Internal Jugular Vein Compression Mitigates Traumatic Axonal Injury in a Rat Model by Reducing the Intracranial Slosh Effect

Smith, David W.; Bailes, Julian E.; Fisher, Joseph A.; Robles, Javier; Turner, Ryan C.; Mills, James D.

doi:10.1227/neu.0b013e318235b991

Cited by 74 publications

(82 citation statements)

References 18 publications

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“…53 It has long been postulated that TBI leads to chronic neurodegeneration. 30,32,47 Recent findings have confirmed that changes in tau, amyloid, and cognition can result from neurotrauma. 9,34,51 The mechanisms underlying how these changes develop is currently unknown.…”

Section: Discussionmentioning

confidence: 92%

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Lucke‐Wold

Turner

Logsdon

et al. 2016

JNS

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abbreviatioNs ATF6 = activating transcription factor 6; BiP = binding immunoglobulin protein; CHOP = C/EBP homology protein; CTE = chronic traumatic encephalopathy; DAB = diaminobenzidine; DHA = docosahexaenoic acid; ER = endoplasmic reticulum; GADD34 = growth arrest and DNA damage-inducible protein 34; GSK3b = glycogen synthase kinase-3b; IHC = immunohistochemistry; IRE1a = inositol requiring enzyme 1a; JNK = c-Jun N-terminal kinase; NFL = National Football League; PBS = phosphate-buffered saline; PERK = protein kinase RNA-like ER kinase; PHF = paired helical filament; p-eIF2a = phosphorylated eukaryotic initiation factor 2a; TBI = traumatic brain injury; WWE = World Wrestling Entertainment; XBP1 = X-box binding protein 1. obJective Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. methods The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. results The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3b. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy. coNclusioNs Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.

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Section: Discussionmentioning

confidence: 92%

Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy

Lucke‐Wold

Turner

Logsdon

et al. 2016

JNS

Self Cite

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“…Increased neck strength (not just mass) may diffuse the forces imparted in a head impact or may limit the cranial excursion and brain movement inside the skull (slosh). 77 Neck strength may be particularly important at the junior and youth athletic levels and in female athletes. 4,5,15,81 In general, modern players have amassed a greater total size (mass), thus increasing the kinetic energy imparted in blows to the head.…”

Section: 75mentioning

confidence: 99%

“…It can also occur with rapid acceleration-deceleration of the body or torso, particularly when the brain is free to move within the cranium, creating a "slosh" phenomenon. 77 Subconcussion has its greatest effect through repetitive occurrences whereby cumulative exposure becomes deleterious.…”

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confidence: 99%

Role of subconcussion in repetitive mild traumatic brain injury

Bailes

Petraglia

Omalu

et al. 2013

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Research now suggests that head impacts commonly occur during contact sports in which visible signs or symptoms of neurological dysfunction may not develop despite those impacts having the potential for neurological injury. Recent biophysics studies utilizing helmet accelerometers have indicated that athletes at the collegiate and high school levels sustain a surprisingly high number of head impacts ranging from several hundred to well over 1000 during the course of a season. The associated cumulative impact burdens over the course of a career are equally important. Clinical studies have also identified athletes with no readily observable symptoms but who exhibit functional impairment as measured by neuropsychological testing and functional MRI. Such findings have been corroborated by diffusion tensor imaging studies demonstrating axonal injury in asymptomatic athletes at the end of a season. Recent autopsy data have shown that there are subsets of athletes in contact sports who do not have a history of known or identified concussions but nonetheless have neurodegenerative pathology consistent with chronic traumatic encephalopathy. Finally, emerging laboratory data have demonstrated significant axonal injury, blood-brain barrier permeability, and evidence of neuroinflammation, all in the absence of behavioral changes. Such data suggest that subconcussive level impacts can lead to significant neurological alterations, especially if the blows are repetitive. The authors propose “subconcussion” as a significant emerging concept requiring thorough consideration of the potential role it plays in accruing sufficient anatomical and/or physiological damage in athletes and military personnel, such that the effects of these injuries are clinically expressed either contemporaneously or later in life.

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“…28,33 The central hypothesis being explored relative to concussion prevention is that mild increases in intracranial volume induce a tighter fit of the brain inside the cranium and thus reduce slosh and inertial cavitation within the brain during concussive blows. 18,21,28,33,39 At present, there is no known approach that allows for the manipulation of intracranial volume or compliance in the human skull; therefore, the benefits of such an approach to protect the brain of humans are yet unknown. While helmet design was developed for, and is effective in, the prevention of skull fractures and lacerations, it does not afford protection against forces inside the cranium.…”

Section: T T Conclusionmentioning

confidence: 99%

“…This most likely negates the proposed benefits of hypoxia-induced edema gained at increased elevation. Because oxygen is known to decrease cerebral blood-flow velocity to the cranium, 28 further research may also be warranted to determine if there are effects of oxygen use on the sideline relative to the risk of concussion incidence during competitive football.…”

Section: Limitationsmentioning

confidence: 99%