A local difference in blood–brain barrier permeability in the caudate putamen and thalamus of a rat brain induced by focused ultrasound

Abstract

A blood–brain barrier (BBB) opening induced by focused ultrasound (FUS) has been widely studied as an effective way of treating brain diseases. We investigate the effect of ultrasound’s incidence angle at caudate putamen (Cp) and thalamus (Th) of the rat brain by inducing the same power of focused ultrasound that corresponds to the acoustic pressure of 0.65 MPa in free field. The BBB permeability (Ktrans) was quantitatively evaluated with dynamic contrast-enhanced magnetic resonance imaging. The group averaged (n = 11) maximum Ktrans at Cp (0.021 ± 0.012 min−1) was 1.39 times smaller than the Ktrans of Th (0.029 ± 0.01 min−1) with p = 0.00343. The group averaged (n = 6) ultrasound’s incidence angles measured using the computed tomography image of rat skulls were compared with the maximum Ktrans and showed a negatively linear relation R2 = 0.7972). The maximum acoustic pressure computed from the acoustic simulation showed higher average acoustic pressures at Th (0.37 ± 0.02 MPa) compared to pressures at Cp (0.32 ± 0.01 MPa) with p = 0.138 × 10−11. More red blood cell were observed at the Th region compared to the Cp region in the tissue staining. These results indicate that localized characteristics of the sonication target within the subject should be considered for safer and more efficient BBB disruption induced by FUS.

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

“…The acoustic pressure of FUS was used by 0.60 MPa (TH) and 0.65 MPa (CP) for group-0.65 MPa and by 0.75 MPa (TH) and 0.80 MPa (CP) for group-0.80 MPa, respectively. In an earlier study, different degrees of BBBD were found depending on the brain region, resulting in smaller BBB permeability in CP compared to TH ( Huh et al, 2020 ). Thus, by applying different acoustic pressures, the two target areas showed comparable degrees of BBBD, comparable patterns of DTI parameters, and histological results.…”

“…Two sonication groups and a sham-controlled group were determined using MR signal analysis. Based on earlier studies, different degrees of BBBD were found depending on the brain region, resulting in smaller BBB permeability in CP compared to TH ( Huh et al, 2020 ); thus, we experimentally determined how to apply a higher acoustic power to CP than to TH, such that the target regions showed comparable degrees of BBBD. We designated the sonication groups as group-0.65 MPa and group-0.80 MPa, which indicated the corresponding acoustic power applied to CP.…”

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

“…BBBD depends on various factors, such as the microbubble dose and sonication angle [ 7 , 28 ]. The selection of optimal ultrasound parameters is critical for safe BBBD as it determines the acoustic cavitation level by microbubble activity [ 29 ].…”

A review of bioeffects induced by focused ultrasound combined with microbubbles on the neurovascular unit

“…This effect can last for as long as 7 weeks (Table 3). 25,28,49,105,111 For some cases, astrocyte reactivity was reported to recover within 2 weeks for single location treatment and within 13 weeks for large volume treatment. 25,111 In a high-grade murine glioma model, moderate and heterogeneous astrocyte activity (GFAP expression) was observed in tumor regions without FUS+MB treatment, whereas increased astrogliosis and astrocyte activity were observed in regions of tumors targeted with FUS.…”

“…Several preclinical studies have observed FUS+MB-induced microglia activation using methods from immunohistochemistry staining of Iba1 to noninvasive PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO) at the site of BBB disruption. 25,28,49,53,111,121 FUS+MB-induced microglia activation occurred as early as 1 hour after sonication and may last for as long as 7 weeks while the recovery time ranges from 24 hours to 13 weeks (Table 4). Both single and multiple treatments of FUS+MB have been shown to activate microglia in the sonicated cortex.…”