries and surprisingly many in high-income countries are managed without intracranial pressure (ICP) monitoring. The impact of the first published protocol (Imaging and Clinical Examination [ICE] protocol) is untested against nonprotocol management. OBJECTIVE: To determine whether patients treated in intensive care units (ICUs) using the ICE protocol have lower mortality and better neurobehavioral functioning than those treated in ICUs using no protocol. METHODS: This study involved nineteen mostly public South American hospitals. This is a prospective cohort study, enrolling patients older than 13 years with sTBI presenting within 24 h of injury (January 2014-July 2015) with 6-mo postinjury follow-up. Five hospitals treated all sTBI cases using the ICE protocol; 14 used no protocol. Primary outcome was prespecified composite of mortality, orientation, functional outcome, and neuropsychological measures. RESULTS: A total of 414 patients (89% male, mean age 34.8 years) enrolled; 81% had 6 months of follow-up. All participants included in composite outcome analysis: average percentile (SD) = 46.8 (24.0) nonprotocol, 56.9 (24.5) protocol. Generalized estimating equation (GEE) used to account for center effects (confounder-adjusted difference [95% CI] = 12.2 [4.6, 19.8], P = .002). Kaplan-Meier 6-month mortality (95% CI) = 36% (30%, 43%) nonprotocol, 25% (19%, 31%) protocol (GEE and confounder-adjusted hazard ratio [95% CI] = .69 [.43, 1.10], P = .118). Six-month Extended Glasgow Outcome Scale for 332 participants: average Extended Glasgow Outcome Scale score (SD) = 3.6 (2.6) nonprotocol, 4.7 (2.8) protocol (GEE and confounder-adjusted and lost to follow-up-adjusted difference [95% CI] = 1.36 [.55, 2.17], P = .001). CONCLUSION: ICUs managing patients with sTBI using the ICE protocol had better functional outcome than those not using a protocol. ICUs treating patients with sTBI without ICP monitoring should consider protocolization. The ICE protocol, tested here and previously, is 1 option.

Feasibility and Utility of a Flexible Outcome Assessment Battery for Longitudinal Traumatic Brain Injury Research: A TRACK-TBI Study.

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.

Risk Factors for High Symptom Burden Three Months after Traumatic Brain Injury and Implications for Clinical Trial Design: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study.

More than 75% of patients presenting to level I trauma centers in the United States with suspicion of TBI sufficient to require a clinical computed tomography scan report injury-related symptoms 3 months later. There are currently no approved treatments, and few clinical trials have evaluated possible treatments. Efficient trials will require subject inclusion and exclusion criteria that balance cost-effective recruitment with enrolling individuals with a higher chance of benefiting from the interventions. Using data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, we examined the relationship of 3-month symptoms to pre-injury, demographic, and acute characteristics as well as 2-week symptoms and blood-based biomarkers to identify and evaluate factors that may be used for sample enrichment for clinical trials. Many of the risk factors for TBI symptoms reported in the literature were supported, but the effect sizes of each were small or moderate (< 0.5). The only factors with large effect sizes when predicting 3-month symptom burden were TBI-related (i.e., post-concussive) and post-traumatic stress symptom levels at 2 weeks (respective effect sizes 1.13 and 1.34). TBI severity was not significantly associated with 3-month symptom burden (p = 0.37). Using simulated data to evaluate the effect of enrichment, we showed that including only people with high symptom burden at 2 weeks would permit trials to reduce the sample size by half, with minimal increase in screening, as compared with enrolling an unenriched sample. Clinical trials aimed at reducing symptoms after TBI can be efficiently conducted by enriching the included sample with people reporting a high early symptom burden.

How Do Scores on the Functional Status Examination (FSE) Correspond to Scores on the Glasgow Outcome Scale-Extended (GOSE)?

This study was designed to determine how raw scores correspond between two alternative measures of functional recovery from traumatic brain injury (TBI), the Functional Status Examination (FSE) and the Glasgow Outcome Scale-Extended (GOSE). Using data from 357 persons with moderate-severe TBI who participated in a large clinical trial, we performed item response theory analysis to characterize the relationship between functional ability measured by the FSE and GOSE at 6 months post-injury. Results revealed that raw scores for the FSE and GOSE can be linked, and a table is provided to translate scores from one instrument to the other. For example, a FSE score of 7 (on its 0-21 scale, where higher scores reflect more impairment) is equivalent to a GOSE score of 6 (where GOSE is scaled on an 8-point scale, with higher scores reflecting less impairment). These results allow clinicians or researchers who have a score for a person on one instrument to cross-reference it to a score on the other instrument. Importantly, this enables researchers to combine data sets where some persons only completed the GOSE and some only the FSE. In addition, an investigator could save participant time by eliminating one instrument from a battery of tests, yet still retain a score on that instrument for each participant. More broadly, the findings help anchor scores from these two instruments to the broader continuum of injury-related functional limitations.

Symptom Frequency and Persistence in the First Year after Traumatic Brain Injury: A TRACK-TBI Study.

Symptom endorsement after traumatic brain injury (TBI) is common acutely post-injury and is associated with other adverse outcomes. Prevalence of persistent symptoms has been debated, especially in mild TBI (mTBI). A cohort of participants ≥17 years with TBI (n = 2039), 257 orthopedic trauma controls (OTCs), and 300 friend controls (FCs) were enrolled in the TRACK-TBI study and evaluated at 2 weeks and 3, 6, and 12 months post-injury using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). TBI participants had significantly higher symptom burden than OTCs or FCs at all times, with average scores more than double. TBI cases showed significant decreases in RPQ score between each evaluation (p < 0.001), decreasing ∼1.7 points per month between 2 weeks and 3 months and 0.2 points per month after that. More than 50% of the TBI sample, including >50% of each of the mild and moderate/severe TBI subsamples, continued to endorse three or more symptoms as worse than pre-injury through 12 months post-injury. A majority of TBI participants who endorsed a symptom at 3 months or later did so at the next evaluation as well. Contrary to reviews that report symptom resolution by 3 months post-injury among those with mTBI, this study of participants treated at level 1 trauma centers and having a computed tomography ordered found that persistent symptoms are common to at least a year after TBI. Additionally, although symptom endorsement was not specific to TBI given that they were also reported by OTC and FC participants, TBI participants endorsed over twice the symptom burden compared with the other groups.

Association Between TBI-Related Hearing Impairment and Cognition: A TRACK-TBI Study.

OBJECTIVE: To examine the association between hearing impairment and cognitive function after traumatic brain injury (TBI). SETTING: A total of 18 level I trauma centers throughout the United States in the T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) study. PARTICIPANTS: From February 2014 to June 2018, a total of 2697 participants with TBI were enrolled in TRACK-TBI. Key eligibility criteria included external force trauma to the head, presentation to a participating level I trauma center, and receipt of a clinically indicated head computed tomographic (CT) scan within 24 hours of injury. A total of 1267 participants were evaluated in the study, with 216 participants with hearing impairment and 1051 participants without hearing impairment. Those with missing or unknown hearing status or cognitive assessment were excluded from analysis. DESIGN: Prospective, observational cohort study. MAIN MEASURES: Hearing impairment at 2 weeks post-TBI was based on self-report. Participants who indicated worse hearing in one or both ears were defined as having hearing impairment, whereas those who denied worse hearing in either ear were defined as not having hearing impairment and served as the reference group. Cognitive outcomes at 6 months post-TBI included executive functioning and processing speed, as measured by the Trail Making Test (TMT) B/A and the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index subscale (WAIS-IV PSI), respectively. RESULTS: TBI-related hearing impairment had a small but significantly greater TMT B/A ratio than without TBI-related hearing impairment: mean difference ( B ) = 0.25; 95% CI, 0.07 to 0.43; P = .005. No significant mean differences on WAIS-IV PSI scores were found between participants with and without TBI-related hearing impairment: B = 0.36; 95% CI, -2.07 to 2.60; P = .825. CONCLUSION: We conclude that TBI-related hearing impairment at 6 months postinjury was significantly associated with worse executive functioning but not cognitive processing speed.

Association of Posttraumatic Epilepsy With 1-Year Outcomes After Traumatic Brain Injury.

Importance: Posttraumatic epilepsy (PTE) is a recognized sequela of traumatic brain injury (TBI), but the long-term outcomes associated with PTE independent of injury severity are not precisely known. Objective: To determine the incidence, risk factors, and association with functional outcomes and self-reported somatic, cognitive, and psychological concerns of self-reported PTE in a large, prospectively collected TBI cohort. Design, Setting, and Participants: This multicenter, prospective cohort study was conducted as part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study and identified patients presenting with TBI to 1 of 18 participating level 1 US trauma centers from February 2014 to July 2018. Patients with TBI, extracranial orthopedic injuries (orthopedic controls), and individuals without reported injuries (eg, friends and family of participants; hereafter friend controls) were prospectively followed for 12 months. Data were analyzed from January 2020 to April 2021. Exposure: Demographic, imaging, and clinical information was collected according to TBI Common Data Elements. Incidence of self-reported PTE was assessed using the National Institute of Neurological Disorders and Stroke Epilepsy Screening Questionnaire (NINDS-ESQ). Main Outcomes and Measures: Primary outcomes included Glasgow Outcome Scale Extended, Rivermead Cognitive Metric (RCM; derived from the Rivermead Post Concussion Symptoms Questionnaire), and the Brief Symptom Inventory-18 (BSI). Results: Of 3296 participants identified as part of the study, 3044 met inclusion criteria, and 1885 participants (mean [SD] age, 41.3 [17.1] years; 1241 [65.8%] men and 644 [34.2%] women) had follow-up information at 12 months, including 1493 patients with TBI; 182 orthopedic controls, 210 uninjured friend controls; 41 patients with TBI (2.8%) and no controls had positive screening results for PTE. Compared with a negative screening result for PTE, having a positive screening result for PTE was associated with presenting Glasgow Coma Scale score (8.1 [4.8] vs.13.5 [3.3]; P < .001) as well as with anomalous acute head imaging findings (risk ratio, 6.42 [95% CI, 2.71-15.22]). After controlling for age, initial Glasgow Coma Scale score, and imaging findings, compared with patients with TBI and without PTE, patients with TBI and with positive PTE screening results had significantly lower Glasgow Outcome Scale Extended scores (mean [SD], 6.1 [1.7] vs 4.7 [1.5]; P < .001), higher BSI scores (mean [SD], 50.2 [10.7] vs 58.6 [10.8]; P = .02), and higher RCM scores (mean [SD], 3.1 [2.6] vs 5.3 [1.9]; P = .002) at 12 months. Conclusions and Relevance: In this cohort study, the incidence of self-reported PTE after TBI was found to be 2.8% and was independently associated with unfavorable outcomes. These findings highlight the need for effective antiepileptogenic therapies after TBI.

Functional Outcomes Over the First Year After Moderate to Severe Traumatic Brain Injury in the Prospective, Longitudinal TRACK-TBI Study.

Importance: Moderate to severe traumatic brain injury (msTBI) is a major cause of death and disability in the US and worldwide. Few studies have enabled prospective, longitudinal outcome data collection from the acute to chronic phases of recovery after msTBI. Objective: To prospectively assess outcomes in major areas of life function at 2 weeks and 3, 6, and 12 months after msTBI. Design, Setting, and Participants: This cohort study, as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, was conducted at 18 level 1 trauma centers in the US from February 2014 to August 2018 and prospectively assessed longitudinal outcomes, with follow-up to 12 months postinjury. Participants were patients with msTBI (Glasgow Coma Scale scores 3-12) extracted from a larger group of patients with mild, moderate, or severe TBI who were enrolled in TRACK-TBI. Data analysis took place from October 2019 to April 2021. Exposures: Moderate or severe TBI. Main Outcomes and Measures: The Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS) were used to assess global functional status 2 weeks and 3, 6, and 12 months postinjury. Scores on the GOSE were dichotomized to determine favorable (scores 4-8) vs unfavorable (scores 1-3) outcomes. Neurocognitive testing and patient reported outcomes at 12 months postinjury were analyzed. Results: A total of 484 eligible patients were included from the 2679 individuals in the TRACK-TBI study. Participants with severe TBI (n = 362; 283 men [78.2%]; median [interquartile range] age, 35.5 [25-53] years) and moderate TBI (n = 122; 98 men [80.3%]; median [interquartile range] age, 38 [25-53] years) were comparable on demographic and premorbid variables. At 2 weeks postinjury, 36 of 290 participants with severe TBI (12.4%) and 38 of 93 participants with moderate TBI (41%) had favorable outcomes (GOSE scores 4-8); 301 of 322 in the severe TBI group (93.5%) and 81 of 103 in the moderate TBI group (78.6%) had moderate disability or worse on the DRS (total score ≥4). By 12 months postinjury, 142 of 271 with severe TBI (52.4%) and 54 of 72 with moderate TBI (75%) achieved favorable outcomes. Nearly 1 in 5 participants with severe TBI (52 of 270 [19.3%]) and 1 in 3 with moderate TBI (23 of 71 [32%]) reported no disability (DRS score 0) at 12 months. Among participants in a vegetative state at 2 weeks, 62 of 79 (78%) regained consciousness and 14 of 56 with available data (25%) regained orientation by 12 months. Conclusions and Relevance: In this study, patients with msTBI frequently demonstrated major functional gains, including recovery of independence, between 2 weeks and 12 months postinjury. Severe impairment in the short term did not portend poor outcomes in a substantial minority of patients with msTBI. When discussing prognosis during the first 2 weeks after injury, clinicians should be particularly cautious about making early, definitive prognostic statements suggesting poor outcomes and withdrawal of life-sustaining treatment in patients with msTBI.

Pathological Computed Tomography Features Associated With Adverse Outcomes After Mild Traumatic Brain Injury: A TRACK-TBI Study With External Validation in CENTER-TBI.

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood. Objective: To identify pathological CT features associated with adverse outcomes after mTBI. Design, Setting, and Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021. Exposures: Acute nonpenetrating head trauma. Main Outcomes and Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months. Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study. Conclusions and Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.

Functional Status Examination Yields Higher Measurement Precision than the Glasgow Outcome Scale-Extended after Moderate-to-Severe Traumatic Brain Injury.

A limited evidence base supports the Functional Status Examination (FSE) as superior to the more commonly used Glasgow Outcome Scale-Extended (GOSE) for precisely characterizing injury-related functional limitations. The aim of this study was to use modern psychometric tools to test the hypothesis that the FSE is more precise than the GOSE in characterizing individual differences in functional limitations after moderate-to-severe traumatic brain injury (TBI). Secondarily, we sought to confirm that the type of interviewee (patient, significant other) does not affect the test performance of the FSE. Using data from 357 individuals with TBI who participated in the Magnesium Sulfate clinical trial and had six-month outcome data, we performed item response theory (IRT) analyses comparing the FSE and GOSE at six months post-injury. Results showed that the FSE yielded higher measurement precision (IRT test information) than the GOSE across most of the disability severity spectrum. The GOSE yielded more information than the FSE at a very high level of disability, because of the GOSE's assignment of a unique score for individuals who are in a vegetative state. Finally, the FSE showed no evidence of differential item functioning by interviewee, indicating it is appropriate to interview either persons with TBI or significant others and combine data across respondents as is typically done. The findings support the FSE as a viable and oftentimes advantageous substitute for the GOSE in clinical trials and translational studies of TBI.

Association of Sex and Age With Mild Traumatic Brain Injury-Related Symptoms: A TRACK-TBI Study.

Importance: Knowledge of differences in mild traumatic brain injury (mTBI) recovery by sex and age may inform individualized treatment of these patients. Objective: To identify sex-related differences in symptom recovery from mTBI; secondarily, to explore age differences within women, who demonstrate poorer outcomes after TBI. Design, Setting, and Participants: The prospective cohort study Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) recruited 2000 patients with mTBI from February 26, 2014, to July 3, 2018, and 299 patients with orthopedic trauma (who served as controls) from January 26, 2016, to July 27, 2018. Patients were recruited from 18 level I trauma centers and followed up for 12 months. Data were analyzed from August 19, 2020, to March 3, 2021. Exposures: Patients with mTBI (defined by a Glasgow Coma Scale score of 13-15) triaged to head computed tomography in 24 hours or less; patients with orthopedic trauma served as controls. Main Outcomes and Measures: Measured outcomes included (1) the Rivermead Post Concussion Symptoms Questionnaire (RPQ), a 16-item self-report scale that assesses postconcussion symptom severity over the past 7 days relative to preinjury; (2) the Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5), a 20-item test that measures the severity of posttraumatic stress disorder symptoms; (3) the Patient Health Questionnaire-9 (PHQ-9), a 9-item scale that measures depression based on symptom frequency over the past 2 weeks; and (4) the Brief Symptom Inventory-18 (BSI-18), an 18-item scale of psychological distress (split into Depression and Anxiety subscales). Results: A total of 2000 patients with mTBI (1331 men [67%; mean (SD) age, 41.0 (17.3) years; 1026 White (78%)] and 669 women [33%; mean (SD) age, 43.0 (18.5) years; 505 (76%) White]). After adjustment of multiple comparisons, significant TBI × sex interactions were observed for cognitive symptoms (B = 0.76; 5% false discovery rate-corrected P = .02) and somatic RPQ symptoms (B = 0.80; 5% false discovery rate-corrected P = .02), with worse symptoms in women with mTBI than men, but no sex difference in symptoms in control patients with orthopedic trauma. Within the female patients evaluated, there was a significant TBI × age interaction for somatic RPQ symptoms, which were worse in female patients with mTBI aged 35 to 49 years compared with those aged 17 to 34 years (B = 1.65; P = .02) or older than 50 years (B = 1.66; P = .02). Conclusions and Relevance: This study found that women were more vulnerable than men to persistent mTBI-related cognitive and somatic symptoms, whereas no sex difference in symptom burden was seen after orthopedic injury. Postconcussion symptoms were also worse in women aged 35 to 49 years than in younger and older women, but further investigation is needed to corroborate these findings and to identify the mechanisms involved. Results suggest that individualized clinical management of mTBI should consider sex and age, as some women are especially predisposed to chronic postconcussion symptoms even 12 months after injury.

Central Curation of Glasgow Outcome Scale-Extended Data: Lessons Learned from TRACK-TBI.

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

Latent Profile Analysis of Neuropsychiatric Symptoms and Cognitive Function of Adults 2 Weeks After Traumatic Brain Injury: Findings From the TRACK-TBI Study.

Importance: Heterogeneity across patients with traumatic brain injury (TBI) presents challenges for clinical care and intervention design. Identifying distinct clinical phenotypes of TBI soon after injury may inform patient selection for precision medicine clinical trials. Objective: To investigate whether distinct neurobehavioral phenotypes can be identified 2 weeks after TBI and to characterize the degree to which early neurobehavioral phenotypes are associated with 6-month outcomes. Design, Setting, and Participants: This prospective cohort study included patients presenting to 18 US level 1 trauma centers within 24 hours of TBI from 2014 to 2019 as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Data were analyzed from January 28, 2020, to January 11, 2021. Exposures: TBI. Main Outcomes and Measures: Latent profiles (LPs) were derived from common dimensions of neurobehavioral functioning at 2 weeks after injury, assessed through National Institutes of Health TBI Common Data Elements (ie, Brief Symptom Inventory-18, Patient Health Questionnaire-9 Depression checklist, Posttraumatic Stress Disorder Checklist for DSM-5, PROMIS Pain Intensity scale, Insomnia Severity Index, Rey Auditory Verbal Learning Test, Wechsler Adult Intelligence Scale-Fourth Edition Coding and Symbol Search subtests, Trail Making Test, and NIH Toolbox Cognitive Battery Pattern Comparison Processing Speed, Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, and Picture Sequence Memory subtests). Six-month outcomes were the Satisfaction With Life Scale (SWLS), Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS), Glasgow Outcome Scale-Extended (GOSE), and Rivermead Post-Concussion Symptoms Questionnaire (RPQ). Results: Among 1757 patients with TBI included, 1184 (67.4%) were men, and the mean (SD) age was 39.9 (17.0) years. LP analysis revealed 4 distinct neurobehavioral phenotypes at 2 weeks after injury: emotionally resilient (419 individuals [23.8%]), cognitively impaired (368 individuals [20.9%]), cognitively resilient (620 individuals [35.3%]), and neuropsychiatrically distressed (with cognitive weaknesses; 350 individuals [19.9%]). Adding LP group to models including demographic characteristics, medical history, Glasgow Coma Scale score, and other injury characteristics was associated with significantly improved estimation of association with 6-month outcome (GOSE R2 increase = 0.09-0.19; SWLS R2 increase = 0.12-0.22; QOLIBRI-OS R2 increase = 0.14-0.32; RPQ R2 = 0.13-0.34). Conclusions and Relevance: In this cohort study of patients with TBI presenting to US level-1 trauma centers, qualitatively distinct profiles of symptoms and cognitive functioning were identified at 2 weeks after TBI. These distinct phenotypes may help optimize clinical decision-making regarding prognosis, as well as selection and stratification for randomized clinical trials.

Smaller Regional Brain Volumes Predict Posttraumatic Stress Disorder at 3 Months After Mild Traumatic Brain Injury.

BACKGROUND: Brain volumes in regions such as the hippocampus and amygdala have been associated with risk for the development of posttraumatic stress disorder (PTSD). The objective of this study was to determine whether a set of regional brain volumes, measured by magnetic resonance imaging at 2 weeks following mild traumatic brain injury, were predictive of PTSD at 3 and 6 months after injury. METHODS: Using data from TRACK-TBI (Transforming Research and Clinical Knowledge in TBI), we included patients (N = 421) with Glasgow Coma Scale scores 13-15 assessed after evaluation in the emergency department and at 2 weeks, 3 months, and 6 months after injury. Probable PTSD diagnosis (PTSD Checklist for DSM-5 score, ≥33) was the outcome. FreeSurfer 6.0 was used to perform volumetric analysis of three-dimensional T1-weighted magnetic resonance images at 3T obtained 2 weeks post injury. Brain regions selected a priori for volumetric analyses were insula, hippocampus, amygdala, superior frontal cortex, rostral and caudal anterior cingulate, and lateral and medial orbitofrontal cortices. RESULTS: Overall, 77 (18.3%) and 70 (16.6%) patients had probable PTSD at 3 and 6 months. A composite volume derived as the first principal component incorporating 73.8% of the variance in insula, superior frontal cortex, and rostral and caudal cingulate contributed to the prediction of 3-month (but not 6-month) PTSD in multivariable models incorporating other established risk factors. CONCLUSIONS: Results, while needing replication, provide support for a brain reserve hypothesis of PTSD and proof of principle for how prediction of at-risk individuals might be accomplished to enhance prognostic accuracy and enrich clinical prevention trials for individuals at the highest risk of PTSD following mild traumatic brain injury.

Satisfaction with Life after Mild Traumatic Brain Injury: A TRACK-TBI Study.

Identifying the principal determinants of life satisfaction following mild TBI (mTBI) may inform efforts to improve subjective well-being in this population. We examined life satisfaction among participants in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study who presented with mTBI (Glasgow Coma Scale [GCS] score = 13-15; n = 1152). An L1-regularization path algorithm was used to select optimal sets of baseline and concurrent symptom measures for prediction of scores on the Satisfaction with Life Scale (SWLS) at 2 weeks and 3, 6, and 12 months post-injury. Multi-variable linear regression models (all n = 744-894) were then fit to evaluate associations between the empirically selected predictors and SWLS scores at each follow-up visit. Results indicated that emotional post-TBI symptoms (all b = -1.27 to -0.77, all p < 0.05), anhedonia (all b = -1.59 to -1.08, all p < 0.01), and pain interference (all b = -1.38 to -0.89, all p < 0.001) contributed to the prediction of lower SWLS scores at all follow-ups. Insomnia predicted lower SWLS scores at 2 weeks, 3 months, and 6 months (all b = -1.11 to -0.83, all ps < 0.01); and negative affect predicted lower SWLS scores at 2 weeks, 3 months, and 12 months (all b = -1.38 to -0.80, all p < 0.005). Other post-TBI symptom domains and baseline socio-demographic, injury-related, and clinical characteristics did not emerge as robust predictors of SWLS scores during the year after mTBI. Efforts to improve satisfaction with life following mTBI may benefit from a focus on the detection and treatment of affective symptoms, pain, and insomnia. The results reinforce the need for tailoring of evidence-based treatments for these conditions to maximize efficacy in patients with mTBI.

Validity of the Brief Test of Adult Cognition by Telephone in Level 1 Trauma Center Patients Six Months Post-Traumatic Brain Injury: A TRACK-TBI Study.

Our objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1422 patients with TBI and 170 orthopedic trauma controls (OTC) from the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6 months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising, brief, phone-based cognitive screening tool for patients with TBI. Although the BTACT's memory items appear to index verbal Episodic Memory, items that purport to assess EFs may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI.

Invariance of the Bifactor Structure of Mild Traumatic Brain Injury (mTBI) Symptoms on the Rivermead Postconcussion Symptoms Questionnaire Across Time, Demographic Characteristics, and Clinical Groups: A TRACK-TBI Study.

This study aimed to elucidate the structure of the Rivermead Postconcussion Symptoms Questionnaire (RPQ) and evaluate its longitudinal and group variance. Factor structures were developed and compared in 1,011 patients with mild traumatic brain injury (mTBI; i.e., Glasgow Coma Scale score 13-15) from the Transforming Research and Clinical Knowledge in TBI study, using RPQ data collected at 2 weeks, and 3, 6, and 12 months postinjury. A bifactor model specifying a general factor and emotional, cognitive, and visual symptom factors best represented the latent structure of the RPQ. The model evinced strict measurement invariance over time and across sex, age, race, psychiatric history, and mTBI severity groups, indicating that differences in symptom endorsement were completely accounted for by these latent dimensions. While highly unidimensional, the RPQ has multidimensional features observable through a bifactor model, which may help differentiate symptom expression patterns in the future.