A local difference in blood-brain barrier permeability in the caudate putamen and thalamus of a rat brain induced by focused ultrasound.
Authors: Huh H, Park TY, Seo H, Han M, Jung B, Choi HJ, Lee EH, Pahk KJ, Kim H, Park J
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 (K<sub>trans</sub>) was quantitatively evaluated with dynamic contrast-enhanced magnetic resonance imaging. The group averaged (n = 11) maximum K<sub>trans</sub> at Cp (0.021 ± 0.012 min<sup>-1</sup>) was 1.39 times smaller than the K<sub>trans</sub> of Th (0.029 ± 0.01 min<sup>-1</sup>) 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 K<sub>trans</sub> and showed a negatively linear relation R<sup>2</sup> = 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<sup>-11</sup>. 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.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To investigate how ultrasound incidence angle and target location (caudate putamen vs thalamus) affect focused ultrasound-induced blood–brain barrier permeability in rats when delivering the same acoustic power.
Animal model / Human subject
Sprague–Dawley rat (Rattus norvegicus), 8 weeks old, male
Disease model
Healthy
MRI or image guidance method
MRI-guided focused ultrasound (MRgFUS) using a pre-clinical MRgFUS system (RK-100); target centers defined relative to bregma/lambda stereotactic coordinates; CT used to measure skull incidence angles.
Targeted brain region(s)
Thalamus
Target coordinates
Cp reference (R2): 1.5 mm anterior to bregma (AP +1.5 mm), 1.5 mm right of midline (ML +1.5 mm), focal depth ~5 mm below skull (DV ~5 mm). Th reference (R6): 3.5 mm anterior to lambda (AP +3.5 mm relative to lambda), 1.5 mm right of midline (ML +1.5 mm), focal depth ~5 mm below skull (DV ~5 mm). Each region had four target centers (Cp R1–R4; Th R5–R8) spaced 1.5 mm apart.
Outcomes and Safety
Summary of Outcomes
Focused ultrasound at a free‑field acoustic pressure corresponding to 0.65 MPa (1.113 MHz) produced localized BBB opening in rats with higher permeability in thalamus (Ktrans 0.029±0.01 min−1) than caudate putamen (Ktrans 0.021±0.012 min−1) and only minor RBC extravasation without overt tissue damage. Effective conditions associated with greater BBB disruption were lower incidence angles (strong negative correlation with Ktrans, R2=0.797) which yielded higher simulated focal pressures (Th ~0.37±0.02 MPa vs Cp ~0.32±0.01 MPa); simulations also showed standing‑wave effects when the skull cap was altered.
Safety-related matter
They observed only a few extravasated red blood cells near blood vessels and no significant tissue damage. The authors caution that excessive acoustic energy can induce adverse effects (extravasation, intracerebral hemorrhage, tissue damage, edema) and cite reports of possible inflammation after pulsed FUS.
Brain Region
Ultrasound Parameters
Ultrasound instrument
RK-100 (FUS Instruments, Toronto, Canada); spherically curved single-element piezoelectric transducer, diameter 75 mm, focal length 60 mm, resonant frequency 1.113 MHz
FUS Frequency
1.113 MHz (carrier); 1 Hz (pulse repetition frequency)
FUS Pressure
0.65 MPa (peak rarefaction focal pressure, free field); 0.37 ± 0.02 MPa (maximum acoustic pressure at Th, computed); 0.32 ± 0.01 MPa (maximum acoustic pressure at Cp, computed)
FUS Mode
pulsed
Pulse duration
10 ms
Duration of a single FUS session
120 s
Focal Characteristics
Focal depth: 5 mm; Focal length: 60 mm; Aperture size: 75 mm
Treatment frequency
Single
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