Journal of Neurotrauma

Traumatic brain injury (TBI) is one of the leading causes of disability and mortality worldwide. The TBI pathogenesis can induce broad pathophysiological consequences and clinical outcomes attributed to the complexity of the brain. Thus, the diagnosis and prognosis are important issues for the management of mild, moderate, and severe forms of TBI. Metabolomics of readily accessible biofluids is a promising tool for establishing more useful and reliable biomarkers of TBI than using clinical findings alone. Metabolites are an integral part of all biochemical and pathophysiological pathways. Metabolomic processes respond to the internal and external stimuli resulting in an alteration of metabolite concentrations. Current high-throughput and highly sensitive analytical tools are capable of detecting and quantifying small concentrations of metabolites, allowing one to measure metabolite alterations after a pathological event when compared to a normal state or a different pathological process. Further, these metabolic biomarkers could be used for the assessment of injury severity, discovery of mechanisms of injury, and defining structural damage in the brain in TBI. Metabolic biomarkers can also be used for the prediction of outcome, monitoring treatment response, in the assessment of or prognosis of post-injury recovery, and potentially in the use of neuroplasticity procedures. Metabolomics can also enhance our understanding of the pathophysiological mechanisms of TBI, both in primary and secondary injury. Thus, this review presents the promising application of metabolomics for the assessment of TBI as a stand-alone platform or in association with proteomics in the clinical setting.

A critical component for accelerating the clinical uptake of research data in the area of pediatric concussion or mild traumatic brain injury (MTBI) pertains to the establishment and utilization of common databases. The objective of the first phase of our CanPedCDE initiative was to agree upon pediatric common data elements (CDEs) that could best characterize children with MTBI over their recovery period. The selection of CDEs for our framework aimed to balance factors such as the comprehensiveness of outcomes collected, their applicability to diverse settings, as well as the costs associated with their use. Selection began by identifying relevant domains of functioning (e.g., post-concussion symptoms, attention, and balance). Two sources were used to make this process more efficient: 1) the World Health Organization International Classification of Functioning (ICF) Traumatic Brain Injury Core Set, and the U.S. National Institute of Neurological Disorders and Stroke Traumatic Brain Injury Common Data Elements, both of which had already suggested relevant domains to include in TBI research. The process was completed in two phases: 1) using an online survey of experts and 2) through an in-person consensus meeting. Measurement tools were also proposed that were best felt to capture these domains. Forty experts in MTBI in children from multiple health-related perspectives (e.g., emergency medicine, pediatrics, neurosurgery, nursing, physiotherapy, and neuroscience), as well as knowledge users, participated in the selection process. The final list of CDEs included 77 distinct areas of functioning, covering all categories of the ICF model. Outcome measures were attached to each element, when applicable. The CanPedCDE initiative addresses a significant limitation in MTBI research to date and may help both researchers and clinicians to organize and standardize their assessment of children and youth post-MTBI in order to move the field in promising directions.

Traumatic brain injury (TBI) is the leading cause of death in the first half of life and a chronic disability for Canadians of all ages. Despite the recognized importance of TBI, there is no integrated national strategy for research and best practices in Canada. We therefore created the Canadian TBI Research Consortium (CTRC) to build an ideal model of collaboration between Canadian TBI researchers. Our objectives were to: (1) Create a collaborative Canadian research network, (2) improve patient survival, functional outcome, and health through sustainable and scalable evidence-based practice implementation, (3) strengthen the healthcare system for patients with TBI, (4) provide international leadership and collaboration in TBI research, (5) build stronger links with patients and their representatives to help set the research agenda, and to participate in analysis of its impacts, and (6) support current researchers and prepare the next generation of leaders in TBI research. Building on the highly successful 30-year history of the Canadian Critical Care Trials Group, we developed a highly collaborative research group that integrates the multi-disciplinary network of TBI researchers in Canada. The CTRC conducts multi-center clinically relevant practice changing research. Our research is developed around investigator-led project-based research using a programmatic approach and multiple methodologies. Through strong and sustainable career development and mentorship programs, we train and develop the next generation of TBI researchers. Our group is composed of more than 100 Canadian researchers from coast to coast, most of them funded by the Canadian Institutes of Health Research and other granting agencies. In conclusion, the CTRC prioritizes investigator-led TBI research and broadens the research agenda by integrating researchers from different disciplines in the field of TBI research to optimize delivery of care and improve the health of Canadians with TBI. Our goals are being accomplished across the whole continuum of care by conducting clinically relevant and practice-changing research.

Characterizing psychological factors that contribute to persistent symptoms after mild traumatic brain injury (MTBI) can inform early intervention. To determine whether fear avoidance, a known risk factor for chronic disability after musculoskeletal injury, is associated with worse clinical outcomes from MTBI, adults were recruited from four outpatient MTBI clinics and assessed at their first clinic visit (mean = 2.7, standard deviation = 1.5 weeks post-injury) and again four to five months later. Of 273 patients screened, 102 completed the initial assessment, and 87 returned for the outcome assessment. The initial assessment included a battery of questionnaires that measure activity avoidance and associated fears. Endurance, an opposite behavior pattern, was measured with the Behavioral Response to Illness Questionnaire. The multi-dimensional outcome assessment included measures of post-concussion symptoms (British Columbia Postconcussion Symptom Inventory), functional disability (World Health Organization Disability Assessment Schedule-12 2.0), return to work status, and psychiatric complications (MINI Neuropsychiatric Interview). A single component was retained from principal components analysis of the six avoidance subscales. In generalized linear modeling, the avoidance composite score predicted symptom severity (95% confidence interval [CI] for B = 1.22–6.33) and disability (95% CI for B = 2.16–5.48), but not return to work (95% CI for B = −0.68–0.24). The avoidance composite was also associated with an increased risk for depression (odds ratio [OR] = 1.76, 95% CI = 1.02–3.02) and anxiety disorders (OR = 1.89, 95% CI = 1.16–3.19). Endurance behavior predicted the same outcomes, except for depression. In summary, avoidance and endurance behavior were associated with a range of adverse clinical outcomes from MTBI. These may represent early intervention targets.

Executive dysfunction represents the most persistent sequela of mild traumatic brain injury. It is, however, largely unclear whether a sport-related concussion similarly contributes to a persistent executive dysfunction even when an athlete has been cleared medically for return to play. Here, individuals with a diagnosis of a sport-related concussion—and their age- and sex-matched controls—completed an oculomotor assessment during the acute and later stages of injury recovery. Prosaccades (i.e., saccade to a target) and executive-related antisaccades (i.e., saccade mirror-symmetrical to a target) were completed: (1) 2–6 days after a concussive event (initial assessment), and (2) 14–20 days after the initial oculomotor assessment when individuals were cleared for return to play (follow-up assessment). At the initial assessment, the concussed group produced antisaccade reaction times (RT) that were 93 ms longer than the control group (p < 0.001), whereas prosaccade RTs did not differ between groups (p = 0.25). At the follow-up assessment, concussed and control groups produced comparable pro- and antisaccade RTs (ps >0.31); however, the former group exhibited a continued increase in directional errors (p < 0.05). That initial assessment antisaccades—but not prosaccades—differed between groups indicates that the acute recovery of a concussion is associated with a selective executive-related oculomotor deficit, and the continued increase in directional errors at the follow-up assessment suggests that such a deficit persists even when an athlete has been cleared medically for return to play. The antisaccade task may therefore serve to assess subtle executive deficits and determine when an athlete may return to play safely.

Chronic subdural hematoma (cSDH) is a frequent yet poorly studied entity. Patients with cSDH are increasingly using antithrombotic medication, are now older, and present with a variety of clinical symptoms, including incidental discoveries. Despite this increasing complexity, management has remained roughly unchanged since the late 1990s. We review here the state of cSDH research under way at Université de Sherbrooke and around the world with a focus on studies addressing specific gaps in the current evidence base. We show that evidence is lacking at many decision points in the typical cSDH patient treatment algorithm. No definition of cSDH is universally accepted, and a formal definition project, along with suggested common data elements to be reported in future trials (CODE-CSDH: formal cSDH definition project) is ongoing. An amendment to International Statistical Classification of Diseases and Related Health Problems (ICD-11) has also been proposed to improve classification and registry research. Within the cSDH clinical assessment, evidence for the occurrence of nonepileptic, stereotypical, and intermittent symptoms (NESIS) is emerging. The GENESIS study (Generation Evidence on the etiology and management of NESIS) will test etiological and therapeutic hypotheses for this patient subpopulation. For patients at high risk of recurrence, the TRACS (TXA for cSDH) and EMMACS studies (Embolization of the Middle Meningeal Artery in Chronic Subdural Hematoma study) are, respectively, assessing the use of tranexamic acid and meningeal artery embolization. The overarching vision is that patients with cSDH might be stratified for operative versus conservative treatment based on the need for mass effect removal, then be offered adjuvant therapies based on their risk of recurrence and thrombotic complications. We believe that such tailoring of therapy to each individual should help improve outcomes.

Liquid crystal display (LCD) screens refresh at a rate of 60 times per second, which can be perceived by concussed individuals who have photosensitivity, leading to computer intolerance. A non-LCD computer screen that refreshes at a much lower rate could relieve this photosensitivity and computer screen intolerance in patients with post-concussion syndrome (PCS). Twenty-nine patients with PCS, computer intolerance, and photosensitivity performed a reading task for a maximum of 30 min, with an LCD computer or a non-LCD device, and were given a comprehension test after completion of the reading task. The Sport Concussion Assessment Tool 3 was administered before and after each reading task. Symptom scores, amount of time spent reading, and performance on the comprehension tests were compared between the two devices. Patients also completed a self-report questionnaire of their subjective experience. The LCD screen computer produced significantly greater symptom exacerbation (median difference = 5, W = 315, p < 0.01) and a greater number of symptoms (median difference = 1, W = 148, p < 0.01) than the non-LCD screens. The non-LCD screen resulted in a longer symptom-free reading time (median = 48 sec, W = 147, p < 0.01), but not a greater number of words read (median = 281, W = 148, p = 0.098). Females were more likely to have greater symptom exacerbation with the LCD screen (U = 14.0, p < 0.01). No significant difference was found in performance on the comprehension test. Subjective reports showed that the non-LCD experience was more favorable, and most patients stated they would recommend this device for other patients with PCS. This study is the first to show the clinical utility of non-LCD screen computers in the management of photosensitivity and computer screen intolerance in patients with PCS. The non-LCD screen computer has the potential to facilitate return-to-work or return-to-school in concussed individuals.

An old wives' tale, and strongly held dogma, maintains that one should be kept awake after a mild traumatic brain injury (mTBI) to prevent a coma. This, however, conflicts with the known benefits of sleep: repair and restoration. We therefore sought to examine the effects of sleep deprivation (SD) in the post-traumatic sleep period on post-concussion symptomology (PCS). Adolescent male and female rats were administered repetitive mTBIs (RmTBI) or sham injuries and were then assigned to 5 h of SD or left undisturbed. All animals were then tested using seven behavioral tasks validated to examine PCS, followed by analysis of serum cytokines, and quantitative real-time PCR for messenger RNA (mRNA) expression. Exposure to 3 SD epochs significantly impaired behavior in 4 of 7 of the measures, while RmTBI also produced dysfunction in 5 of 7 tests, but the effects of SD and RmTBI were not cumulative. SD induced long-lasting changes in serum levels of Tnf-α, IL6, and IL-1ß. mRNA expression in the pre-frontal cortex, hippocampus, hypothalamus, and anterior cingulate cortex was modified in response to SD and RmTBI; but similar to the behavioral measures, the mRNA changes were not cumulative. Consequently, we report that SD often produced impairments similar or worse than RmTBI, and sleep hygiene should become a priority for adolescent health.

Acute traumatic spinal cord injury (SCI) entered the arena of prospective, randomized clinical trials almost 40 years ago, with the undertaking of the National Acute Spinal Cord Study (NASCIS) I trial. Since then, a number of clinical trials have been conducted in the field, spurred by the devastating physical, social, and economic consequences of acute SCI for patients, families, and society at large. Many of these have been controversial and attracted criticism. The current review provides a critical summary of select past and current clinical trials in SCI, focusing in particular on the findings of prospective, randomized controlled trials, the challenges and barriers encountered, and the valuable lessons learned that can be applied to future trials.

Inflammatory changes after spinal cord injury (SCI) have been reported in animal models, but human studies are relatively limited. We examined cerebrospinal fluid (CSF) collected from subjects enrolled in a phase II placebo-controlled trial of minocycline for evidence of inflammatory and structural changes after acute human SCI. CSF was collected from 29 subjects every 6 h for 7 days and investigated for eight molecules. CSF from 6 normal subjects (lumbar microdiscectomy patients without central nervous system pathology) was also examined for comparison. Cumulative levels of CSF molecules were compared between patients with motor complete and motor incomplete injury, between those receiving minocycline or placebo, and correlated to neurological outcome at 1 year (alpha = 0.05). We found that levels of C-C motif chemokine ligand 2 (monocyte chemoattractant), C-X-C motif chemokine 10 (CXCL10; T-cell chemoattractant), interleukin-1β (IL-1β), matrix metalloproteinase-9 (MMP-9), neurofilament heavy chain (NfH), and heme oxygenase-1 (HO-1) were significantly elevated after SCI. Neural cell adhesion molecule and nitric oxide oxidation products (NOx) were not significantly altered. Levels of IL-1β, MMP-9, and HO-1 were higher in subjects with more severe motor impairment. Higher cumulative levels of IL-1β, MMP-9, and CXCL10 exhibited moderate, but significant, correlation with worse motor recovery at 12 months. Only HO-1 and NfH appeared to vary with minocycline treatment; HO-1 lacked a later peak compared to placebo-treated subjects while NfH did not manifest its early peak with treatment. These analyses of CSF biomarkers imply a pathophysiological role for particular molecules and suggest mechanistic targets for minocycline in human traumatic SCI.

Current biomarker research in spinal cord injury (SCI) and traumatic brain injury has focused on a number of structural protein candidates, including the microtubule-associated protein tau. Evidence from models of traumatic brain injury has demonstrated that hyperphosphorylation of tau (p-tau) occurs in injured axons and demonstrates its utility as a biomarker for brain injury; however, the potential of p-tau as a biomarker for SCI is not yet known. Therefore, the present study determined whether tau is hyperphosphorylated in injured spinal cord axons, and then examined cerebrospinal fluid (CSF) and serum concentrations of p-tau and total-tau protein after a clinically relevant severe impact-compression SCI in rats. We found that severe SCI at T8 showed the presence of p-tau in damaged axons with a similar time course and distribution pattern to β-APP, a biomarker of axonal injury. The presence of p-tau and β-APP positive axons extended no farther than 5000 μm rostral and caudal to the injury epicenter, and was at its maximum at one day post-SCI. CSF levels of p-tau and total-tau significantly increased at one day post-SCI; however, only serum p-tau levels were significantly elevated in rats with SCI compared with naïve rats. These results suggest that CSF and serum p-tau may be a useful biomarker for severe traumatic SCI.

Magnetic resonance imaging (MRI) has transformed the way surgeons and researchers study and treat spinal cord injury. In this narrative review, we explore the historical context of imaging the human spinal cord and describe how MRI has evolved from providing the first visualization of the human spinal cord in the 1980s to a remarkable set of imaging tools today. The article focuses in particular on the role of Canadian researchers to this field. We begin by outlining the clinical context of traumatic injury to the human spinal cord and describe why current MRI standards fall short when it comes to treating this disabling condition. Parts 2 and 3 of this work explore an exciting and dramatic shift in the use of MRI technology to aid in our understanding and treatment of traumatic injury to the spinal cord. We explore the use of functional imaging (part 2) and structural imaging (part 3) and explore how these techniques have evolved, how they are used, and the challenges that we face for continued refinement and application to patients who live with the neurological and functional deficits caused by injury to the delicate spinal cord.

Loss of function after spinal cord injury (SCI) results from the primary injury that causes interruption of axonal tracts, neuronal and glial cell death, and the secondary injury in which inflammation drives lesion expansion, and further loss of gray and white matter. There are two main therapeutic strategies for the treatment of SCI: pro-reparative sprouting strategies that aim to promote functional recovery through enhancing the plasticity of spared axons and neuroprotection/anti-inflammatory strategies that aim to decrease secondary injury. Chondroitin sulfate proteoglycans (CSPGs) are matrix molecules that are major constituents of the glial scar at the SCI epicenter and of perineuronal nets found throughout the central nervous system. In this review, we summarize the wealth of literature describing the application of anti-CSPG strategies that target either CSPG synthesis or degradation or signalling after SCI. The weight of the evidence suggests that the balance between neuroprotection and neuroplasticity achieved by any one anti-CSPG strategy depends on the when and the where of its application.

Rehabilitative motor training is currently one of the most widely used approaches to promote moderate recovery following injuries of the central nervous system. Such training is generally applied in the clinical setting, whereas it is not standard in preclinical research. This is a concern as it is becoming increasingly apparent that neuroplasticity enhancing treatments require training or some form of activity as a co-therapy to promote functional recovery. Despite the importance of training and the many open questions regarding its mechanistic consequences, its use in preclinical animal models is rather limited. Here we review approaches, findings and challenges when training is applied in animal models of spinal cord injury, and we suggest recommendations to facilitate the integration of training using an appropriate study design, into pre-clinical studies.