Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular, Histopathological, and Behavioral Outcomes in Rats

Rodriguez, Uylissa A.; Zeng, Yaping; Deyo, Donald J.; Parsley, Margaret A.; Hawkins, Bridget E.; Prough, Donald S.; DeWitt, Douglas S.

doi:10.1089/neu.2017.5256

Cited by 50 publications

(48 citation statements)

References 155 publications

(158 reference statements)

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“…Previous studies on CBF and TBI have typically used methods that measure spatially averaged flow. While we also found striking reductions in mean CBF, OCT also allowed us to further visualize flow disruptions in the individual penetrating vessels or capillaries where the vast majority of O 2 exchange and glucose delivery occurs (59, 61–64). The precise impact of capillary stalls on neural tissue is difficult to predict.…”

Section: Discussionmentioning

confidence: 74%

“…CBF continued to decline to levels that were unexpectedly low for our mild injury paradigm, with speckle imaging values falling to ~40% of pre-injury baseline, and OCT-based flow measurements in penetrating vessels reduced to 27% of control. Other mild TBI work has typically found smaller decreases on the order of 60 – 70% of control levels (20, 21, 59, 60). However, most of these studies measured CBF at 4 hours or later (20, 21, 60) and thus may have missed larger initial reductions.…”

Section: Discussionmentioning

confidence: 95%

“…Furthermore, human data are typically only available several hours after injury. While some animal studies have detected early changes in CBF between 1 hour to 3 days after TBI (18, 19, 21, 59), the full time course of deficits is poorly characterized, and will be important for defining windows for treatment.…”

Section: Discussionmentioning

confidence: 99%

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Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

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Keywords: traumatic brain injury, mouse, weight drop injury, cerebral blood flow, capillary, in 21 vivo, laser speckle contrast imaging, optical coherence tomography, two-photon imaging 22 23 24 Acknowledgments: We thank Tim Otchy, Jennifer Morgan, and members of the Davison and 25 Boas laboratories for comments and discussion. This work was supported by Boston University 26 startup funds.Abstract 30 Traumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The 31 bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can 32 still lead to long-term neuropathology manifesting months or years later. Although the cellular 33 stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is 34 metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of 35 TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to 36 characterize deficits in the cortical microcirculation during both acute and chronic phases after 37 mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, 38 decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-39 2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking 40 flow deficits in the capillary network, where 18% of vessels were completely occluded for 41 extended periods after injury, and an additional >50% showed substantial stoppages. Decreased 42 CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our 43 data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that 44 acute post-injury periods may be key therapeutic windows for interventions that restore flow 45 and mitigate metabolic stress. 46 47 88 dysfunction across the cortical microvasculature, where a large fraction of individual capillaries 89were occluded for periods of minutes or longer, leading to localized regions with complete loss 90 5 of perfusion. CBF largely returned to normal by 3 hours after injury and showed no measurable 91 deficits when tracked until 3 weeks. Reduced CBF was paralleled by pronounced 92 vasoconstriction, identifying a potential mechanism contributing to disrupted flow. This rapid 93 and extensive vascular dysfunction highlights the importance of immediate post-injury periods 94 for delivering interventions, and suggests that relieving vasoconstriction will be a promising 95 avenue for countering the effects of mild injury. 96 97 Methods 98 99 Animals and surgical procedures 100 All experiments were performed in 2-5 month-old male and female C57BL6/J mice in accordance 101 with guidelines of the Boston University Institutional Animal Care and Use Committee. Animals 102 were group housed on a 12-hour light/dark cycle with ad libitum access to food and water. 103 Chronic cranial windows were implanted using standard procedures (30, 31). Brie...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 95%

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Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

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“…To better investigate the hypothesis that bTBI, like non-blast TBI, results in impaired cerebral vascular reactivity, we tested a mechanism contributing to compromised autoregulation by measuring myogenic dilatory responses to reduced intravascular pressure ex vivo in isolated, pressurized rodent MCA segments (Figure 1) collected from rats subjected to mild bTBI using an Advanced Blast Simulator (ABS) shock tube model (Figure 2 and Figure 3) (see Rodriguez et al 39 Table 1) that uses compressed air delivered directly to a driver chamber to generate Freidlander-like 40 over-and under-pressure waves (see Rodriguez et al 39 Figure 1A). 1.…”

Section: Introductionmentioning

confidence: 99%

Effects of Blast-induced Neurotrauma on Pressurized Rodent Middle Cerebral Arteries

Rodriguez¹,

Zeng²,

Parsley³

et al. 2019

JoVE

Self Cite

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Though there have been studies on the histopathological and behavioral effects of blast exposure, fewer have been dedicated to blast's cerebral vascular effects. Impact (i.e., non-blast) traumatic brain injury (TBI) is known to decrease pressure autoregulation in the cerebral vasculature in both humans and experimental animals. The hypothesis that blast-induced traumatic brain injury (bTBI), like impact TBI, results in impaired cerebral vascular reactivity was tested by measuring myogenic dilatory responses to reduced intravascular pressure in rodent middle cerebral arterial (MCA) segments from rats subjected to mild bTBI using an Advanced Blast Simulator (ABS) shock tube. Adult, male Sprague-Dawley rats were anesthetized, intubated, ventilated and prepared for Sham bTBI (identical manipulation and anesthesia except for blast injury) or mild bTBI. Rats were randomly assigned to receive Sham bTBI or mild bTBI followed by sacrifice 30 or 60 min post-injury. Immediately after bTBI, righting reflex (RR) suppression times were assessed, euthanasia at the time points post-injury was completed, the brain was harvested and the individual MCA segments were collected, mounted and pressurized. As the intraluminal pressure perfused through the arterial segments was reduced in 20 mmHg increments from 100 to 20 mmHg, MCA diameters were measured and recorded. With decreasing intraluminal pressure, MCA diameters steadily increased significantly above baseline in the Sham bTBI groups while MCA dilator responses were significantly reduced (p < 0.05) in both bTBI groups as evidenced by the impaired, smaller MCA diameters recorded for the bTBI groups. In addition, RR suppression in the bTBI groups was significantly (p < 0.05) higher than in the Sham bTBI groups. MCA's collected from the Sham bTBI groups exhibited typical vasodilatory properties to decreases in intraluminal pressure while MCA's collected following bTBI exhibited significantly impaired myogenic vasodilatory responses to reduced pressure that persisted for at least 60 min after bTBI.

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“…In addition, the shearing forces described previously can contribute to the capillary disruption and vasoconstriction by tearing the microvasculature, causing the decreased CBF observed in TBI (Bouma, Muizelaar, Bandoh, & Marmarou, ; Bouma, Muizelaar, Choi, Newlon, & Young, ; DeWitt & Prough, ; McKee & Daneshvar, ). Further adding to the ischemic conditions, TBI is also associated with impaired pressure autoregulation or loss of cerebral vascular response to arterial blood pressure changes (Engelborghs et al., ; Lang et al., ; Lewelt, Jenkins, & Miller, ; Rodriguez et al., ). Autoregulation normally acts to preserve proper CBF when the cerebral perfusion pressure changes (Armstead, ; Castro, Azevedo, & Sorond, ).…”

Section: Ischemiamentioning

confidence: 99%

The overlooked aspect of excitotoxicity: Glutamate‐independent excitotoxicity in traumatic brain injuries

Tehse

Taghibiglou

2019

Eur J of Neuroscience

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Traumatic brain injury (TBI) is a leading major cause of morbidity and mortality in youth and individuals under 45 year age. A wide variety of cellular and molecular mechanisms have been identified contributing to the pathogenesis of TBI. A better understanding of the pathophysiology behind TBI is essential for providing more effective treatment. Excitotoxicity as one of the secondary molecular events is a major contributing factor in apoptosis and neuronal death following the initial injury in TBI. Excitotoxicity is the rapid overload and influx of calcium into the cell cytoplasm, activating a series of deleterious signaling cascades causing the cell to undergo apoptosis. Conventional understanding is that the rapid influx of calcium is initiated through glutamate release. However, there are overlooked glutamate‐independent mechanisms that cause the rapid calcium influx into the neuronal cytoplasm, evoking or contributing to excitotoxicity. Therefore, the focus of this review will be on the role of the glutamate‐independent excitotoxic mechanisms of the mechanosensitive response of NMDA receptors, mechanoporation of the cell membrane, ischemia, and the release of calcium from intracellular stores. In conclusion, the shear and stretch forces during a TBI event may result in the mechanosensitive activation of NMDA receptors which contribute to glutamate‐independent excitotoxicity.

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Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular, Histopathological, and Behavioral Outcomes in Rats

Cited by 50 publications

References 155 publications

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Effects of Blast-induced Neurotrauma on Pressurized Rodent Middle Cerebral Arteries

The overlooked aspect of excitotoxicity: Glutamate‐independent excitotoxicity in traumatic brain injuries

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