Localized Modification of Water Molecule Transport After Focused Ultrasound-Induced Blood–Brain Barrier Disruption in Rat Brain

Abstract

Interstitial solutes can be removed by various overlapping clearance systems, including blood–brain barrier (BBB) transport and glymphatic clearance. Recently, focused ultrasound (FUS)-induced BBB disruption (BBBD) has been applied to visualize glymphatic transport. Despite evidence that FUS–BBBD might facilitate glymphatic transport, the nature of fluid movement within the sonication region is yet to be determined. In this study, we sought to determine whether FUS–BBBD may facilitate the local movement of water molecules. Two different FUS conditions (0.60–0.65 MPa and 0.75–0.80 MPa) were used to induce BBBD in the caudate-putamen and thalamus regions of healthy Sprague–Dawley rats. The water diffusion caused by FUS–BBBD was analyzed using the apparent diffusion coefficient (ADC), axial diffusivity, radial diffusivity (RD), and fractional anisotropy, obtained at 5 min, 24 and 48 h, as well as the water channel expression of aquaporin-4 (AQP-4) immunostaining at 48 h after FUS-induced BBBD. In addition, hematoxylin and eosin histopathology and Fluoro-Jade C (FJC) immunostaining were performed to analyze brain damage. The signal changes in ADC and RD in the sonication groups showed significant and transient reduction at 5 min, with subsequent increases at 24 and 48 h after FUS-induced BBBD. When we applied higher sonication conditions, the ADC and RD showed enhancement until 48 h, and became comparable to contralateral values at 72 h. AQP-4 expression was upregulated after FUS-induced BBBD in both sonication conditions at 48 h. The results of this study provide preliminary evidence on how mechanical forces from FUS alter water dynamics through diffusion tensor imaging (DTI) measures and AQP4 expression.

Verification of Blood-Brain Barrier Disruption Based on the Clinical Validation Platform Using a Rat Model with Human Skull

“…When analyzing the MR images, Evans blue dye, and histology based on the cavitation dose, BBBD was observed. Indeed, we studied the long-term effects of BBBD in our previous study, showing that the brain was restored to a normal state within 72 h after BBBD [ 53 ]. Furthermore, our ultrasound parameters were derived based on previous results using a 1 MHz FUS transducer.…”

Novel Animal Model of Spontaneous Cerebral Petechial Hemorrhage Using Focused Ultrasound in Rats

“…The microbubble solution was diluted 50-fold in saline and injected intravenously at a dose of 10 μL/kg. Microbubbles with less than two hours of activation were used (manufacturer’s guidelines <12 h) to ensure a similar level of microbubble concentration among all experiments [ 12 ]. The sonication intensities were (1) sham, (2) 1.5 MPa, (3) 1.8 MPa, and (4) 2.0 MPa.…”

“…Sonication was applied synchronously to an in nous injection of microbubbles (Definity, Lantheus Medical Imaging, N.Billerica which consisted of C3D8 gas encapsulated by an outer phospholipid shell. The micr ble solution was diluted 50-fold in saline and injected intravenously at a dose of 10 Microbubbles with less than two hours of activation were used (manufacturer's lines <12 h) to ensure a similar level of microbubble concentration among all exper [12]. The sonication intensities were (1) sham, (2) 1.5 MPa, (3) 1.8 MPa, and (4) 2.0 M (A) (B)…”

“…The following MRI parameters were employed for 2D fa echo T1-weighted images: field of view = 40 mm × 40 mm, matrix size = 128 × 128 slices = 8, slice thickness = 1.5 mm, slice gap = 0, repetition time (TR) = 500 ms, ech (TE) = 6.5 ms, number of averages = 30, scan time = 5 min; T2-weighted images: TR ms, TE = 33 ms, number of averages = 32, scan time = 5 min, and the other parameter equal to those of the T1-weighted images. The SWI parameters were as follows: f view, 50 × 50 mm; matrix size, 128 × 128; axial slices = 16, slice thickness = 1.5 mm gap = 0, flip angle = 30, TR = 27 ms; TE,20 ms; number of averages = 15, scan time, 1 During MRI scans, the animal's body temperature was maintained at 35-37 °C u warm water blanket [12]. T2-weighted MR images were obtained to locate the focal before sonication, and SWI, T2, T1-weighted images, and T1-contrast enhanced i were acquired at each time point (5 min, 48 h) after the FUS (Figure 2).…”

Low-Intensity Focused Ultrasound Technique in Glioblastoma Multiforme Treatment

“…Below this range (for instance, at a pressure of 0.28 MPa), the uptake of nanoclusters was negligible in glioblastoma, while having no significant difference at 0.61, 0.72, and 0.85 MPa, respectively ( 60 ). Recently, it has also been shown that with increasing pressure, the diffusion of water molecules increases due to the upregulation of aquaporin-4 ( 75 ). Moreover, these parameters also determine whether the therapeutics uptake will be early/fast or slow/late ( 8 ).…”