Journal of Neurotrauma

Diffusion tensor imaging (DTI) of brain white matter (WM) may be useful for characterizing the nature and degree of brain injury after sport-related concussion (SRC) and assist in establishing objective diagnostic and prognostic biomarkers. This study aimed to conduct a systematic review using an a priori quality rating strategy to determine the most consistent DTI-WM changes post-SRC. Articles published in English (until June 2020) were retrieved by standard research engine and gray literature searches (N = 4932), using PRISMA guidelines. Eligible studies were non-interventional naturalistic original studies that conducted DTI within 6 months of SRC in current athletes from all levels of play, types of sports, and sex. A total of 29 articles were included in the review, and after quality appraisal by two raters, data from 10 studies were extracted after being identified as high quality. High-quality studies showed widespread moderate-to-large WM differences when SRC samples were compared to controls during the acute to early chronic stage (days to weeks) post-SRC, including both increased and decreased fractional anisotropy and axial diffusivity and decreased mean diffusivity and radial diffusivity. WM differences remained stable in the chronic stage (2–6 months post-SRC). DTI metrics were commonly associated with SRC symptom severity, although standardized SRC diagnostics would improve future research. This indicates that microstructural recovery is often incomplete at return to play and may lag behind clinically assessed recovery measures. Future work should explore interindividual trajectories to improve understanding of the heterogeneous and dynamic WM patterns post-SRC.

Agitation is a common behavioral problem following traumatic brain injury (TBI); however, the precise proportion of patients who experience agitation in the early stages of recovery is unknown. The aim of this systematic review and meta-analysis was to evaluate the prevalence of agitation in TBI patients undergoing inpatient care, and whether this prevalence differed by post-traumatic amnesia (PTA) status and setting (acute and rehabilitation). We also aimed to describe the prevalence of sub-types of agitated behavior (disinhibited, aggressive, and emotionally labile). We searched five databases and one clinical trials register, with additional review of websites and key journals to identify any relevant records up to July 2020. We included studies describing the proportion of hospitalized TBI patients age 16 years or older demonstrating agitated behavior. We included comparative studies with and without concurrent controls, randomized controlled trials, pseudo-randomized controlled trials, and case series. Methodological quality was critically appraised using a Joanna Briggs Institute checklist. Sixteen studies met eligibility criteria, with a total of 5592 participants. The pooled prevalence of agitation was 31.73% (95% confidence interval [CI], 25.25%-39.00%) during inpatient care (acute and rehabilitation), 32.23% (95% CI, 27.13%-37.80%) during rehabilitative care and 44.06% (95% CI, 36.15%-52.28%) for inpatients in PTA specifically. Disinhibited behaviors were the most common. There was substantial heterogeneity between studies. Additional high-quality research featuring large samples, frequent and long-term measurement of agitation, use of validated scales, and consideration of variables such as PTA status will further improve estimates of agitation prevalence following TBI.

Traumatic acute subdural hematoma (aSDH) is associated with a high mortality rate caused by post-operative cerebral infarction. Recently, brain natriuretic peptide (BNP) was considered a reliable biomarker in the acute phase of traumatic brain injuries. We therefore aimed in this study to analyze BNP levels on admission, identify the predictors of their elevation, and assess the relationship between BNP and the risk of post-operative cerebral infarction. Patients with isolated, unilateral, traumatic aSDH who were admitted to our department between July 2017 and May 2020 were enrolled in this study. On admission, cranial computer tomography (CCT) and BNP sampling were simultaneously performed. Additionally, the time between head trauma and BNP sampling (TTS) was assessed. Admission radiographic variables included hematoma volumes, midline shift, and degree of brain edema. Cerebral infarction was detected on postoperative CCT. In total, 130 patients were included in this study. Surgical treatment was performed in 82.3% (n = 107) of cases. The multiple regression analysis showed that larger hematoma volumes (p = 0.032) and advanced age (p = 0.005) were independent predictors of elevated BNP when TTS <24 h. The binomial logistical regression analysis identified BNP with a cutoff value of <29.4 pg/mL (TTS = 3–12 h, adjusted odds ratio [aOR] = 16.5, p = 0.023) as an independent predictor of post-operative cerebral infarction. Elevated BNP levels in the first 24 h post-trauma were related to larger hematoma volumes and advanced age. Further, an increased risk of post-operative cerebral infarction was identified in patients with lower BNP levels in the post-traumatic period 3–12 h.

Biomarkers play an increasing role in medicinal biology. They are used for diagnosis, management, drug target identification, drug responses, and disease prognosis. We have discovered that calpain-1 and calpain-2 play opposite functions in neurodegeneration, with calpain-1 activation being neuroprotective, while prolonged calpain-2 activation is neurodegenerative. This notion has been validated in several mouse models of acute neuronal injury, in particular in mouse models of traumatic brain injury (TBI) and repeated concussions. We have identified a selective substrate of calpain-2, the tyrosine phosphatase, PTPN13, which is cleaved in brain after TBI. One of the fragments generated by calpain-2, referred to as P13BP, is also found in the blood after TBI both in mice and humans. In humans, P13BP blood levels are significantly correlated with the severity of TBI, as measured by Glasgow Coma Scale scores and loss of consciousness. The results indicate that P13BP represents a novel blood biomarker for TBI.

Post-traumatic stress disorder (PTSD) is a common condition in post-deployment service members (SM). SMs of the conflicts in Iraq and Afghanistan also frequently experience traumatic brain injury (TBI) and exposure to blasts during deployments. This study evaluated the effect of these conditions and experiences on functional brain connectomes in post-deployment, combat-exposed veterans. Functional brain connectomes were created using 5-min resting-state magnetoencephalography data. Well-established clinical interviews determined current PTSD diagnosis, as well as deployment-acquired mild TBI and history of exposure to blast. Linear regression examined the effect of these conditions on functional brain connectomes beyond covariates. There were significant interactions between blast-related mild TBI and PTSD after correction for multiple comparisons including number of nodes (non-standardized parameter estimate [PE] = -12.47), average degree (PE = 0.05), and connection strength (PE = 0.05). A main effect of blast-related mild TBI was observed on the threshold level. These results demonstrate a distinct functional connectome presentation associated with the presence of both blast-related mild TBI and PTSD. These findings suggest the possibility that blast-related mild TBI alterations in functional brain connectomes affect the presentation or progression of recovery from PTSD. The current results offer mixed support for hyper-connectivity in the chronic phase of deployment TBI.

Concussion is a major health concern, making it critical to identify factors that influence risk and resilience. The salience network (SN) likely plays a key role in concussion risk, given its roles in orienting attention, functional adaptability, and interoceptive awareness. The SN's functions are thought to be mediated through causal control of other networks, including the default mode network (DMN) and executive control network (ECN). It was therefore hypothesized that the SN of at-risk individuals would have altered functional and structural connectivity with the DMN and ECN. For this prospective study, 167 university athletes had baseline clinical assessments and magnetic resonance imaging scans and were monitored for the rest of their varsity career, with any concussions recorded. Athletes concussed in the same season as imaging (CSS; n = 17) and those concussed in later seasons (CLS; n = 15) were matched to controls that were not concussed after imaging. Functional connectivity and white matter fractional anisotropy (FA) were compared between concussed and control groups. Prior to injury, CSS athletes had significantly elevated total symptom severity scores, elevated SN-DMN functional connectivity and reduced FA of connecting white matter tracts, whereas CLS athletes showed no significant clinical or imaging effects. These findings provide new insights into the neurobiology of concussion risk and resilience, as indices of SN-DMN network connectivity are associated with short-term but not long-term concussion risk.

Magnetic resonance imaging (MRI) is used rarely in the acute evaluation of traumatic brain injury (TBI) but may identify findings of clinical importance not detected by computed tomography (CT). We aimed to characterize the association of cytotoxic edema and hemorrhage, including traumatic microbleeds, on MRI obtained within hours of acute head trauma and investigated the relationship to clinical outcomes. Patients prospectively enrolled in the Traumatic Head Injury Neuroimaging Classification study (NCT01132937) with evidence of diffusion-related findings or hemorrhage on neuroimaging were included. Blinded interpretation of MRI for diffusion-weighted lesions and hemorrhage was conducted, with subsequent quantification of apparent diffusion coefficient (ADC) values. Of 161 who met criteria, 82 patients had conspicuous hyperintense lesions on diffusion-weighted imaging (DWI) with corresponding regions of hypointense ADC in proximity to hemorrhage. Median time from injury to MRI was 21 (10–30) h. Median ADC values per patient grouped by time from injury to MRI were lowest within 24 h after injury. The ADC values associated with hemorrhagic lesions are lowest early after injury, with an increase in diffusion during the subacute period, suggesting transformation from cytotoxic to vasogenic edema during the subacute post-injury period. Of 118 patients with outcome data, 60 had Glasgow Outcome Scale Extended scores ≤6 at 30/90 days post-injury. Cytotoxic edema on MRI (odds ratio [OR] 2.91 [1.32–6.37], p = 0.008) and TBI severity (OR 2.51 [1.32–4.74], p = 0.005) were independent predictors of outcome. These findings suggest that in patients with TBI who had findings of hemorrhage on CT, patients with DWI/ADC lesions on MRI are more likely to do worse.

Research suggests coaches play a central role in establishing a context conducive to concussion reporting, particularly via direct verbal communication about concussion. Informed by qualitative interviews and stakeholder feedback, we developed a web-based concussion education platform for collegiate coaches (GoHuddle). The goal of GoHuddle is to encourage concussion safety-supportive coach communication using behavioral modeling and experiential learning. We then conducted a pre-post survey study to examine the impact of engaging with the platform on coach concussion communication, with outcomes of: (a) expected likelihood of communicating with athletes about concussive symptom reporting; (b) expected likelihood of pressuring medical staff to return athletes to play; and (c) belief in the usefulness of engaging in the communication described in a and b (i.e., response efficacy). We also assessed feasibility and acceptability of the platform in the collegiate sport context. The platform was sent to 435 coaches at five institutions, and 334 (77%) completed surveys (70% male, 37.8 years mean age). After completing GoHuddle, coaches had 2.5 greater odds of expecting to discuss concussion with their team (odds ratio [OR] 2.53, p < 0.001). Response efficacy for talking about concussion also increased significantly post-intervention (OR 3.78, p < 0.001). No significant change was seen in expectancies regarding pressure on medical staff to return athletes to play “as soon as possible.” A high proportion (82%) of coaches would recommend this platform for coach concussion education. In conclusion, this study suggests GoHuddle is a feasible and acceptable approach to coach concussion education, and use of this platform holds promise for shifting coach communication about concussion.

Common methods for evaluating history of traumatic brain injury (TBI) include self-report, electronic medical record review (EMR), and structured interviews such as the Head Trauma Events Characteristics (HTEC). Each has strengths and weaknesses, but little is known regarding how TBI diagnostic rates or the associated symptom profile differ among them. This study examined 200 Veterans recruited within the VA Portland Health Care System, each evaluated for TBI using self-report, EMR, and HTEC. Participants also completed validated questionnaires assessing chronic symptom severity in broad health-related domains (pain, sleep, quality of life, post-concussive symptoms). The HTEC was more sensitive (80% of participants in our cohort) than either self-report or EMR alone (40%). As expected from the high sensitivity, participants screening positive for TBI through the HTEC included many people with mild or no post-concussive symptoms. Participants were grouped according to degree of concordance across these diagnostic methods: no TBI, n = 43; or TBI-positive in any one method (TBI-1dx, n = 53), positive in any two (TBI-2dx, n = 45), or positive in all three (TBI-3dx, n = 59). The symptom profile of the TBI-1dx group was indistinguishable from the no TBI group. The TBI-3dx group had the most severe symptom profile. Our results show that understanding the exact methods used to ascertain TBI is essential when interpreting results from other studies, given that results and conclusions may differ dramatically depending on the method. This issue will become even more critical when interpreting data merged from multiple sources within newer, centralized repositories (e.g., Federal Interagency Traumatic Brain Injury Research [FITBIR]).

Although post-traumatic stress disorder (PTSD) has been associated with worse cognitive outcomes after mild traumatic brain injury (TBI), its impact has not been evaluated after more severe TBI. This study aimed to determine whether PTSD symptoms are related to cognition after complicated mild, moderate, severe, and penetrating TBI. Service members (n = 137) with a history of complicated mild/moderate TBI (n = 64) or severe/penetrating TBI (n = 73) were prospectively enrolled from United States Military Treatment Facilities. Participants completed a neuropsychological assessment one year or more post-injury. Six neuropsychological composite scores and an overall test battery mean (OTBM) were considered. Participants were excluded if there was evidence of invalid responding. Hierarchical linear regressions were conducted evaluating neuropsychological performance. The interaction between TBI severity and PTSD Checklist-Civilian version total score was significant for processing speed (β = 0.208, p = 0.034) and delayed memory (β = 0.239, p = 0.021) and trended toward significance for immediate memory (β = 0.190, p = 0.057) and the OTBM (β = 0.181, p = 0.063). For each of these composite scores, the relationship between PTSD symptoms and cognition was stronger in the complicated mild/moderate TBI group than the severe/penetrating TBI group. Within the severe/penetrating TBI group, PTSD symptoms were unrelated to cognitive performance. In contrast, within the complicated mild/moderate TBI group, PTSD symptoms were significantly related to processing speed (R²Δ = 0.077, β = -0.280, p = 0.019), immediate memory (R²Δ = 0.197, β = -0.448, p < 0.001), delayed memory (R²Δ = 0.176, β = -0.423, p < 0.001), executive functioning (R²Δ = 0.100, β = -0.317, p = 0.008), and the OTBM (R²Δ = 0.162, β = -0.405, p < 0.001). The potential impact of PTSD symptoms on cognition, over and above the impact of brain injury alone, should be considered with service members and veterans with a history of complicated mild/moderate TBI. In addition, in research comparing cognitive outcomes between patients with histories of complicated-mild, moderate, severe, and/or penetrating TBI, it will be important to account for PTSD symptoms.

Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members. A TBI is a risk factor for the later development of neurodegenerative diseases, including Alzheimer disease (AD)-like disorders. Studies of acute TBI in humans and animals have suggested that increased processing of the amyloid precursor protein (APP) toward the amyloid beta protein (Aβ) may explain the epidemiological associations with AD. In a previous study, however, we found in both rat and mouse models of blast overpressure exposure that rather than increasing, rodent brain Aβ42 levels were decreased after acute blast exposure. Here we subjected APP/presenilin 1 transgenic mice (APP/PS1 Tg) to an extended sequence of repetitive low-level blast exposures (34.5 kPa) administered three times per week over eight weeks. If initiated at 20 weeks of age, these repetitive exposures, which were designed to mimic human subclinical blast exposures, reduced anxiety and improved cognition as well as social interactions in APP/PS1 Tg mice, returning many behavioral parameters in APP/PS1 Tg mice to levels of non-transgenic wild type mice. Repetitive low-level blast exposure was less effective at improving behavioral deficits in APP/PS1 Tg mice when begun at 36 weeks of age. While amyloid plaque loads were unchanged, Aβ 42 levels and Aβ oligomers were reduced in the brain of mice exposed to repetitive low-level blast exposures initiated at 20 weeks of age, although levels did not directly correlate with behavioral parameters in individual animals. These results have implications for understanding the nature of blast effects on the brain and their relationship to human neurodegenerative diseases.

Post-traumatic epilepsy (PTE) is acquired epilepsy after traumatic brain injury (TBI). Despite the availability of more than 20 antiseizure medications (ASMs), there is no way at present to prevent epileptogenesis in TBI survivors, and many cases of PTE become drug-resistant. Importantly, the adverse effects of ASMs can significantly affect patients' quality of life. Mammalian models are commonly used for studying refractory PTE, but are expensive and laborious. Zebrafish models have become popular for studying epilepsy, but most focus on larvae, and there have been no reports to date of pharmacological screening in an adult zebrafish model of acquired epilepsy. Valid animal models are critical for understanding PTE and for developing novel therapeutics. The aim of the present study was to characterize the cognitive impairments of a zebrafish model of TBI that leads to the development of PTE. Using combined behavioral and electrophysiological approaches, we also characterized the pharmacological effects of the most commonly used ASMs to manage PTE (valproate, carbamazepine, and phenytoin). Zebrafish with PTE exhibited impairments in learning and memory, difficulty in decision making, and reduced social preference. Valproate and carbamazepine had a limited protective effect against behavioral seizures, and all three drugs failed to significantly reduce electrographical seizures. The negative impacts of TBI and ASMs in zebrafish parallel those observed in other animals, making the zebrafish model of PTE a promising high-throughput model of refractory and drug-resistant epilepsy.