A Clinical System for Non-invasive Blood-Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer

Abstract

Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is currently being investigated in clinical trials. Here, we describe a portable clinical system with a therapeutic transducer suitable for humans, which eliminates the need for in-line magnetic resonance imaging (MRI) guidance. A neuronavigation-guided 0.25-MHz single-element FUS transducer was developed for non-invasive clinical BBB opening. Numerical simulations and experiments were performed to determine the characteristics of the FUS beam within a human skull. We also validated the feasibility of BBB opening obtained with this system in two non-human primates using U.S. Food and Drug Administration (FDA)-approved treatment parameters. Ultrasound propagation through a human skull fragment caused 44.4 ± 1% pressure attenuation at a normal incidence angle, while the focal size decreased by 3.3 ± 1.4% and 3.9 ± 1.8% along the lateral and axial dimension, respectively. Measured lateral and axial shifts were 0.5 ± 0.4 mm and 2.1 ± 1.1 mm, while simulated shifts were 0.1 ± 0.2 mm and 6.1 ± 2.4 mm, respectively. A 1.5-MHz passive cavitation detector transcranially detected cavitation signals of Definity microbubbles flowing through a vessel-mimicking phantom. T₁-weighted MRI confirmed a 153 ± 5.5 mm³ BBB opening in two non-human primates at a mechanical index of 0.4, using Definity microbubbles at the FDA-approved dose for imaging applications, without edema or hemorrhage. In conclusion, we developed a portable system for non-invasive BBB opening in humans, which can be achieved at clinically relevant ultrasound exposures without the need for in-line MRI guidance. The proposed FUS system may accelerate the adoption of non-invasive FUS-mediated therapies due to its fast application, low cost and portability.

Keywords: Blood–brain barrier; Clinical system; Drug delivery; Focused ultrasound.

Fig. 1 :

Clinical setup with a single-element transducer and neuronavigation guidance.

Fig. 2 :

Numerical simulations of ultrasound propagation with different single-element transducers (top to bottom: 1, 2, 3) emitting pulses of variable length (left to right: 1, 5, 25, 2,500 cycles). Transducer 3 was the only configuration that was able to treat deep structures without presenting multiple sidelobes within the human skull. Color bar: normalized focal pressure. Each pressure profile was self-normalized to the maximum acoustic pressure within the skull to illustrate the −3dB focal volume. Pressure values refer to the maximum instantaneous pressure at each location.

Fig. 3 :

Numerical simulations of ultrasound propagation with the clinical focused ultrasound (FUS) transducer targeting structures of variable depth within a human skull. Examples are shown for transducer axial offset of −30 mm to 20 mm (offset = 0mm when the focus in free field coincides with the midline). Center frequency: 0.25 MHz, pulse length: 2,500 cycles. Color bar: normalized focal pressure. Each pressure profile was self-normalized to the maximum acoustic pressure within the skull to illustrate the −3dB focal volume. Pressure values refer to the maximum instantaneous pressure at each location.

Fig. 4:

Lateral (top) and axial (bottom) profiles of the simulated pressure field within a human skull. Lateral sidelobes and interference patterns emerge for pulse lengths larger than 1 cycle. The spatial length of interference away from the distal skull bone increases linearly with the pulse length.

Fig. 5 :

Simulated human skull-induced focal distortion. (a) Full width at half maximum (FHWM) change due to the presence of the human skull. FWHM changes were first averaged across the pulse lengths for each axial offset (n = 4 pulse lengths), and then averaged across all depths (n=6 axial offsets). (b) Simulated focal shifts along the axial (red crosses) and lateral (blue boxes) dimensions. Diagonal dotted-dashed line and parallel dotted line denote axial and lateral shifts equal to zero, respectively (n=4 pulse lengths). (c) Average focal shifts across the lateral and axial dimensions (n=6 axial offsets). Data presented as mean ± standard deviation.

Fig. 6:

Experimental human skull-induced focal distortion. (a) Experimental setup for measuring focal distortion using a hydrophone. A raster scan was performed to measure the focal volume in (b, c-left) free field and (b, c-right) with a human skull fragment. Pressure maximum was 10 mm closer to the transducer compared to the geometric focus. White crosses denote the position of the free-field focus. Green crosses denote the position of the focus following transcranial propagation. (d) full width at half maximum change and (e) focal shifts along the lateral and axial dimensions. Data presented as mean ± standard deviation (n=10 scans with ultrasound propagating through skull segments of different thickness).

Fig. 7:

Passive cavitation detection through the human skull. (a) In vitro setup for passive cavitation detection. A 0.8-mm tube filled with Definity microbubbles was used as a vessel-mimicking phantom. (b) Spectra of control (transparent orange line) and microbubble (black line) acoustic emissions for mechanical index (MI) of 0.4 (left), 0.6 (middle), and 0.8 (right) in free field. (c) Spectra of control and microbubble acoustic emissions through the human skull. (d) Cavitation levels in free-field (circles, plus signs) and through the human skull (crosses, diamonds), for control (light bars) and microbubbles (dark bars), at MI of 0.4 (left), 0.6 (middle), and 0.8 (right). Data presented as mean ± standard deviation (n=10 pulses). *: p < 0.05.

Fig. 8:

Skull heating using the clinical focused ultrasound transducer at mechanical index (MI) of 0.4 (red line), 0.6 (green line), and 0.8 (blue line) and clinically-relevant ultrasound parameters (center frequency: 0.25 MHz, pulse length: 2,500 cycles or 10 ms, pulse repetition frequency: 2 Hz, duty cycle: 2%, total duration: 2 minutes). A higher duty cycle (i.e., 20%) was used as a positive control for heating (black line). Data presented as mean ± standard deviation (n=3).

Fig. 9:

In vivo feasibility in a non-human primate (NHP) model. Coronal T₁-weighted, T₂-weighted and susceptibility-weighted imaging (SWI) for NHPs 1 (left) and 2 (right). T₁-weighted MRI confirmed blood-brain barrier opening in the thalamus (NHP 1) and dorsolateral prefrontal cortex (NHP 2), using the clinical focused ultrasound (FUS) transducer with clinically relevant parameters (MI: 0.4) and FDA-approved Definity microbubble dose (10 μl/kg). T₂-weighted and SWI showed that there is no acute hemorrhage or edema after the FUS treatment. Color bar: normalized contrast enhancement. Scale bar: 1 cm.

Fig. 10:

In vivo passive cavitation detection measurements confirmed that stable cavitation dominated throughout ultrasound treatment at clinically-relevant conditions. Spectral amplitude (a, d) before and (b, e) after microbubble injection, for non-human primate (NHP) 1 (a, b) and NHP 2 (d, e). Spectrogram of the entire treatment session for NHP 1 (c) and NHP 2 (f). Higher harmonic emissions were detected, with no substantial increase in the broadband floor after microbubble entrance into the focal volume (white dashed lines). (g)-(h) Stable harmonic cavitation levels (black line) rose right after microbubble administration (dashed line) and remained relatively constant throughout the sonication, for both NHP 1 (g) and 2 (h). Stable ultraharmonic (blue line) and inertial cavitation levels (red line) had a moderate increase, indicating absence of violent cavitation events at MI of 0.4. Arrows indicate the time points shown in (b) and (e). (i) Average stable harmonic (black), stable ultraharmonic (blue) and inertial (red) cavitation dose during focused ultrasound treatment for NHP 1 (filled bars) and NHP 2 (patterned bars), following microbubble administration (t > 15s). Data presented as mean ± standard deviation (n = 210 pulses).