Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging.

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To investigate whether the mechanical index (MI) and cavitation index (CI) can accurately gauge the level of focused ultrasound (FUS)-induced blood–brain barrier (BBB) opening using dynamic contrast-enhanced MRI and passive cavitation detection analyses.

Animal model / Human subject Male Sprague - Dawley rats (250-300g, 8 week-old)

Disease model Blood-brain barrier opening (focused ultrasound-induced)

MRI or image guidance method Dynamic contrast-enhanced MRI (DCE-MRI)/contrast-enhanced MRI was used to assess and correlate the extent of BBB opening; passive cavitation detection (PCD) was used to monitor cavitation during focused ultrasound.

Targeted brain region(s) Not Specified In The Provided Text

Target coordinates AP 0mm, ML 3.5mm from bregma

Cargo name and characteristics Ultrasound contrast microbubbles — gas-filled (lipid/protein/shell) microbubble contrast agents used as cavitation nuclei for focused ultrasound (FUS)-mediated blood–brain barrier (BBB) opening; induce stable cavitation monitored by cavitation index (CI) and mechanical index (MI). (Study also used MRI contrast for DCE-MRI assessment.)

Route of administration Intravenous

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) with intravenous microbubbles produced a dose‑dependent, transient opening of the blood–brain barrier (BBB). DCE‑MRI pharmacodynamic and pharmacokinetic metrics (SI change, Gd‑AUC, Ktrans, Ve) increased monotonically with exposure and correlated highly with both Mechanical Index (MI) and Cavitation Index (CI). Low MI/CI exposures produced mild, reversible BBB opening with light Evans‑Blue (EB) leakage and were dominated by stable cavitation (increased stable cavitation dose, SCD) without detectable inertial cavitation. Higher MI/CI exposures produced greater BBB permeability, larger Gd and EB accumulation, longer BBB‑closure half‑lives, and were accompanied by inertial cavitation (increased inertial cavitation dose, ICD), erythrocyte extravasation and histologic damage. BBB closure occurred over hours and half‑life increased with exposure level. Overall, both MI and CI are valid indices to gauge FUS‑induced BBB opening (MI performed slightly better across conditions), with suggested safety thresholds (MI ≲0.6 for intact reversible opening; CI ≲0.45 in the >0.8 MHz range to avoid extensive extravasation). These findings support using DCE‑MRI plus MI/CI/PCD monitoring to control therapeutic, noninvasive CNS drug delivery and to minimize hemorrhagic adverse effects.

Duration of biological effect BBB-opening half-life ≈ 2.47–2.67 hours for intermediate FUS exposure and ≈ 3.24–4.34 hours for excessive FUS exposure (BBB recovery followed up to 24 h).

Safety-related matter The paper reports safety-related adverse effects associated with higher FUS exposure: high MI/CI values induced more aggressive BBB opening with increased Evans blue leakage and erythrocyte extravasations (histology confirmed), and severe erythrocyte extravasations/brain damage were observed at excessive exposure levels. Exposures exceeding ~0.6 MI were consistently associated with erythrocyte extravasation and brain damage, whereas exposures in the ~0.25–0.6 MI range could induce intact/mild BBB opening without significant erythrocyte extravasation or brain damage. Passive cavitation detection showed that mild exposures produced increases in stable cavitation dose (SCD) without inertial cavitation dose (ICD), but higher exposures markedly increased ICD (examples: large % increases) which the authors implicate in erythrocyte extravasations. The authors note that CI > ~0.45 can involve extensive inertial cavitation and caution that CI alone may be insufficient outside its applicable range. They propose using MI and CI together (and DCE‑MRI monitoring) to gauge and control BBB opening for safer FUS-mediated CNS drug delivery.

Brain Region

Ultrasound Parameters

Ultrasound instrument 0.4-MHz FUS transducer (Imasonic, France; diameter = 60 mm, radius of curvature = 80 mm, and electric-to-acoustic efficiency = 70%)

FUS Frequency Not specified in the provided text 0.4MHz and 1.0MHz

FUS Intensity Not reported in provided text

FUS Pressure 0.25-0.83MPa

FUS Mode pulsed

Pulse duration 10ms

Duration of a single FUS session 90 sec

Focal Characteristics 0.4MHz 2mm and 10mm; 1MHz for 1.2mm and 9.8mm

Treatment frequency single session

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