When describing clinical or experimental traumatic brain injury (TBI), the adjectives 'mild,' 'moderate' and 'severe' are misleading. 'Mild' clinical TBI frequently results in long-term disability. ...'Severe' rodent TBI actually resembles mild or complicated mild clinical TBI.
Many mild TBI patients appear to have recovered completely but have postconcussive symptoms, deficits in cognitive and executive function and reduced cerebral blood flow. After moderate TBI, 31.8% of patients died or were discharged to skilled nursing or hospice. Among survivors of moderate and severe TBI, 44% were unable to return to work. On MRI, 88% of mild TBI patients have evidence of white matter damage, based on measurements of fractional anisotropy and mean diffusivity/apparent diffusion coefficient. After sports concussion, clinically recovered patients have abnormalities in functional connectivity on functional MRI. Methylphenidate improved fatigue and cognitive impairment and, combined with cognitive rehabilitation, improved memory and executive functioning. In comparison to clinical TB, because the entire spectrum of experimental rodent TBI, although defined as moderate or severe, more closely resembles mild or complicated mild clinical TBI.
Many patients after mild or moderate TBI suffer long-term sequelae and should be considered a major target for translational research. Treatments that improve outcome in rodent TBI, even when the experimental injuries are defined as severe, might be most applicable to mild or moderate TBI.
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.
The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the ...pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow cytometry, and immunofluorescence assays were utilized to analyze post-traumatic NLRP3 inflammasome expression and determine its cellular source. We found that NLRP3 inflammasome expression was significantly increased in the peri-contusional cortex and that microglia were the primary source of this expression. The effects of MCC950 on mice with TBI were then determined using post-assessments including analyses of neurological deficits, brain water content, traumatic lesion volume, neuroinflammation, blood-brain barrier (BBB) integrity, and cell death. MCC950 treatment resulted in a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions. The therapeutic window for MCC950 against TBI was as long as 6 h. Furthermore, the neuroprotective effect of MCC950 was associated with reduced microglial activation, leukocyte recruitment, and pro-inflammatory cytokine production. In addition, MCC950 preserved BBB integrity, alleviated TBI-induced loss of tight junction proteins, and attenuated cell death. Notably, the efficacy of MCC950 was abolished in microglia-depleted mice. These results indicate that microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to TBI, and specific NLRP3 inflammasome inhibition using MCC950 may be a promising therapeutic approach for patients with TBI.
•Microglia-derived NLRP3 inflammasome involved in the inflammatory response to TBI.•MCC950 attenuated NLRP3 inflammasome activation and subsequent IL-1β secretion.•MCC950 reduced post-TBI inflammatory response and blood-brain barrier disruption.•Microglia contributed to the neuroprotective effect of MCC950 after TBI.•Therapeutic window for MCC950 in protecting against TBI was as long as 6 h.
Abstract
Since the original descriptions of postconcussive pathophysiology, there has been a significant increase in interest and ongoing research to study the biological underpinnings of concussion. ...The initial ionic flux and glutamate release result in significant energy demands and a period of metabolic crisis for the injured brain. These physiological perturbations can now be linked to clinical characteristics of concussion, including migrainous symptoms, vulnerability to repeat injury, and cognitive impairment. Furthermore, advanced neuroimaging now allows a research window to monitor postconcussion pathophysiology in humans noninvasively. There is also increasing concern about the risk for chronic or even progressive neurobehavioral impairment after concussion/mild traumatic brain injury. Critical studies are underway to better link the acute pathobiology of concussion with potential mechanisms of chronic cell death, dysfunction, and neurodegeneration. This “new and improved” article summarizes in a translational fashion and updates what is known about the acute neurometabolic changes after concussive brain injury. Furthermore, new connections are proposed between this neurobiology and early clinical symptoms as well as to cellular processes that may underlie long-term impairment.
Abstract
The scope and purpose of this work is 2-fold: to synthesize the available evidence and to translate it into recommendations. This document provides recommendations only when there is ...evidence to support them. As such, they do not constitute a complete protocol for clinical use. Our intention is that these recommendations be used by others to develop treatment protocols, which necessarily need to incorporate consensus and clinical judgment in areas where current evidence is lacking or insufficient. We think it is important to have evidence-based recommendations to clarify what aspects of practice currently can and cannot be supported by evidence, to encourage use of evidence-based treatments that exist, and to encourage creativity in treatment and research in areas where evidence does not exist. The communities of neurosurgery and neuro-intensive care have been early pioneers and supporters of evidence-based medicine and plan to continue in this endeavor. The complete guideline document, which summarizes and evaluates the literature for each topic, and supplemental appendices (A-I) are available online at https://www.braintrauma.org/coma/guidelines.
Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety ...of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma have been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting methodological challenges and critical future directions of research in this field. This article is part of a Special Issue entitled SI:Traumatic Brain Injury.
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•Mild traumatic brain injury (MTBI) is extremely common.•Some studies have found an association between MTBI and neurodegenerative diseases.•Chronic traumatic encephalopathy (CTE) is associated with repetitive MTBI.•Prevalence of CTE is unknown as it can only be diagnosed on autopsy.•Large prospective longitudinal studies of MTBI and neurodegeneration are needed.
Abstract
Introduction
Slow waves and spindles are essential oscillations occurring during NREM sleep that may be disrupted by moderate to severe traumatic brain injury (TBI). We investigated these ...oscillations in the acute and chronic trauma stage.
Methods
Four groups were tested with whole-night polysomnography: hospitalized patients with acute TBI (n=10, 29.7±13.8y) or severe orthopedic injuries (n=15, 39.9±17.1y), chronic TBI including 9 returning from the acute TBI group (n=43, 31.9±13.5y), and healthy controls (n=36, 30.5±12.7y). Characteristics for slow waves (density, amplitude, slope, frequency, duration) and spindles (density, amplitude, frequency, duration) were quantified over N2 and N3 sleep for the first three sleep cycles, and groups were compared using one-way ANOVAs.
Results
One-way ANOVAs showed group effects only for slow wave density (F=4.11 to 6.04, p=0.009 to 0.0008)) and spindle density (F=3.3 to 8.8, p=0.02 to 0.00003). These effects were present for the 2nd and 3rd sleep cycles, but not the 1st. More specifically, slow wave density in acute TBI was higher than in controls, and returned to normal levels in the chronic stage. Conversely, spindle density in acute TBI was lower than in controls and returned to normal levels in the chronic stage. No group difference was observed for the orthopedic group.
Conclusion
Our results suggest that immediately after a severely disruptive event such as a TBI, the brain needs additional deeper sleep to recover, resulting in more slow waves but also in less spindles. These changes are only present in the 2nd and 3rd sleep cycles, reflecting an absence of the expected dissipation of slow waves, which may suggest increased homeostatic sleep pressure due to the brain injury. Limits to interpretation include the hospital environment and medication, but the absence of changes in the orthopedic group under similar conditions emphasizes the effect of the brain injury itself.
Support
Canadian Institutes of Health Research (CIHR) and Fonds de Recherche Québec-Santé (FRQS)
ABSTRACTTraumatic brain injury (TBI) is a risk factor for dementia. Mixed neurodegenerative pathologies have been described in late survivors of TBI, but the mechanisms driving post-TBI ...neurodegeneration remain elusive. Increasingly, blood-brain barrier (BBB) disruption has been recognized in a range of neurologic disorders including dementias, but little is known of the consequences of TBI on the BBB. Autopsy cases of single moderate or severe TBI from the Glasgow TBI Archive (n = 70) were selected to include a range from acute (10 hours–13 days) to long-term (1–47 years) survival, together with age-matched uninjured controls (n = 21). Multiple brain regions were examined using immunohistochemistry for the BBB integrity markers fibrinogen and immunoglobulin G. After TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multifocal, abnormal, perivascular, and parenchymal fibrinogen and immunoglobulin G immunostaining localized to the gray matter, with preferential distribution toward the crests of gyri and deep neocortical layers. In contrast, when present, controls showed only limited localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.