Clinical correlates in an experimental model of repetitive mild brain injury

Mannix, Rebekah; Meehan, William P.; Mandeville, Joseph B.; Grant, P. Ellen; Gray, Tory; Berglass, Jacqueline; Zhang, Jimmy; Bryant, John M.; Rezaie, Shervin; Chung, Joon Yong; Peters, Nicholas; Lee, Christopher; Tien, Lee W.; Kaplan, David L.; Feany, Mel Β.; Whalen, Michael J.

doi:10.1002/ana.23858

Cited by 143 publications

(189 citation statements)

References 50 publications

(73 reference statements)

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“…[65][66][67][68][69] Increasing amounts of head movement have also been incorporated, [70][71][72] to more closely approximate human head kinematics following mTBI. 73 As such, WD models are increasingly utilized to model repeated mTBI.…”

Section: Closed-head Models Of Tbimentioning

confidence: 99%

“…54,56,65,70 One repeated mTBI study reported significant acute neuronal death in the entorhinal cortex and around hemorrhagic lesions, following 5 CCI mTBI given at 24 h intervals. 150 Findings were deemed an outcome of both injury number and inter-injury interval, as a 48-h interval prevented neurodegeneration 150 ; however, a study using similar injury parameters and experimental design did not report neurodegenerative changes.…”

Section: Cell Death Following Repeated Mtbimentioning

confidence: 99%

“…When 4 mTBIs at 24-h intervals are delivered in both WD rotational and CCI models, the astrocytic response is exacerbated at 1, 53,150 7, 72 and 14 d, 57 persisting to 6 mo, with concomitant cognitive deficits. 70 Increasing the inter-injury interval to 1 wk results in no observable response, 70 indicating that longer inter-injury intervals may be protective. Intermediate inter-injury intervals of 48 h yield variable outcomes.…”

Section: Astrocyte Reactivity Following Repeated Mtbimentioning

confidence: 99%

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Repeated mild traumatic brain injury: potential mechanisms of damage

2016

Cell Transplant

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Mild traumatic brain injury (mTBI) represents a significant public healthcare concern, accounting for the majority of all head injuries. While symptoms are generally transient, some patients go on to experience long-term cognitive impairments and additional mild impacts can result in exacerbated and persisting negative outcomes. To date, studies using a range of experimental models have reported chronic behavioral deficits in the presence of axonal injury and inflammation following repeated mTBI; assessments of oxidative stress and myelin pathology have thus far been limited. However, some models employed induced acute focal damage more suggestive of moderate-severe brain injury and are therefore not relevant to repeated mTBI. Given that the nature of mechanical loading in TBI is implicated in downstream pathophysiological changes, the mechanisms of damage and chronic consequences of single and repeated closed-head mTBI remain to be fully elucidated. This review covers literature on potential mechanisms of damage following repeated mTBI, integrating known mechanisms of pathology underlying moderate-severe TBIs, with recent studies on adult rodent models relevant to direct impact injuries rather than blast-induced damage. Pathology associated with excitotoxicity and cerebral blood flow-metabolism uncoupling, oxidative stress, cell death, blood-brain barrier dysfunction, astrocyte reactivity, microglial activation, diffuse axonal injury, and dysmyelination is discussed, followed by a summary of functional deficits and preclinical assessments of therapeutic strategies. Comprehensive characterization of the pathology underlying delayed and persisting deficits following repeated mTBI is likely to facilitate further development of therapeutic strategies to limit long-term sequelae.

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Section: Closed-head Models Of Tbimentioning

confidence: 99%

Section: Cell Death Following Repeated Mtbimentioning

confidence: 99%

Section: Astrocyte Reactivity Following Repeated Mtbimentioning

confidence: 99%

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Repeated mild traumatic brain injury: potential mechanisms of damage

2016

Cell Transplant

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“…It should be noted, however, that animal models of repetitive concussive brain injury have shown a decrease in cognitive function in the absence of such potential confounding variables. [55][56][57] "Second impact syndrome" is a term used to describe a devastating brain injury associated with cerebral edema that occurs after an often minor blow to the head is sustained before full recovery from a concussion. [58][59][60][61] Although second impact syndrome is often associated with football, it has been observed in other sports, such as ice hockey, boxing, and skiing.…”

Section: Cumulative and Catastrophic Head And Neck Injuries In Footballmentioning

confidence: 99%

Tackling in Youth Football

Brenner¹,

LaBella²,

Brooks³

et al. 2015

Pediatrics

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American football remains one of the most popular sports for young athletes. The injuries sustained during football, especially those to the head and neck, have been a topic of intense interest recently in both the public media and medical literature. The recognition of these injuries and the potential for longterm sequelae have led some physicians to call for a reduction in the number of contact practices, a postponement of tackling until a certain age, and even a ban on high school football. This statement reviews the literature regarding injuries in football, particularly those of the head and neck, the relationship between tackling and football-related injuries, and the potential effects of limiting or delaying tackling on injury risk.

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“…In recent years, there has been an increase in the number of military personnel exposed to traumatic head injury, leading the Department of Defense to designate TBI as the signature injury of the troops serving in Iraq and Afghanistan (Hoge et al, 2009). The nonspecific nature of TBI symptomatology (Darwish et al, 2012;Mannix et al, 2013), compounded by the variable presentation of TBI, has made the diagnostic and prognostic approach challenging. Not surprisingly, considerable effort has been directed toward identifying a panel of peripheral blood markers reflective of the severity of brain injury.…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of Traumatic Injury Are Transported from Brain to Blood via the Glymphatic System

et al. 2015

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The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100␤, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-toblood transport depends on glymphatic activity.

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Clinical correlates in an experimental model of repetitive mild brain injury

Cited by 143 publications

References 50 publications

Repeated mild traumatic brain injury: potential mechanisms of damage

Repeated mild traumatic brain injury: potential mechanisms of damage

Tackling in Youth Football

Biomarkers of Traumatic Injury Are Transported from Brain to Blood via the Glymphatic System

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