Biomarker-guided neuromodulation aids memory in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset of patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.

Connectomic assessment of injury burden and longitudinal structural network alterations in moderate-to-severe traumatic brain injury.

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network-wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been relatively limited. In this study, we propose a novel connectomic measure that we call network normality score (NNS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate-to-severe TBI patients, we demonstrate that structural network topology of patients is more heterogeneous and significantly different than that of healthy controls at 3 months postinjury, where dissimilarity further increases up to 12 months. We also show that NNS captures injury burden as quantified by posttraumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally, we compare NNS to major graph theory measures used in TBI literature and demonstrate the superiority of NNS in characterizing the disease.

Discordance between Documented Criteria and Documented Diagnosis of Traumatic Brain Injury in the Emergency Department.

Accurate diagnosis of traumatic brain injury (TBI) is critical to ensure that patients receive appropriate follow-up care, avoid risk of subsequent injury, and are aware of possible long-term consequences. However, diagnosis of TBI, particularly in the emergency department (ED), can be difficult because the symptoms of TBI are vague and nonspecific, and patients with suspected TBI may present with additional injuries that require immediate medical attention. We performed a retrospective chart review to evaluate accuracy of TBI diagnosis in the ED. Records of 1641 patients presenting to the ED with suspected TBI and a head computed tomography (CT) were reviewed. We found only 47% of patients meeting the American Congress of Rehabilitation Medicine criteria for TBI received a documented ED diagnosis of TBI in medical records. After controlling for demographic and clinical factors, patients presenting at a level I trauma center, with cause of injury other than fall, without CT findings of TBI, and without loss of consciousness were more likely to lack documented diagnosis despite meeting diagnostic criteria for TBI. A greater proportion of patients without documented ED diagnosis of TBI were discharged home compared to those with a documented diagnosis of TBI (58% vs. 40%; p < 0.001). Together, these data suggest that many patients who have sustained a TBI are discharged home from the ED without a documented diagnosis of TBI, and that improved awareness and implementation of diagnostic criteria for TBI is important in the ED and for in- and outpatient providers.

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

OBJECTIVES: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. DESIGN: Randomized prospective clinical trial. SETTING: Ten ICUs in the United States. PATIENTS: One hundred nineteen severe traumatic brain injury patients. INTERVENTIONS: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended. MEASUREMENTS AND MAIN RESULTS: A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy. CONCLUSIONS: Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.

Diagnosis, prognosis, and clinical management of mild traumatic brain injury.

Concussion and mild traumatic brain injury (TBI) are interchangeable terms to describe a common disorder with substantial effects on public health. Advances in brain imaging, non-imaging biomarkers, and neuropathology during the past 15 years have required researchers, clinicians, and policy makers to revise their views about mild TBI as a fully reversible insult that can be repeated without consequences. These advances have led to guidelines on management of mild TBI in civilians, military personnel, and athletes, but their widespread dissemination to clinical management in emergency departments and community-based health care is still needed. The absence of unity on the definition of mild TBI, the scarcity of prospective data concerning the long-term effects of repeated mild TBI and subconcussive impacts, and the need to further develop evidence-based interventions to mitigate the long-term sequelae are areas for future research that will improve outcomes, reduce morbidity and costs, and alleviate delayed consequences that have only recently come to light.

Using the abbreviated injury severity and Glasgow Coma Scale scores to predict 2-week mortality after traumatic brain injury.

BACKGROUND: Prediction of outcome after traumatic brain injury (TBI) remains elusive. We tested the use of a single hospital Glasgow Coma Scale (GCS) Score, GCS Motor Score, and the Head component of the Abbreviated Injury Scale (AIS) Score to predict 2-week cumulative mortality in a large cohort of TBI patients admitted to the eight U.S. Level I trauma centers in the TBI Clinical Trials Network. METHODS: Data on 2,808 TBI patients were entered into a centralized database. These TBI patients were categorized as severe (GCS score, 3-8), moderate (9-12), or complicated mild (13-15 with positive computed tomography findings). Intubation and chemical paralysis were recorded. The cumulative incidence of mortality in the first 2 weeks after head injury was calculated using Kaplan-Meier survival analysis. Cox proportional hazards regression was used to estimate the magnitude of the risk for 2-week mortality. RESULTS: Two-week cumulative mortality was independently predicted by GCS, GCS Motor Score, and Head AIS. GCS Severity Category and GCS Motor Score were stronger predictors of 2-week mortality than Head AIS. There was also an independent effect of age (<60 vs. ≥60) on mortality after controlling for both GCS and Head AIS Scores. CONCLUSIONS: Anatomic and physiologic scales are useful in the prediction of mortality after TBI. We did not demonstrate any added benefit to combining the total GCS or GCS Motor Scores with the Head AIS Score in the short-term prediction of death after TBI.

Computed tomography and outcome in moderate and severe traumatic brain injury: hematoma volume and midline shift revisited.

Intracranial lesion volume and midline shift are powerful outcome predictors in moderate and severe traumatic brain injury (TBI), and therefore they are used in TBI and computed tomography (CT) classification schemes, like the Traumatic Coma Data Bank (TCDB) classification. In this study we aimed to explore the prognostic value of lesion volume and midline shift in moderate and severe TBI as measured from acute cranial CT scans. Also, we wanted to determine interrater reliability for the evaluation of these CT abnormalities. We included all consecutive moderate and severe TBI patients admitted to our hospital who were aged ≥16 years, over an 8-year period, as part of the prospective Radboud University Brain Injury Cohort Study. Six months post-trauma we assessed outcomes using the Glasgow Outcome Scale-Extended (GOS-E). We analyzed 605 patients and found an association of both lesion volume and midline shift with outcome; increases were associated with a higher frequency of patients with an unfavorable outcome or death. A cut-off value, such as that used in the TCDB CT classification (lesion volume 25 mL and midline shift 5 mm), was not found. The average interrater difference in volume measurement was 6.8 mL, and it was 0.2 mm for the determination of degree of shift. Using lesion volume and midline shift as continuous variables in prognostic models might be preferable over the use of threshold values, although an association of these variables with outcome in relation to other CT abnormalities was not tested. The data provided here will be useful for stratification of patients enrolled in clinical trials of neuroprotective therapies.

Physiologic and functional outcome correlates of brain tissue hypoxia in traumatic brain injury.

OBJECTIVE: Assess the prevalence of brain tissue hypoxia in patients with severe traumatic brain injuries (TBI), and to characterize the relationship between brain tissue hypoxia and functional outcome. DESIGN: Retrospective review of severe TBI patients. SETTING: Intensive care unit of a level I trauma center. PATIENTS: Twenty-seven patients with severe TBI requiring intracranial pressure (ICP) monitoring. Median age was 22 yrs, and a majority (63%) had traumatic subarachnoid hemorrhage. INTERVENTIONS: Hourly assessments of ICP, brain tissue oxygen, mean arterial pressure, fraction of inspired oxygen (FiO2), partial pressure of arterial carbon dioxide (PaCO2), and hemoglobin concentration (hemoglobin) were recorded. Outcome was assessed 6-9 months postinjury. MEASUREMENTS AND MAIN RESULTS: Mean (SD) ICP and BTpO2 were 13.7 (6.6) cm H2O and 30.8 (13.6) mm Hg. A total of 13.5% (379) of the BTpO2 values recorded were < 20 mm Hg, only 86 of which were associated with ICP > or = 20 cm H2O. This prevalence was comparable with episodes of ICP elevations above 20 cm H2O (14.1%, 397). Hypoxic episodes were more common when cerebral perfusion pressure was below 60 mm Hg (relative risk = 3.0, p < 0.0001). We did not find an association in hypoxic risk and hemoglobin in the range of 7-12 g/dL or PaCO2 in the range of 25-40 mm Hg. Subjects with hourly episodes (epochs) of hypoxia > 20% of the time had poorer scores on outcome measures compared with those with fewer hypoxic epochs. CONCLUSIONS: Hypoxic episodes are common after severe TBI, and most are independent of ICP elevations. Most episodes of hypoxia occur while cerebral perfusion pressure and mean arterial pressure are within the accepted target range. There is no clear association between PaCO2 and hemoglobin with BTpO2. The young age and high prevalence of traumatic subarachnoid hemorrhage in this cohort may limit its generalizability. Increased frequency of hypoxic episodes is associated with poor functional outcome.

Usefulness of the abbreviated injury score and the injury severity score in comparison to the Glasgow Coma Scale in predicting outcome after traumatic brain injury.

BACKGROUND: Assessment of injury severity is important in the management of patients with brain trauma. We aimed to analyze the usefulness of the head abbreviated injury score (AIS), the injury severity score (ISS), and the Glasgow Coma Scale (GCS) as measures of injury severity and predictors of outcome after traumatic brain injury (TBI). METHODS: Data were prospectively collected from 410 patients with TBI. AIS, ISS, and GCS were recorded at admission. Subjects' outcomes after TBI were measured using the Glasgow Outcome Scale (GOS-E) at 12 months postinjury. Uni- and multivariate analyses were performed. RESULTS: Outcome information was obtained from 270 patients (66%). ISS was the best predictor of GOS-E (rs = -0.341, p < 0.001), followed by GCS score (rs = 0.227, p < 0.001), and head AIS (rs = -0.222, p < 0.001). When considered in combination, GCS score and ISS modestly improved the correlation with GOS-E (R = 0.335, p < 0.001). The combination of GCS score and head AIS had a similar effect (R = 0.275, p < 0.001). Correlations were stronger from patients 8). CONCLUSIONS: GCS score, AIS, and ISS are weakly correlated with 12-month outcome. However, anatomic measures modestly outperform GCS as predictors of GOS-E. The combination of GCS and AIS/ISS correlate with outcome better than do any of the three measures alone. Results support the addition of anatomic measures such as AIS and ISS in clinical studies of TBI. Additionally, most of the variance in outcome is not accounted for by currently available measures of injury severity.

Waiting for the patient to "sober up": Effect of alcohol intoxication on glasgow coma scale score of brain injured patients.

BACKGROUND: Between 35% to 50% of traumatic brain injury (TBI) patients are under the influence of alcohol. Alcohol intoxication may limit the ability of the Glasgow Coma Scale (GCS) to accurately assess severity of TBI. We hypothesized that alcohol intoxication significantly depresses GCS scores of TBI patients. METHODS: A 10-year, retrospective analysis of a Level I trauma center registry was undertaken. The study population consisted of all blunt injured TBI patients tested for blood alcohol concentration (BAC, n = 1,075). Patients were divided into two groups; intoxicated (mean BAC 202 +/- 77 mg/dL, n = 504) and nonintoxicated (BAC = 0, n = 571). TBI was classified using ICD-9 codes as concussion alone (ICD-9 850, n = 90) and intracranial injury (ICI, ICD-9 851-854, n = 985). Severity was further classified using the Abbreviated Injury Score (AIS). Mean GCS score was compared between the two groups. Patients who were either intubated or hypotensive upon arrival were analyzed separately to rule out confounding effects on GCS score. Severely intoxicated patients (BAC >250 mg/dL, [mean +/- SD] 309 +/- 54 SD, n = 118) were similarly compared. Finally, multivariate linear regression analysis was undertaken to determine whether BAC level was an independent predictor of GCS score while controlling for confounding factors. RESULTS: Intoxicated and nonintoxicated TBI patients were clinically similar. Alcohol intoxication had little effect on GCS score, with less than a single point difference in all types of TBI, except the most severely injured (AIS 5 injuries, GCS score difference 1.4 points). These results were not altered by endotracheal intubation, systemic hypotension, or severe intoxication. Similarly, BAC was not a significant independent predictor of GCS score in a multivariate model. CONCLUSION: Alcohol intoxication does not result in clinically significant changes in GCS score for patients with blunt TBI. Hence, alterations in GCS score after TBI should not be attributed to alcohol intoxication, as doing so might result in inappropriate delays in monitoring and therapeutic interventions.