Stereotactic Transcranial Focused Ultrasound Targeting System for Murine Brain Models

Abstract

An inexpensive, accurate focused ultrasound stereotactic targeting method guided by pretreatment magnetic resonance imaging (MRI) images for murine brain models is presented. An uncertainty of each sub-component of the stereotactic system was analyzed. The entire system was calibrated using clot phantoms. The targeting accuracy of the system was demonstrated with an in vivo mouse glioblastoma (GBM) model. The accuracy was quantified by the absolute distance difference between the prescribed and ablated points visible on the pre treatment and posttreatment MR images, respectively. A precalibration phantom study ( N = 6 ) resulted in an error of 0.32 ± 0.31, 0.72 ± 0.16, and 1.06 ± 0.38 mm in axial, lateral, and elevational axes, respectively. A postcalibration phantom study ( N = 8 ) demonstrated a residual error of 0.09 ± 0.01, 0.15 ± 0.09, and 0.47 ± 0.18 mm in axial, lateral, and elevational axes, respectively. The calibrated system showed significantly reduced ( ) error of 0.20 ± 0.21, 0.34 ± 0.24, and 0.28 ± 0.21 mm in axial, lateral, and elevational axes, respectively, in the in vivo GBM tumor-bearing mice ( N = 10 ).

Fig. 1.

Mouse fixture frame and the stereotactic setup. a) shows the stereotactic setup and the sequence used for co-registration. The fixture frame (2) is screwed (3) into the treatment bed (1), and pins of histotripsy transducer (4) are inserted into the treatment bed for completion of co-registration. CAD design of the fixture frame is shown on panel b). Panel c) shows a photograph of the frame holding a mouse head with ear bars.

Fig. 2.

Axial and frontal setup of the stereotactic FUS setup and the associated components. Major components of the stereotactic setup are ultrasound transducer, treatment bed, and fixture frame. Minor components of the stereotactic setup include a water tank, a transducer holder and a 3-axis positioner (a). All components were adjusted to minimize angular registration errors. b) & c) illustrate ways these associated components (motor positioner to transducer connection and water tank misalignment) can contribute to imperfect co-registration of the stereotactic setup. An optical rod that is connected to the motor holds both the transducer holder and the histotripsy transducer. The longer the optical rod hangs down, the larger the tilt, as illustrated in (b). In addition, the motor stage, on which the motor is mounted to, needs to align with the water tank (c). Any source of misalignment causes misdirected translation by the motor system. These errors can be calculated by the cosine law. Labels: 1) motorized 3-axis positioner, 2) spirit level, 3) transducer holder, 4) water tank, 5) Positioner to transducer connector, 6) motor stage, 7) Histotripsy transducer.

Fig. 3.

Treatment planning procedure for murine stereotactic FUS. Fiducial markers (1) and tumor (2) are localized. Center of the tumor is prescribed as an ablation point (3) and the transducer is steered towards the target point before initiating FUS pulse delivery.

Fig. 4.

Calculating the targeting error. From the center of a fixed internal brain structure marked in x, the distance to the prescribed region and the distance to the centroid of the histotripsy lesion are compared to determine the targeting inaccuracy.

Fig. 5.

Stereotactic FUS system calibration through a linear correction factor. Without correction (“No Correction”), the difference between prescribed point to ablation point, i.e., error, was >1 millimeter. After understanding that a system bias exists and a constant multiplicative factor can be applied to reduce the targeting error (“Theoretical Correction Applied”), another batch of clot phantom experiments showed reduced error to submillimeter (“Post-correction”). On a), CD stands for correct distance, K for constant multiplicative factor, and wST for wrong steering distance originally calculated that did not account for the system bias.

Fig. 6.

Histotripsy ablation of multiple tumor-bearing mice. T2 weighted pre-treatment image shows GBM tumor (left) with red dots as prescribed ablation points. The ablated region appears dark (thought to be coagulated blood) on the post-treatment image (right) indicated by the blue dot. The tumor appears in the left brain in the images because the mice are lying supine when imaged.