Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Abstract

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...

Non-Invasive Continuous Optical Monitoring of Cerebral Blood Flow after Traumatic Brain Injury in Mice Using Fiber Camera-Based Speckle Contrast Optical Spectroscopy

“…The pilot study successfully measured blood flow in mice's heads for approximately 30 min, demonstrating the feasibility of providing continuous, longitudinal measurements of blood flow. The results align well with those of Abookasis et al [64], who observed a 13% decrease, and Witkowski et al [65], who also observed a similar decrease by using the superficial optical speckle imaging method. Buckley et al used DCS for monitoring repetitive concussions in mice for 24 h and several days and observed a cerebral blood flow (CBF) decrease at 4 h and a gradual daily based decrease in CBF until day 8 [66].…”

Editorial: Small and mighty: Brain capillaries in health and disease

“…Mild traumatic brain injury (mTBI) significantly impacts the microvasculature and leads to blood flow reductions in capillary networks (Witkowski et al, 2019 ; Han et al, 2020 ). The article by Wu et al developed a modified dielectric elastomer actuator inducing an mTBI by mechanical stretching.…”