Journal of Neurotrauma

Traumatic intracranial hypertension (tIH) is a common and potentially lethal complication of moderate to severe traumatic brain injury (m-sTBI). It often develops with little warning and is managed reactively with the tiered application of intracranial pressure (ICP)-lowering interventions administered in response to an ICP rising above a set threshold. For over 45 years, a variety of research groups have worked toward the development of technology to allow for the preemptive management of tIH in the hope of improving patient outcomes. In 2022, the first operationalizable tIH prediction system became a reality. With such a system, ICP lowering interventions could be administered prior to the rise in ICP, thus protecting the patient from potentially damaging tIH episodes and limiting the overall ICP burden experienced. In this review, we discuss related approaches to ICP forecasting and IH prediction algorithms, which collectively provide the foundation for the successful development of an operational tIH prediction system. We also discuss operationalization and the statistical assessment of tIH algorithms. This review will be of relevance to clinicians and researchers interested in development of this technology as well as those with a general interest in the bedside application of machine learning (ML) technology.

Traumatic brain injury (TBI) has been associated with several lasting impairments that affect quality of life. Pre-clinical models of TBI have been studied to further our understanding of the underlying short-term and long-term symptomatology. Neuromodulation techniques have become of great interest in recent years as potential rehabilitative therapies after injury because of their capacity to alter neuronal activity and neural circuits in targeted brain regions. This systematic review aims to provide an overlook of the behavioral and neurochemical effects of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) in pre-clinical TBI models. After screening 629 abstracts, 30 articles were pooled for review. These studies showed that tDCS, TMS, DBS, or VNS delivered to rodents restored TBI-induced deficits in coordination, balance, locomotor activity and improved cognitive impairments in memory, learning, and impulsivity. Potential mechanisms for these effects included neuroprotection, a decrease in apoptosis, neuroplasticity, and the restoration of neural circuit abnormalities. The translational value, potential applicability, and the interpretation of these findings in light of outcome data from clinical trials in patients with TBI are discussed.

Fatigue may be among the most profound and debilitating consequences of pediatric traumatic brain injury (TBI); however, neurostructural risk factors associated with post-injury fatigue remain elusive. This prospective study aimed to evaluate the independent value of susceptibility-weighted imaging (SWI) biomarkers, over-and-above known risk factors, to predict fatigue symptom severity in children with TBI.

Forty-two children were examined with structural magnetic resonance imaging (sMRI), including a SWI sequence, within eight weeks post-injury. The PedsQL Multi-Dimensional Fatigue Scale (MFS) was administered 24 months post-injury. Compared with population expectations, the TBI group displayed significantly higher levels of general fatigue (Cohen d = 0.44), cognitive fatigue (Cohen d = 0.59), sleep/rest fatigue (Cohen d = 0.37), and total fatigue (Cohen d = 0.63). In multi-variate models adjusted for TBI severity, child demographic factors, and depression, we found that subacute volume of SWI lesions was independently associated with all fatigue symptom domains. The magnitude of the brain-behavior relationship varied by fatigue symptom domain, such that the strongest relationships were observed for the cognitive fatigue and total fatigue symptom scales. Overall, we found that total subacute volume of SWI lesions explained up to 24% additional variance in multi-dimensional fatigue, over-and-above known risk factors. The subacute SWI has potential to improve prediction of post-injury fatigue in children with TBI. Our preliminary findings suggest that volume of SWI lesions may represent a novel, independent biomarker of post-injury fatigue, which could help to identify high-risk children who are likely to benefit from targeted psychoeducation and/or preventive strategies to minimize risk of long-term post-injury fatigue.

Despite enormous research interest in diffusion tensor imaging and diffusion kurtosis imaging (DTI; DKI) following mild traumatic brain injury (MTBI), it remains unknown how diffusion in white matter evolves post-injury and relates to acute MTBI characteristics. This prospective cohort study aimed to characterize diffusion changes in white matter the first year after MTBI. Patients with MTBI (n = 193) and matched controls (n = 83) underwent 3T magnetic resonance imaging (MRI) within 72 h and 3- and 12-months post-injury. Diffusion data were analyzed in three steps: 1) voxel-wise comparisons between the MTBI and control group were performed with tract-based spatial statistics at each time-point; 2) clusters of significant voxels identified in step 1 above were evaluated longitudinally with mixed-effect models; 3) the MTBI group was divided into: (A) complicated (with macrostructural findings on MRI) and uncomplicated MTBI; (B) long (1-24 h) and short (< 1 h) post-traumatic amnesia (PTA); and (C) other and no other concurrent injuries to investigate if findings in step 1 were driven mainly by aberrant diffusion in patients with a more severe injury. At 72 h, voxel-wise comparisons revealed significantly lower fractional anisotropy (FA) in one tract and significantly lower mean kurtosis (Kmean) in 11 tracts in the MTBI compared with control group. At 3 months, the MTBI group had significantly higher mean diffusivity in eight tracts compared with controls. At 12 months, FA was significantly lower in four tracts and Kmean in 10 tracts in patients with MTBI compared with controls. There was considerable overlap in affected tracts across time, including the corpus callosum, corona radiata, internal and external capsule, and cerebellar peduncles. Longitudinal analyses revealed that the diffusion metrics remained relatively stable throughout the first year after MTBI. The significant group*time interactions identified were driven by changes in the control rather than the MTBI group. Further, differences identified in step 1 did not result from greater diffusion abnormalities in patients with complicated MTBI, long PTA, or other concurrent injuries, as standardized mean differences in diffusion metrics between the groups were small (0.07 ± 0.11) and non-significant. However, follow-up voxel-wise analyses revealed that other concurrent injuries had effects on diffusion metrics, but predominantly in other metrics and at other time-points than the effects observed in the MTBI versus control group analysis. In conclusion, patients with MTBI differed from controls in white matter integrity already 72 h after injury. Diffusion metrics remained relatively stable throughout the first year after MTBI and were not driven by deviating diffusion in patients with a more severe MTBI.

Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0–96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24–34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (−3.2% [−9.3 to −2.2] and −1.9% [−4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's ρ = −0.68, p-value = 0.01) and low CMD glucose (ρ = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.

The purpose of this study was to examine the association of serum tau, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L1 (UCHL-1) concentrations evaluated within the first 12 months after a military-related TBI, with longitudinal changes in neurobehavioral functioning extending two or more years post-injury. Participants were 84 United States service members and veterans (SMVs) prospectively enrolled in the Defense and Veterans Brain Injury Center of Excellence/Traumatic Brain Injury Center 15-Year Longitudinal TBI Study, separated into three discreet groups: (a) uncomplicated mild TBI (MTBI; n = 28), (b) complicated mild, moderate, severe, and penetrating TBI combined (STBI; n = 29], and (c) non-injured controls (NIC, n = 27). Participants completed a battery of self-report neurobehavioral symptom measures (e.g., depression, post-traumatic stress disorder [PTSD], post-concussion, anxiety, somatic, cognitive, and neurological symptoms) within 12 months of injury (baseline), and then again at two or more years post-injury (follow-up). At baseline, participants also completed a blood draw to determine serum concentrations of tau, NFL, GFAP, and UCHL-1 using an ultra-sensitivity assay method. In the MTBI and STBI groups (using hierarchical regression analyses), (1) baseline tau concentrations predicted the deterioration of neurobehavioral symptoms from baseline to follow-up on measures of anxiety, PTSD, depression, post-concussion, somatic, and neurological symptoms (accounting for 10–28% of the variance); (2) NFL predicted the deterioration of depression, post-concussion, somatic, cognitive, and neurological symptoms (10–32% variance); (3) GFAP predicted the deterioration of post-concussion, PTSD, depression, anxiety, somatic, neurological, and cognitive symptoms (11–43% variance); and (4) UCHL-1 predicted the deterioration of anxiety, somatic, and neurological symptoms (10–16% variance). In the NIC group, no meaningful associations were found between baseline biomarker concentrations and the deterioration of neurobehavioral symptoms on the majority of measures. This study reports that elevated tau, NFL, GFAP, and UCHL-1 concentrations within the first 12 months of injury are associated with the deterioration of neurobehavioral symptoms that extends to the chronic phase of recovery after a TBI. These findings suggest that a blood-based panel including these biomarkers could be a useful prognostic tool to identifying those individuals at risk of poor future outcome after TBI.

Post-acute care after spinal cord injury (SCI) or traumatic brain injury (TBI) influences neurological function regained. Inpatient rehabilitation facilities (IRFs) have more intensive care and result in lower mortality and better functional outcomes compared with skilled nursing facilities (SNFs). This study sought to quantify inpatient rehabilitation access by insurance and estimate the cost implications. We conducted a retrospective observational cohort study utilizing 2015-2017 California Office of Statewide Health Planning and Development database of injured adults with SCI and/or TBI. The primary predictor was insurance status. The outcome was discharge destination (home, IRFs, SNFs, long-term acute care [LTAC]) modeled using multi-variable multinomial mixed-effects logistic regression controlling for age, diagnosis, Weighted Elixhauser Comorbidity Index, and New Injury Severity Score. Cost of care for discharge to IRFs versus SNFs was estimated by adjusted quantile regression. Cost simulation predicted the adjusted cost difference if all publicly insured participants were discharged to an IRF. We identified 83,230 patients with an injury mechanism and a primary acute care hospitalization diagnosis of TBI (90.9%), SCI (8.3%), or both (0.8%) who were discharged to an IRF, SNF, LTAC, or home. Publicly insured patients were more likely than privately insured patients to go to SNFs versus IRFs (odds ratio [OR]: 2.17, 95% confidence interval [CI 2.01-2.34]). Sub-group analysis of 6416 participants showed an adjusted median total cost difference of $18,461 (95% CI [$5,908-$38,064]) and adjusted cost-per-day of the post-acute encounter of $1,045 (95% CI [$752-$2,399]) higher for discharge to IRFs versus SNFs. Cost simulation demonstrated an additional adjusted cost of $364M annually for universal IRF access for the publicly insured. Publicly insured SCI and TBI Californians are less frequently discharged to IRFs compared with their privately insured counterparts resulting in a lower short-term cost of care. However, the consequences of decreased intensive rehabilitation utilization in terms of functional recovery and long-term cost implications require further investigation.

Traumatic brain injury (TBI) is a major cause of death and disability in the United States, exacting a debilitating physical, social, and financial strain. Therefore, it is crucial to examine the impact of TBI on medically underserved communities in the U.S. The purpose of the current study was to review the literature on TBI for evidence of racial/ethnic differences in the U.S. Results of the review showed significant racial/ethnic disparities in TBI outcome and several notable differences in other TBI variables. American Indian/Alaska Natives have the highest rate and number of TBI-related deaths compared with all other racial/ethnic groups; Blacks/African Americans are significantly more likely to incur a TBI from violence when compared with Non-Hispanic Whites; and minorities are significantly more likely to have worse functional outcome compared with Non-Hispanic Whites, particularly among measures of community integration. We were unable to identify any studies that looked directly at underlying racial/ethnic biological variations associated with different TBI outcomes. In the absence of studies on racial/ethnic differences in TBI pathobiology, taking an indirect approach, we looked for studies examining racial/ethnic differences in oxidative stress and inflammation outside the scope of TBI as they are known to heavily influence TBI pathobiology. The literature indicates that Blacks/African Americans have greater inflammation and oxidative stress compared with Non-Hispanic Whites. We propose that future studies investigate the possibility of racial/ethnic differences in inflammation and oxidative stress within the context of TBI to determine whether there is any relationship or impact on TBI outcome.

Treatment and prevention of elevated intracranial pressure (ICP) is crucial in patients with severe traumatic brain injury (TBI). Elevated ICP is associated with secondary brain injury, and both intensity and duration of an episode of intracranial hypertension, often referred to as “ICP dose,” are associated with worse outcomes. Prediction of such harmful episodes of ICP dose could allow for a more proactive and preventive management of TBI, with potential implications on patients' outcomes. The goal of this study was to develop and validate a machine-learning (ML) model to predict potentially harmful ICP doses in patients with severe TBI. The prediction target was defined based on previous studies and included a broad range of doses of elevated ICP that have been associated with poor long-term neurological outcomes. The ML models were used, with minute-by-minute ICP and mean arterial blood pressure signals as inputs. Harmful ICP episodes were predicted with a 30 min forewarning. Models were developed in a multi-center dataset of 290 adult patients with severe TBI and externally validated on 264 patients from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) dataset. The external validation of the prediction model on the CENTER-TBI dataset demonstrated good discrimination and calibration (area under the curve: 0.94, accuracy: 0.89, precision: 0.87, sensitivity: 0.78, specificity: 0.94, calibration-in-the-large: 0.03, calibration slope: 0.93). The proposed prediction model provides accurate and timely predictions of harmful doses of ICP on the development and external validation dataset. A future interventional study is needed to assess whether early intervention on the basis of ICP dose predictions will result in improved outcomes.

Social participation (SP) is one of many objectives in the rehabilitation of patients with traumatic brain injury (TBI). Studies on predictors of SP specific to post-acute universally accessible specialized rehabilitation pathways following TBI are scarce. Our objectives were to: 1) characterize SP, as well as a set of pre-injury, injury-related, and post-injury variables in individuals participating in inpatient-outpatient or outpatient rehabilitation pathways within a universally accessible and organized trauma continuum of care; and 2) examine the ability of pre-injury, injury-related, and post-injury variables in predicting SP outcome after TBI according to rehabilitation path. Participants (N = 372) were adults admitted to an inpatient-outpatient rehabilitation pathway or an outpatient rehabilitation pathway after sustaining a TBI between 2016 and 2020, and for whom Mayo-Portland Adaptability Intentory-4 (MPAI-4) outcomes were prospectively obtained at the start and end of rehabilitation. Additional data was collected from medical files. For both rehabilitation pathways, predicted SP outcome was MPAI-4 Participation score at discharge from outpatient rehabilitation. Multiple regression models investigated the predictive value of each variable for SP outcome, separately for each care pathway. Main findings show that for the inpatient-outpatient sample, three variables (education years, MPAI-4 Ability and Adjustment scores at rehabilitation intake) significantly predicted SP outcome, with the regression model accounting for 49% of the variance. For the outpatient sample, five variables (pre-morbid hypertension and mental health diagnosis, total indirect rehabilitation hours received, MPAI-4 Abilities and Adjustment scores at rehabilitation intake) significantly predicted SP outcome, with the regression model accounting for 47% of the variance. In conclusion, different pre-morbid and post-injury variables are involved in predicting SP, depending on the rehabilitation path followed. The predictive value of those variables could help clinicians identify patients more likely of showing poorer SP at discharge and who may require additional or different interventions.

National regulations to curb the coronavirus disease 2019 (COVID-19) transmission and health care resource reallocation may have impacted incidence and treatment for neurotrauma, including traumatic brain injury (TBI) and spinal trauma, but these trends have not been characterized in Sub-Saharan Africa. This study analyzes differences in epidemiology, management, and outcomes preceding and during the COVID-19 pandemic for neurotrauma patients in a Rwandan tertiary hospital. The study setting was the Centre Hospitalier Universitaire de Kigali (CHUK), Rwanda's national referral hospital. Adult injury patients presenting to the CHUK Emergency Department (ED) were prospectively enrolled from January 27, 2020 to June 28, 2020. Study personnel collected data on demographics, injury characteristics, serial neurological examinations, treatment, and outcomes. Differences in patients before (January 27, 2020 to March 21, 2020) and during (June 1, 2020 to June 28, 2020) the COVID-19 pandemic were assessed using chi-squared and Mann-Whitney U tests. The study population included 216 patients with neurotrauma (83.8% TBI, 8.3% spine trauma, and 7.9% with both). Mean age was 34.1 years (standard deviation [SD] = 12.5) and 77.8% were male. Patients predominantly experienced injury following a road traffic accident (RTA; 65.7%). Weekly volume for TBI (mean = 16.5 vs. 17.1, p = 0.819) and spine trauma (mean = 2.0 vs. 3.4, p = 0.086) was similar between study periods. During the pandemic, patients had lower Glasgow Coma Scale (GCS) scores (mean = 13.8 vs. 14.3, p = 0.068) and Kampala Trauma Scores (KTS; mean = 14.0 vs. 14.3, p = 0.097) on arrival, denoting higher injury severity, but these differences only approached significance. Patients treated during the pandemic period had higher occurrence of hemorrhage, contusion, or fracture on computed tomography (CT) imaging (47.1% vs. 26.7%, p = 0.003) and neurological decline (18.6% vs. 7.5%, p = 0.016). Hospitalizations also increased significantly during COVID-19 (54.6% vs. 39.9%, p = 0.048). Craniotomy rates doubled during the pandemic period (25.7% vs. 13.7%, p = 0.003), but mortality was unchanged (5.5% vs. 5.7%, p = 0.944). Neurotrauma volume remained unchanged at CHUK during the COVID-19 pandemic, but presenting patients had higher injury acuity and craniotomy rates. These findings may inform care during pandemic conditions in Rwanda and similar settings.

Blast-induced traumatic brain injury (bTBI) has been a health concern in both military and civilian populations due to recent military and geopolitical conflicts. Military service members are frequently exposed to repeated bTBI throughout their training and deployment. Our group has previously reported compounding functional deficits as a result of increased number of blast exposures. In this study, we further characterized the decrease in long-term potentiation (LTP) by varying the blast injury severity and the inter-blast interval between two blast exposures. LTP deficits were attenuated with increasing inter-blast intervals. We also investigated changes in microglial activation; expression of CD68 was increased and expression of CD206 was decreased after multiple blast exposures. Expression of macrophage inflammatory protein (MIP)-1α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1, interferon gamma-inducible protein (IP)-10, and regulated on activation, normal T cell expressed and secreted (RANTES) increased, while expression of IL-10 decreased in the acute period after both single and repeated bTBI. By partially depleting microglia prior to injury, LTP deficits after injury were significantly reduced. Treatment with the novel drug, MW-189, prevented LTP deficits when administered immediately following a repeated bTBI and even when administered only for an acute period (24 h) between two blast injuries. These findings could inform the development of therapeutic strategies to treat the neurological deficits of repeated bTBI suggesting that microglia play a major role in functional neuronal deficits and may be a viable therapeutic target to lessen the neurophysiological deficits after bTBI.

Chronic mental health problems are common among military veterans who sustained blast-related traumatic brain injuries. The reasons for this association remain unexplained. Male rats exposed to repetitive low-level blast overpressure (BOP) exposures exhibit chronic cognitive and post-traumatic stress disorder (PTSD)-related traits that develop in a delayed fashion. We examined blast-induced alterations on the transcriptome in four brain areas (anterior cortex, hippocampus, amygdala, and cerebellum) across the time frame over which the PTSD-related behavioral phenotype develops. When analyzed at 6 weeks or 12 months after blast exposure, relatively few differentially expressed genes (DEGs) were found. However, longitudinal analysis of amygdala, hippocampus, and anterior cortex between 6 weeks and 12 months revealed blast-specific DEG patterns. Six DEGs (hyaluronan and proteoglycan link protein 1 [Hapln1], glutamate metabotropic receptor 2 [Grm2], purinergic receptor P2y12 [P2ry12], C-C chemokine receptor type 5 [Ccr5], phenazine biosynthesis-like protein domain containing 1 [Pbld1], and cadherin related 23 [Cdh23]) were found altered in all three brain regions in blast-exposed animals. Pathway enrichment analysis using all DEGs or those uniquely changed revealed different transcription patterns in blast versus sham. In particular, the amygdala in blast-exposed animals had a unique set of enriched pathways related to stress responses, oxidative phosphorylation, and mitochondrial dysfunction. Upstream analysis implicated tumor necrosis factor (TNF)α signaling in blast-related effects in amygdala and anterior cortex. Eukaryotic initiating factor eIF4E (EIF4e), an upstream regulator of P2ry12 and Ccr5, was predicted to be activated in the amygdala. Quantitative polymerase chain reaction (qPCR) validated longitudinal changes in two TNFα regulated genes (cathepsin B [Ctsb], Hapln1), P2ry12, and Grm2. These studies have implications for understanding how blast injury damages the brain and implicates inflammation as a potential therapeutic target.

Mild traumatic brain injury (mTBI) produces subtle cerebrovascular impairments that persist over time and promote increased ischemic stroke vulnerability. We recently established a role for vascular impairments in exacerbating stroke outcomes 1 week after TBI, but there is a lack of research regarding long-term impacts of mTBI-induced vascular dysfunction, as well as a significant need to understand how mTBI promotes stroke vulnerability in both males and females. Here, we present data using a mild closed head TBI model and an experimental stroke occurring either 7 or 28 days later in both male and female mice. We report that mTBI induces larger stroke volumes 7 days after injury, however, this increased vulnerability to stroke persists out to 28 days in female but not male mice. Importantly, mTBI-induced changes in blood–brain barrier permeability, intravascular coagulation, angiogenic factors, total vascular area, and glial expression were differentially altered across time and by sex. Taken together, these data suggest that mTBI can result in persistent cerebrovascular dysfunction and increased susceptibility to worsened ischemic outcomes, although these dysfunctions occur differently in male and female mice.