We sought to study which intracranial pressure (ICP)-lowering treatments are actually administered following the diagnosis of a clinical intracranial hypertension episode (CLICHÉ) during modern, routine care. We performed a secondary analysis of data from patients with ICP only (normal or blinded partial pressure of brain tissue oxygen [PbtO2]) in the Brain Tissue Oxygen Monitoring and Management in Severe Traumatic Brain Injury (BOOST II) randomized trial. We identified “minimalist” (forme fruste) CLICHÉs (defined by 5 min of ICP > 20 lasting ≤ 60 min, requiring only Tier One treatments) and catalogued all interventions by frequency, grouping and distribution of administration. Tier One treatments were not rank-ordered. Of the 119 randomized patients, 70 had 509 CLICHÉs that met forme fruste definition with complete datasets (71

Generalizable neuroimaging biomarkers that detect cerebral cortical changes after traumatic brain injury (TBI) and predict patient outcomes are needed to improve care and to develop targeted therapies. We used morphometric inverse divergence (MIND) analysis of structural MRI to investigate cortical gray matter morphological networks cross-sectionally and longitudinally after TBI and correlate these with symptoms, disability and cognition six months after injury. Our findings support the Triple Network Model from functional MRI of post-traumatic alterations in the relationship between task-positive, default mode and salience networks. However, the strongest associations between early cortical similarity metrics and long-term patient outcomes involved the dorsal attention network and the limbic network as well as similarity metrics across Mesulam's hierarchy of laminar differentiation. Since MIND mapping of cortical gray matter networks only requires data that is a routine part of standard clinical MRI protocols and does not need image harmonization across different scanners, this work reports a promising new tool that is immediately available for advancing research and clinical care in TBI.

Biomarkers are needed to characterize mechanistic endophenotypes after neurotrauma and inform prognosis and therapy. Vascular endothelial growth factor-A (VEGF-A) is associated with inflammation and vascular permeability, which are implicated in secondary brain injury. We describe changes in plasma VEGF-A levels at injury (D1) and 2 weeks (W2) postinjury, and their associations with traumatic brain injury (TBI) severity and 6-month (M6) Glasgow Outcome Scale-Extended (GOSE) scores in a subset of Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) participants with TBI (n = 317), orthopedic trauma controls (OTC, n = 82), and healthy controls (HC, n = 69). D1 VEGF-A levels were higher in TBI (median [IQR] = 175.8 [114.2-273.1]) compared with OTC (134.3 [97.4-200.6], p = 0.001) and HC (133.6 [89.2-188.2], p = 0.003). VEGF-A levels for both Glasgow Coma Scale (GCS) 3-12 (187.1 [131.7-271.6], p < 0.001) and GCS 13-15 with CT lesions (167.6 [111.4-273.9], p = 0.04) were significantly higher than control groups. This was not the case for GCS 13-15 without CT findings (160.5 [99.2-255.7], p = 0.11, p = 0.09 vs. HC and OTC, respectively). D1 levels did not significantly differ between GCS 3-12 and GCS 13-15 (p = 0.09), but W2 VEGF-A levels remained elevated for GCS 3-12 (231.6 [120.2-511.5], p < 0.0001 vs. HC) while GCS 13-15 returned to HC levels. VEGF-A levels were higher in all TBI participants with intracranial pathology on CT compared with those without (D1: p = 0.024; W2: p < 0.0001). VEGF-A levels for all TBI returned to HC values by M6. D1 VEGF-A levels did not differ by M6 GOSE, but W2 levels were higher in those with moderate functional disability (GOSE 1-6; p = 0.04) and with unfavorable outcomes (GOSE 1-4; p < 0.0001). W2 VEGF-A was associated with increased odds of unfavorable outcome (GOSE 1-4) at M6 (aOR = 1.44 per log unit increase, 95% CI: 1.02-2.05) after accounting for demographic and clinical variables, but D1 levels were not. Our findings suggest that VEGF-A is a candidate biomarker of traumatic vascular injury and may hold promise for identifying and monitoring of a potentially treatable endophenotype after TBI.

INTRODUCTION:Traumatic brain injury (TBI) represents a significant global health burden and often results in functional impairment. Blood pressure variability (BPV), a surrogate marker of autonomic dysfunction, has been shown to influence outcomes in patients with cerebrovascular disease. Increased BPV has been strongly linked to deviation from optimal cerebral perfusion pressure, which may elevate the risk of secondary brain injury and poor outcomes after TBI. This study aimed to investigate the association of early BPV with clinical and functional outcomes, as well as brain injury biomarkers, in patients with TBI. METHOD:We conducted a retrospective cohort study using data from the Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study (TRACK-TBI), which prospectively enrolled acute TBI patients across 18 United States Level 1 trauma centers between 2014-2018. The study population included adults with moderate-to-severe TBI who required intracranial pressure monitoring. The primary exposure was early BPV, calculated from hourly blood pressure measurements during the first 24 h after ICU admission; 72-hour BPV was examined in sensitivity analyses. Two BPV metrics were evaluated: systolic standard deviation (SSD) and average real variability (ARV). The primary outcome was the 6-month Glasgow Outcome Scale-Extended score specific to TBI (GOSE-TBI). Secondary outcomes included in-hospital mortality, GOSE-TBI at 3 and 12 months, Disability Rating Scale (DRS) at 3 months, 6 months, and 12 months, and blood-based brain injury biomarkers [glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and the inflammatory biomarker C-reactive protein (CRP)]. Multivariable regression models were used to assess associations between BPV, clinical outcomes, and biomarker levels. RESULTS:A total of 108 patients were included. The mean age (SD) was 41.3 years (17.3), 81% were male, and 81% identified as White. There were no statistically significant associations between 24-hour BPV and 6-month GOSE for either ARV (OR 0.84, 95% CI 0.68-1.05; p = 0.133) or SSD (OR 0.86, 95% CI 0.69-1.08; p = 0.194). Among secondary outcomes, higher 24-hour SSD was associated with increased odds of in-hospital mortality (OR 1.13, 95% CI 1.00-1.27; p = 0.048). Higher average 72-hour SSD was also associated with higher hs-CRP levels (Ratio 1.04, 95% CI 1.00-1.07; p = 0.036). CONCLUSION:Early BPV was not associated with GOSE-TBI at 6 months or most blood-based brain injury biomarkers. However, higher 24-hour SSD may be associated with increased in-hospital mortality. The prognostic value of BPV warrants confirmation in future prospective studies.

Patients with traumatic brain injury (TBI) and Glasgow Coma Scale scores of 13-15 (historically called mild TBI [mTBI]) commonly experience changes in cognitive functioning, including processing speed, memory, and executive functioning. In a prospective sample (N = 523) of individuals of European descent who had been treated in a U.S. level 1 trauma center for mTBI, we examined the prognostic value of four polygenic risk scores (PRS) for cognitive outcomes at 6-months postinjury. To estimate the impact of mTBI on cognition, primary cognitive outcomes were scaled as z-scores reflecting changes in performance relative to predicted preinjury performance. The PRS examined were previously developed and validated to predict cognition-related outcomes of educational attainment (Education-PRS), intelligence (Intelligence-PRS), and Alzheimer's disease (AD-mild traumatic brain injury (APOE)-PRS and AD + APOE-PRS). Both the Education-PRS and Intelligence-PRS displayed bivariate associations with all four cognitive outcomes (β = 0.19-0.32), whereas neither Alzheimer's disease PRS was significantly associated with any outcome. After controlling for other factors known to predict cognitive outcomes of TBI (e.g., sex, education, mTBI severity defined by a combination of Glasgow Coma Scale scores and the presence/absence of acute intracranial findings on clinical neuroimaging), the Education-PRS and Intelligence-PRS remained independently predictive of verbal episodic memory (β = 0.10-0.16), whereas their associations with processing speed and executive functioning were mostly nonsignificant and were mediated through educational attainment. Looking across primary z-score and secondary raw score outcomes, cognitive outcomes 6 months post-mTBI were good on average, and PRS made small independent contributions to outcome prediction. The mediation model findings may support theories of cognitive reserve, which propose that individuals with stronger preinjury cognitive processing abilities (often estimated by educational history) can better compensate for TBI. Moreover, findings indicate that PRS may contribute modestly to multivariable models predicting cognitive function after TBI.

Background Biomarkers like glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) are being globally recommended as a valuable component in the evaluation of acute TBI. Having a regulatory-approved whole-blood test is imperative to provide consistent and democratized approach to healthcare. This prospective, national multicenter cohort trial (NCT04171960) evaluated the performance of a whole-blood, point-of-care (POC) GFAP/UCH-L1 panel in determining need for head computed tomography (CT) in adult patients presenting to the emergency department (ED) with suspected traumatic brain injury (TBI). Methods Adults presenting to the ED with suspected TBI, Glasgow Coma Scale score 13–15, completed head CT scan, and blood collected within 24 h of injury were included. GFAP and UCH-L1 measured in whole-blood through a POC TBI biomarker test were analyzed using prespecified cutoffs and combined into a single test result and compared with CT findings. Findings 970 enrolled participants [mean age 46.8 (18–97); 36%female; 69%White, 18%Black; 19%Hispanic/Latino] were analyzed. 683 participants (70.4%) had ‘elevated’ and 287 (29.6%) had ‘not elevated’ TBI blood test result. For detection of CT intracranial injury, the whole-blood TBI test had sensitivity of 96.5% (95%CI 93.6–98.1%) and NPV 96.5% (95%CI 93.7–98.1%). Interpretation The GFAP/UCH-L1 whole-blood test had high sensitivity and NPV for prediction of intracranial injury within 24 h of TBI. The platform received U.S.-FDA clearance and expands clinical use of the TBI test beyond the laboratory. This test provides results in 15 min; supporting rapid triage and decision-making in suspected TBI. Funding Defense Health Agency (DHA) under Contract No. W81XWH19C0071.

OBJECTIVE:Traumatic brain injury (TBI) research and intracranial pressure (ICP) management depends on bedside ICP (B-ICP) crisis identification. We analyzed background-collected electronic ICP (E-ICP) data to study the concordance of this identification. DESIGN:Post hoc comparison of background-collected continuous E-ICP data to routine B-ICP information during severe TBI management in the Brain Tissue Oxygen Monitoring and Management in Severe TBI (BOOST II) randomized trial. SETTING:Ten U.S. ICUs. PATIENTS:Seventy of 110 randomized BOOST II severe TBI patients with complete datasets for this study. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We studied "minimalist" B-ICP episodes lasting less than or equal to 60 minutes and requiring only tier 1 treatments (83% of total BOOST II I isolated ICP episodes). Bedside clinicians (BCs) identified and treated 509 minimalist B-ICP episodes, defined by 5 minutes of B-ICP greater than or equal to 20 mm Hg (B-ICP 5 ). Corresponding E-ICP during this defining period (E-ICP 5 ) confirmed only 47% of these. The 241 "concordant" B-ICP episodes (both B-ICP 5 and E-ICP 5 ≥ 20 mm Hg) had average E-ICP values for the entire B-ICP episodes (E-ICP AVG ) less than 20 mm Hg in 38%. The 286 "discordant" B-ICP episodes (B-ICP 5 ≥ 20 mm Hg but E-ICP 5 < 20 mm Hg) had E-ICP AVG values less than 20 mm Hg in 76% and both E-ICP AVG and maximal E-ICP's (E-ICP MAX ) values less than 20 mm Hg in 31%. Testing for confounding (e.g., brief, first, or easily controlled B-ICP episodes) did not provide explanations. Insufficient data were available to evaluate temporal asynchrony between BC and electronic datapoints. Study limitations were lacking a rigid end-of-B-ICP episode definition and inability to fully control for temporal synchrony confounding. CONCLUSIONS:Our findings suggest that current methods of clinical identification of B-ICP episodes may not reliably distinguish true episodes of sustained ICP for the most common B-ICP episode type. We suggest developing open-source, real-time, temporally synchronized electronic B-ICP episode definition methods to direct future treatment and research.

OBJECTIVE:Beta-blockers have been studied for their impact on traumatic brain injury (TBI). We aimed to examine the association of preinjury beta-blocker exposure with early brain injury biomarker levels and outcomes following TBI. METHODS:We retrospectively studied adults (≥40 y) participating in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. The exposure was preinjury beta-blocker utilization. Primary outcome was blood-based brain injury biomarker levels on day 1 following injury. Secondary outcomes included biomarkers on days 3 and 5, hospital mortality, and the 6-month Glasgow Outcome Scale-Extended. Inverse probability-weighted models assessed the association between preinjury beta-blocker exposure, biomarker levels, and outcomes, stratified by TBI severity. RESULTS:A total of 1185 patients were included, with 101 on preinjury beta-blockers (BB+): 21 in the moderate/severe group and 80 in the mild TBI group. BB+patients were older than BB- in both mild (67 vs. 57 y, P <0.001) and moderate/severe TBI (64 vs. 56 y, P =0.003). Hypertension was more common in BB+patients (78% mild, 67% moderate/severe, P <0.001). Preinjury beta-blocker use was not associated with day 1 biomarker levels. The 6-month GOSE scores in the BB+ moderate/severe TBI were lower, but the effect was marginal (B= -1.20, 95% CI: -2.39 to -0.01, P =0.049). CONCLUSION:Our study did not find a clear association between preinjury beta-blocker exposure and day 1 blood-based brain injury biomarkers or clinical outcomes. These findings warrant confirmation in future studies with larger cohorts.

The Glasgow Outcome Scale Extended (GOSE) is the most widely used outcome measure for hospital-based studies of traumatic brain injury (TBI). The GOSE may be administered several ways, the choice depending on the purpose of the research. In this investigation, we evaluated the effect of administering the GOSE to collect functional disability attributed to all injuries sustained (GOSE-All) or excluding the impact of extracranial injuries (GOSE-TBI). We examined the differences in reported disability between the two administration methods at 2 weeks, 3 months, 6 months, and 12 months after injury. Data are summarized from 2288 individuals who were enrolled in the prospective observational Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) cohort study. The distribution of scores is summarized by time after injury, brain injury severity, and extracranial injury severity. Dichotomizing the GOSE varying ways, differences in the prevalence of unfavorable outcomes for GOSE-All versus GOSE-TBI range from none to 42 percentage points. Discrepancies in disability captured by GOSE-All and GOSE-TBI decrease with greater TBI severity, no serious extracranial injuries, and longer time post-injury. It is important for researchers, given the aims of their studies, to decide in advance whether GOSE classification should be based on the effects of all injuries sustained or excluding the effects of extracranial injuries so as to emphasize the effects of the brain injury, as well as how disability due to emotional consequences of injury and other circumstances will be scored. Instructions to the respondent and outcomes examiner need to be clear about what causes of disability are to be included. The TBI Common Data Elements should include information that reflects the method that was used to collect the GOSE data and data repositories should disclose which data collection method was used for a given study.

Insomnia and depression are common co-morbidities associated with mild traumatic brain injury (mTBI). Data from Transforming Research and Clinical Knowledge in TBI, a longitudinal cohort study of TBI and orthopedic controls (OTC), were used to examine insomnia trajectories and the temporal relationship between insomnia and depressive symptoms during recovery. mTBI (n = 1,557) and OTC (n = 226) adult patients with no psychiatric or sleep disorder history were assessed at 2 weeks and 3, 6, and 12 months post-injury, and at three long-term assessments between 2 and 10 years post-injury. Latent class growth analysis identified five insomnia trajectory classes during the first year post-injury, revealing 25% with persistent insomnia, 4% improving, and 71% below the clinical cutoff. A random intercept cross-lagged panel model tested the lagged effects between insomnia and depression. In addition to being longitudinally correlated (φ = 0.74, p < 0.001), depressive symptomatology operated as a leading indicator of worsening insomnia from 3 to 6 months post-injury (β = 0.20, p = 0.001) across the whole sample. The multigroup model revealed less insomnia (α = -0.31, p = 0.006) and depressive symptoms (α = -0.52, p < 0.001) in OTC relative to mTBI. From 1 to 5-10 years post-injury, mTBI low insomnia classes remained stable, while the highest class improved moderately (-5.50, 95% confidence interval: -7.84, -3.16, p < 0.001). Our findings suggest depressive symptoms may lead to worsening insomnia during the subacute recovery period and that a subset of patients with mTBI may suffer from new-onset insomnia that persists for more than 5 years.

Background The impact of comorbid post-traumatic stress disorder (PTSD) and depression on cognitive outcomes after traumatic brain injury (TBI) is not well understood.Objective To investigate associations of PTSD and depression with cognitive performance over the first year post-injury.Methods 1550 participants with Glasgow Coma Scale 13–15 TBI from the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Study were included. Participants underwent in-person assessments at 2 weeks, 6 months and 1 year post-injury. Meeting screening criteria for PTSD was determined using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders. Meeting screening criteria for depression was determined using the Patient Health Questionnaire–9. Cognition was assessed using a five-test battery. Linear mixed effects models were used to examine associations of PTSD and depression with cognition after TBI.Findings Participants had a mean age of 41 years, 34% were female, 65% did not meet screening criteria for PTSD or depression, 3% met screening criteria for depression only, 16% met screening criteria for PTSD only and 16% met screening criteria for both depression and PTSD in the first year post-TBI. Mean performance on all cognitive tests improved at a similar rate over the first year post-injury in all PTSD/depression groups, but cognitive test performance was consistently worse among individuals with concurrent PTSD and/or depression compared with individuals with neither.Conclusions Individuals with TBI meeting screening criteria for PTSD and/or depression have consistently worse cognitive performance over the first year post-injury compared with individuals without psychiatric comorbidities, but the average rate of cognitive improvement over the first year was similar regardless of PTSD/depression status.Clinical implications Further work is warranted to determine if cognitive and psychiatric-focused interventions may improve rates of cognitive improvement post-injury among individuals with comorbid PTSD and/or depression so that these individuals may ultimately achieve levels of cognition comparable to individuals without psychiatric comorbidities.

Background:Beta-blockers have been studied for potential benefits in traumatic brain injury (TBI). This study aimed to investigate the association between early beta-blocker exposure and brain injury biomarkers following moderate-severe TBI. Methods:We conducted a retrospective cohort study using data from the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. Patients ⩾ 17 years with moderate-severe TBI (Glasgow Coma Scale 3-12) admitted to an intensive care unit (ICU) were included. Early beta-blocker exposure was defined as administration within the first 72 h of admission. The primary outcome was blood-based brain injury biomarker levels on day 3 post-injury. Biomarkers included glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and the inflammatory biomarker C-reactive protein (CRP). Propensity-weighted models analyzed the association between beta-blocker exposure and biomarker levels. Results:Among 450 patients, 31 (7%) received beta-blockers (BB+). The mean (SD) age of BB+ patients was 51.4 (16.2) years, compared to 39.5 (17.0) years for unexposed patients (BB-). BB+ group was associated with a decreased NSE level on day 3 (ratio = 0.71, 95% CI 0.52-0.96, p = 0.026), although this was not significant after adjusting for multiple comparisons (p = 0.13). For secondary outcomes, UCH-L1 levels increased on day 5 in the BB+ group (ratio = 1.62, 95% CI 1.12- 2.36, p = 0.011), but this was not significant after adjustment (p = 0.55). The NSE level on day 14 decreased in the BB+ group (ratio 0.45, 95% CI 0.30-0.66, p < 0.001) and remained significant after adjustment (p = 0.005). Conclusions:There was no association between early beta-blocker exposure and the primary outcome which was blood-based brain injury biomarker levels on day 3. In exploratory analysis, we found that early beta-blocker may associated with decreased NSE level on day 14. Due to the retrospective nature of the study and the use of propensity-weighted analysis to identify associations, direct clinical practice changes cannot be recommended. However, the significant association with NSE level warrants further investigation through prospective studies or randomized controlled trials to confirm the potential neuroprotective effect of early beta-blocker exposure on neuronal cellular injury.

Research on mild traumatic brain injury (mTBI) and its impact on young adults is limited, despite this being an important time in their lives to work toward independence and career development. We analyzed data on 663 persons aged 17-29 years old with mTBI (i.e., TBI with Glasgow Coma Scale scores 13-15) and 170 controls who did not experience an injury from the multicenter, Transforming Research and Clinical Knowledge in TBI study. We assessed participants with mTBI, subdivided into those with computed tomography (CT) evidence of TBI (CT+) and those without (CT-), at 12 months post-injury with measures to examine symptom persistence, work and school status, and functional outcomes. Results indicated differences between mTBI and control participants related to return-to-work, return-to-school, and persistent symptoms. Those in the mTBI group were more likely to experience adverse symptoms and detrimental functional effects compared with controls at 12-months post-injury. However, other factors that may not have been measured could have contributed to these outcomes. Young adults are in a transition period where they are working to achieve independence and to establish careers; however, if they sustain a TBI, they, their families, and their medical providers may not understand how the injury contributes to their outcomes, and they may also have limited experience in seeking resources for care. Outcomes for mTBI could also disrupt their career and life trajectories, making this an important area for further investigation and intervention.