LAUSR

Understanding the effects of BBB disrupting technologies on the neurovascular unit is important for safety and for optimal timing of therapeutic agents administration. We studied the effects of two novel BBB disrupting methods employing pulsed electrical fields (PEFs) on wash-in/wash-out rates and on vascular dilatation/constriction in mice and rats. The first method uses high, minimal-invasive PEFs inducing electroporation in endothelial cells. The second employs low, non-invasive PEFs inducing tight-junction function alterations. Both were found to induce transient BBB disruption. Contrast-enhanced T1-weighted MRI (T1-Gd) and treatment response assessment maps (TRAMs) based on delayed-contrast MRI, were applied to depict BBB permeability, wash-in/wash-out rates and vascular dilatation/constriction. T1-Gd, acquired following high PEFs application, showed immediate enhancement in the treatment area, lasting for ~1 hour. However, TRAMs, obtained at different times post treatment (immediately-24 hours) indicated vasodilatation with fast wash-in/wash-out immediately post treatment (preventing efficient tissue accumulation of peripherally administered drugs) and delayed (~1 hour post PEFs) vasoconstriction, lasting several hours. This was followed by large volumes of subtle BBB disruption, visible mainly on TRAMs. These volumes exceeded the original volumes observed immediately post treatment, suggesting this may be the optimal time for drug administration. Low PEFs however, induced subtle BBB disruption, depicted only in the TRAMs, with slow contrast accumulation, reaching a plateau at ~40 min post treatment. The TRAMs showed significantly increased sensitivity to BBB disruption compared to T1-Gd also in mice post traumatic brain injury. Lesion volumes depicted in the TRAMs were x2.5 larger than the enhancing volumes on T1-Gd (p<0.02). The results significantly correlated with histological assessment of blood vessels coverage by astrocytes end-feet (r2=0.77, p<0.05), an histological indicator for BBB integrity. These results demonstrate the TRAMs advantages in depicting BBB disruption with high sensitivity/resolution, thus providing additional information regarding the neurovascular unit function.