A pre-clinical MRI-guided all-in-one focused ultrasound system for murine brain studies

Abstract

This paper describes the design and initial proof-of-concept of a single pre-clinical transcranial focused ultrasound (FUS) system capable of performing histotripsy (mechanical ablation), hyperthermia, blood-brain barrier opening (BBBO), sonodynamic therapy, or neuromodulation in a murine brain. We have termed it the All-in-One FUS system for murine brain studies, which is the first FUS system of its kind. The 1.5 MHz ultrasound transducer was fabricated and driven using a custom electronic driver to produce 3-cycle pulses with a focal peak-negative pressure (P-) of up to 87 MPa at a low duty cycle (< 0.1%) for histotripsy as well as 50% duty cycle pulsed-ultrasound with a spatial-peak temporal-average intensity (I_spta) of up to 251 W/cm² for the other FUS modalities. This All-in-One system can be guided by MRI or stereotactically to maximize its flexibility. To validate the design of the system, histotripsy, BBBO, and hyperthermia were performed in naïve brains of two mice for each modality. Histotripsy and BBBO were performed using MRI-based stereotactic co-registration. The therapeutic effect was confirmed using T2-weighted MR-images for histotripsy, and T1-weighted Gadolinium contrast-enhanced MR-images for BBBO. For hyperthermia, an MRI-compatible insert was designed to fit inside the 80 mm imaging coil of a 7-Tesla small-animal MRI-system, with T2-weighted MR-images used to confirm targeting, and MR-thermometry used to monitor the thermal dose delivered.

Keywords: Blood-brain barrier opening; Brain; Histotripsy; Hyperthermia; Magnetic resonance imaging (MRI); Therapeutic ultrasound.

Fig. 1

Exploded cross-sectional drawing of the transducer’s front view (left), top view photograph of the 3D printed scaffold (right).

Fig. 2

CAD design of the supporting structures used for: MRI-based stereotactic co-registration of the transcranial treatments performed outside the MRI scanner (A); platform for transcranial treatments performed inside the MRI scanner (B).

Fig. 3

Schematic of a single channel of the electronic driver. A pair of SiC transistors alternate sourcing and sinking current output to the transducer through an LC impedance matching circuit.

Fig. 4

Fabricated transducer and its electronic driver (a), in-vivo setup using MRI-based stereotactic-guidance used for histotripsy, BBBO treatments outside the MRI-scanner (b), in-vivo setup using MRI-guided treatment and monitoring for hyperthermia (c).

Fig. 5

Free-field lateral (left) and axial (right) field maps of the transducer.

Fig. 6

Pressure-voltage curves of the transducer for the 3-cycle histotripsy pulses with the directly measured pressure values denoted by ‘o’s and the summed pressure values denoted by ‘*’s (a, b). Representative pressure-temporal waveforms for histotripsy (c), hyperthermia (d) & BBBO (e).

Fig. 7

The representative histotripsy lesion, viewed in a T2-w sagittal MR-image as a hypointense region (blue arrow) (a), and the hydrophone acoustic receive signals in the time showing signals corresponding to the bubble nucleation and subsequent collapse (b) and broadband signals in the frequency domain conducive with inertial cavitation (c).

Fig. 8

T1-weighted Gd-enhanced images showing two focal regions of BBBO corresponding to the two targeted locations (blue arrows) (a), T2* images showing no hypointense regions of bleeding/edema (blue arrows) (b), hydrophone signal showing stable cavitation (c).

Fig. 9

Anatomical T2w MR-image showing the entire setup inside the scanner (a). The mouse brain with the target location (blue arrow) shown in the T2w image. MR-thermometry (gradient-echo) images right when the ultrasound is turned on (t = 96 s), when the heating reaches its peak (t = 192 s), and 1 min after the ultrasound is turned off (t = 249.6 s).