Characterization of Vasogenic and Cytotoxic Brain Edema Formation After Experimental Traumatic Brain Injury by Free Water Diffusion Magnetic Resonance Imaging.

Brain edema formation is a key factor for secondary tissue damage after traumatic brain injury (TBI), however, the type of brain edema and the temporal profile of edema formation are still unclear. We performed free water imaging, a bi-tensor model based diffusion MRI analysis, to characterize vasogenic brain edema (VBE) and cytotoxic edema (CBE) formation up to 7 days after experimental TBI. Male C57/Bl6 mice were subjected to controlled cortical impact (CCI) or sham surgery and investigated by MRI 4h, 1, 2, 3, 5, and 7 days thereafter (n = 8/group). We determined mean diffusivity (MD) and free water (FW) in contusion, pericontusional area, ipsi- and contralateral brain tissue. Free (i.e., non-restricted) water was interpreted as VBE, restricted water as CBE. To verify the results, VBE formation was investigated by in-vivo 2-Photon Microscopy (2-PM) 48h after surgery. We found that MD and FW values decreased for 48h within the contusion, indicating the occurrence of CBE. In pericontusional tissue, MD and FW indices were increased at all time points, suggesting the formation of VBE. This was consistent with our results obtained by 2-PM. Taken together, CBE formation occurs for 48h after trauma and is restricted to the contusion, while VBE forms in pericontusional tissue up to 7 days after TBI. Our results indicate that free water magnetic resonance imaging may represent a promising tool to investigate vasogenic and cytotoxic brain edema in the laboratory and in patients.

Longitudinal Characterization of Blood-Brain Barrier Permeability after Experimental Traumatic Brain Injury by In Vivo 2-Photon Microscopy.

Vasogenic brain edema (VBE) formation remains an important factor determining the fate of patients with traumatic brain injury (TBI). The spatial and temporal development of VBE, however, remains poorly understood because of the lack of sufficiently sensitive measurement techniques. To close this knowledge gap, we directly visualized the full time course of vascular leakage after TBI by in vivo 2-photon microscopy (2-PM). Male C57BL/6 mice (n = 6/group, 6-8 weeks old) were assigned randomly to sham operation or brain trauma by controlled cortical impact. A cranial window was prepared, and tetramethylrhodamine-dextran (TMRM, MW 40,000 Da) was injected intravenously to visualize blood plasma 4 h, 24 h, 48 h, 72 h, or seven days after surgery or trauma. Three regions with increasing distance to the primary contusion were investigated up to a depth of 300 µm by 2-PM. No TMRM extravasation was detected in sham-operated mice, while already 4 h after TBI vascular leakage was significantly increased (p < 0.05 vs. sham) and reached its maximum at 48 h after injury. Vascular leakage was most pronounced in the vicinity of the contusion. The rate of extravasation showed a biphasic pattern, peaking 4 h and 48-72 h after trauma. Taken together, longitudinal quantification of vascular leakage after TBI in vivo demonstrates that VBE formation after TBI develops in a biphasic manner suggestive of acute and delayed mechanisms. Further studies using the currently developed dynamic in vivo imaging modalities are needed to investigate these mechanisms and potential therapeutic strategies in more detail.