Journal of Neurotrauma

Mild traumatic brain injury (mTBI) is the most common form of traumatic brain injury. Post-concussive symptoms typically resolve after a few weeks although up to 20% of people experience these symptoms for >3 months, termed persistent post-concussive symptoms (PPCS). Subtle white matter (WM) microstructural damage is thought to underlie neurological and cognitive deficits experienced post-mTBI. Evidence suggests that diffusion magnetic resonance imaging (dMRI) and blood-based biomarkers could be used as surrogate markers of WM organization. We conducted a scoping review according to PRISMA-ScR guidelines, aiming to collate evidence for the use of dMRI and/or blood-based biomarkers of WM organization, in mTBI and PPCS, and document relationships between WM biomarkers and symptoms. We focused specifically on biomarkers of axonal or myelin integrity post-mTBI. Biomarkers excluded from this review therefore included the following: astroglial, perivascular, endothelial, and inflammatory markers. A literature search performed across four databases, EMBASE, Scopus, Google Scholar, and ProQuest, identified 100 records: 68 analyzed dMRI, 28 assessed blood-based biomarkers, and 4 used both. Blood biomarker studies commonly assessed axonal cytoskeleton proteins (i.e., tau); dMRI studies assessed measures of WM organization (i.e., fractional anisotropy). Significant biomarker alterations were frequently associated with heightened symptom burden and prolonged recovery time post-injury. These data suggest that dMRI and blood-based biomarkers may be useful proxies of WM organization, although few studies assessed these complementary measures in parallel, and the relationship between modalities remains unclear. Further studies are warranted to assess the benefit of a combined biomarker approach in evaluating alterations to WM organization after mTBI.

Human neural stem cells (hNSCs) possess significant therapeutic potential for the treatment of traumatic brain injury (TBI), a leading cause of global death and disability. Recent pre-clinical studies have shown that hNSCs reduce tissue damage and promote functional recovery through neuroprotective and regenerative signaling and cell replacement. Yet the overall efficacy of hNSCs for TBI indications remains unclear. Therefore, this systematic review aims to evaluate hNSC interventions compared with controls in pre-clinical TBI models. Through this process, variations in hNSC administration protocols were consolidated, and key knowledge gaps were identified. Meta-analysis was applied to primary outcomes of lesion volume, Morris Water Maze (MWM) performance, modified Neurological Severity Scores (mNSS), and the rotarod task. Narrative review of secondary outcomes included hNSC survival and differentiation, endogenous neuron survival, axonal injury, and inflammation. Overall, hNSC intervention reduced lesion volume, enhanced MWM performance, and led to trending decreases in acute and chronic neurological deficits at acute and chronic time points. These results suggest hNSCs demonstrate clear efficacy in pre-clinical TBI models. However, further studies are needed to address key questions regarding optimal hNSC administration (e.g., dosing, treatment window) and underlying mechanisms of action prior to progressing to human clinical trials.

To introduce the UChicago PBI Imaging score, a novel characterization of imaging features using head computed tomography (HCT) in patients with gunshot wounds to the head (GSWH) resulting in penetrating brain injury (PBI) and to quantify the association with mortality. We retrospectively collected and analyzed data from 230 patients with GSWH admitted to our Level 1 trauma center between May 1, 2018, and October 31, 2023. HCT images obtained on hospital arrival were evaluated for predefined imaging features by two blinded readers and arbitrated, when needed, by a third. The average contribution of each radiological feature to mortality at hospital discharge was assessed using a SuperLearner ensemble model trained on ∼77% of the cohort. Each feature’s contribution was scaled to ensure the additive final score per patient ranged between 0 and 100. The HCT features predicting in-hospital mortality, ranked from highest to lowest importance, were transhemispheric projectile below the level of the third ventricle (18 [16.8, 19.9]), presence of blood in the lateral ventricles (ventricles casted) (18[16.8, 19.6]), brainstem involvement (14 [12.7, 15.1]), transhemispheric projectile above the level of the third ventricle (11 [9.7, 11.6]), presence of any amount of blood in the ambient cistern (9[8.2, 10]), presence of any amount of blood in the lateral ventricles (9 [7.9, 9.8]), cerebellar involvement (9 [7.9, 9.5]), any evidence of ventricular effacement (4 [3.4, 4.6]), midline shift (MLS) >0 mm (4 [3.4, 4.4]), perforating injury (3 [2.4, 3.2]), and presence of an intracerebral hematoma (ICH) >20 mm in the largest diameter (2 [1.4, 1.9]). The UChicago PBI Imaging score showed a strong performance, achieving an area under the curve (AUC) of 0.86 (95% CI: [0.77, 0.96]) on a test set of 56 patients who were not included in model training. This indicates better prediction accuracy compared to both the Rotterdam score (AUC 0.8, 95% CI: [0.68, 0.96]) and the Marshall score (AUC 0.66, 95% CI: [0.52, 0.81]). Our model performed particularly well for patients with a Glasgow Coma Scale (GCS) score between 5 and 9. In this range, our model’s performance (AUC 0.86) remained stable, while the Rotterdam and Marshall Scores showed notably lower predictive accuracy, with AUCs of 0.61 and 0.52, respectively. A dedicated evaluation of GSWH HCT reveals an association between disease burden, as quantified by unique features not native to blunt TBI imaging models, and mortality. Specifically, transhemispheric injury below the level of the third ventricle along with blood-casting bilateral ventricles and brainstem involvement was highly associated with mortality. The model is optimized for intermediate GCS scores where greater prognostic uncertainty exists. This study parallels efforts to refine TBI classification, underscoring the necessity for precise imaging-based classification in PBI to identify imaging biomarkers and ultimately enhance prognostication and targeted treatment.

This study compared the roles of extraparenchymal autonomic nervous system (ANS) control of cerebral blood flow (CBF) versus intraparenchymal cerebrovascular autoregulation in 487 patients with aneurysmal subarachnoid hemorrhage (SAH) and 413 patients with traumatic brain injury (TBI). Vasomotion intensity of extraparenchymal and intraparenchymal vessels were quantified as the amplitude of oscillations of arterial blood pressure (ABP) and intracranial pressure (ICP) in the very low frequency range of 0.02–0.07 Hz, or periods of 55–15 sec, computed with a bandpass filter. A version of the pressure reactivity index (PRx-55-15) was computed as the correlation of the filtered waveforms, ABP-55-15 and ICP-55-15. Since ABP-55-15 is measured in the radial artery, any influence of cerebral factors must be mediated by the ANS. ICP-55-15 is measured in the brain and is influenced by intraparenchymal chemical and metabolic factors in addition to the ANS. Patient outcome was assessed using the Extended Glasgow Outcome Score (GOSe). Ten-day mean cerebral perfusion pressure (CPP) was negatively correlated with GOSe in the TBI cohort (R = −0.13, p = 0.01) but positively correlated with GOSe in the SAH cohort, (R = 0.32, p < 0.00001), indicating a much greater dependence on ANS support in the form of elevated CPP in SAH. The optimal CPP range for TBI was 60–70 mmHg, but for SAH it was 110–120 mmHg. The percentage of monitoring time with PRx-55-15 < 0.8, indicating very pressure-active cerebral vessels that resist ANS influence via systemic ABP, is positively correlated with GOSe in the TBI cohort (R = 0.14, p = 0.003), but negatively correlated with GOSe in the SAH cohort (R = −0.10, p = 0.004). The TBI cohort optimal PRx-55-15 for patient outcome was −1.0, while the SAH optimum was 0.3. For the TBI cohort, the correlation of ABP-55-15 amplitude with 10-day mean ICP-55-15 amplitude was 0.29. For the SAH cohort the correlation was 0.51, which is stronger (p = 0.0001). The TBI cohort had a median GOSe of 5 (interquartile range [IQR] 3–7), while SAH had a median of 3 (IQR 3–5), which is worse (p < 0.00001). The higher optimal CPP in patients with SAH, more passive optimal pressure reactivity, and greater dependence of cerebral on systemic vasomotion indicate that they require more active support by the ANS and systemic circulation for CBF than patients with TBI. CBF in patients with TBI is more reliant on cerebrovascular autoregulation based on metabolic demand. This appears to be deficient following SAH, making the heightened ANS support necessary. Although this support is beneficial, it does not fully compensate for the loss of cerebrovascular autoregulation, as reflected in the problems in the SAH cohort with delayed cerebral ischemia and poor outcome.

Psychopathology, including depression, anxiety, and post-traumatic stress, is a significant yet inadequately addressed feature of moderate-severe traumatic brain injury (TBI). Progress in understanding and treating post-TBI psychopathology may be hindered by limitations associated with conventional diagnostic approaches, specifically the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). The Hierarchical Taxonomy of Psychopathology (HiTOP) offers a promising, transdiagnostic alternative to psychiatric classification that may more effectively capture the experiences of individuals with TBI. However, HiTOP lacks validation in the TBI population. To address this gap, we administered a comprehensive questionnaire battery, including 56 scales assessing homogeneous symptom components and maladaptive traits within HiTOP, to 410 individuals with moderate-severe TBI. We evaluated the reliability and unidimensionality of each scale and revised those with psychometric problems. Using a top-down, exploratory latent variable approach (bass-ackwards modeling), we subsequently constructed a hierarchical model of psychopathological dimensions tailored to TBI. The results showed that, relative to norms, participants with moderate-severe TBI experienced greater problems in the established HiTOP internalizing and detachment spectra, but fewer problems with thought disorder and antagonism. Fourteen of the 56 scales demonstrated psychometric problems, which often appeared reflective of the TBI experience and associated disability. The Hierarchical Taxonomy of Psychopathology Following Traumatic Brain Injury (HiTOP-TBI) model encompassed broad internalizing and externalizing spectra, splitting into seven narrower dimensions: Detachment, Dysregulated Negative Emotionality, Somatic Symptoms, Compensatory and Phobic Reactions, Self-Harm and Psychoticism, Rigid Constraint, and Harmful Substance Use. This study presents the most comprehensive empirical classification of psychopathology after TBI to date. It introduces a novel, TBI-specific transdiagnostic questionnaire battery and model, which addresses the limitations of conventional DSM and ICD diagnoses. The empirical structure of psychopathology after TBI largely aligned with the established HiTOP model (e.g., a detachment spectrum). However, these constructs need to be interpreted in relation to the unique experiences associated with TBI (e.g., considering the injury’s impact on the person’s social functioning). By overcoming the limitations of conventional diagnostic approaches, the HiTOP-TBI model has the potential to accelerate our understanding of the causes, correlates, consequences, and treatment of psychopathology after TBI.

Protective factors, including psychological resilience, cognitive reserve, and brain reserve, may be positively associated with recovery after pediatric mild traumatic brain injury (mTBI) but are yet to be studied concurrently. We sought to examine these factors as moderators of post-concussive symptoms (PCS) in pediatric mTBI compared with mild orthopedic injury (OI). Participants included 967 children (633 mTBI, 334 OI) aged 8–16.99 years, recruited from 5 Canadian pediatric emergency departments as part of a prospective longitudinal cohort study. At 10 days post-injury, psychological resilience was measured using the Connor–Davidson Resilience Scale and brain reserve was measured using total brain volume derived from structural magnetic resonance imaging. Cognitive reserve was measured at 3 months post-injury using IQ scores from the Wechsler Abbreviated Scale of Intelligence-Second Edition. Cognitive and somatic PCS were measured using child and parent ratings on the Health and Behavior Inventory, completed weekly for 3 months and biweekly to 6 months. Analyses involved generalized least-squares regression models using restricted cubic splines. Covariates included age at injury, sex, racialized identity, material and social deprivation, pre-injury migraine and concussion history, and retrospective pre-injury PCS. Psychological resilience moderated group differences in parent-reported PCS. At 30 days post-injury, estimated group differences in parent-reported cognitive and somatic PCS (mTBI > OI) were larger at higher (75th percentile) resilience scores (Est = 2.25 [0.87, 3.64] and Est = 2.38 [1.76, 3.00], respectively) than at lower (25th percentile) resilience scores (Est = 1.44 [0.01, 2.86] and Est = 2.08 [1.45, 2.71], respectively). Resilience did not moderate group differences in child-reported PCS but was negatively associated with child-reported PCS in both groups (ps ≤ 0.001). Brain reserve (i.e., total brain volume [TBV]) also moderated group differences, but only for parent-reported somatic PCS (p = 0.018). Group difference (mTBI > OI) at 30 days was larger at smaller (25th percentile) TBV (Est = 2.78 [2.17, 3.38]) than at larger (75th percentile) TBV (Est = 1.95 [1.31, 2.59]). TBV was not associated with parent-reported cognitive PCS or child-reported PCS. IQ did not moderate PCS in either group but had a significant non-linear association in both groups with child-reported somatic PCS (p = 0.018) and parent-reported PCS (p < 0.001), with higher PCS scores at both lower and higher IQs. These findings suggest that higher resilience predicts fewer PCS, but less strongly after mTBI than OI; greater brain reserve may reduce the effect of mTBI on somatic PCS; and cognitive reserve has an unexpected curvilinear association with PCS across injury types. The results highlight the importance of protective factors as predictors of recovery and potential targets for intervention following pediatric mTBI.

Few studies have examined long-term mortality following traumatic brain injury (TBI) in a military population. This is a secondary analysis of a prospective, longitudinal study that examines long-term mortality (up to 10 years) post-TBI, including analyses of life expectancy, causes of death, and risk factors for death in service members and veterans (SM/V) who survived the acute TBI and inpatient rehabilitation. Among 922 participants in the study, the mortality rate was 8.3% following discharge from inpatient rehabilitation. The mean age of death was 54.5 years, with death occurring on average 3.2 years after injury, and with an average 7-year life expectancy reduction. SM/V with TBI were nearly four times more likely to die compared with the U.S. general population. Leading causes of death were external causes of injury, circulatory disease, and respiratory disorders. Also notable were deaths due to late effects of TBI itself and suicide. Falls were a significant mechanism of injury for those who died. Those who died were also more likely to be older at injury, unemployed, non-active duty status, not currently married, and had longer post-traumatic amnesia, longer rehabilitation stays, worse independence and disability scores at rehabilitation discharge, and a history of mental health issues before injury. These findings indicate that higher disability and less social supportive infrastructure are associated with higher mortality. Our investigation into the vulnerabilities underlying premature mortality and into the major causes of death may help target future prevention, surveillance, and monitoring interventions.