MR-guided transcranial brain HIFU in small animal models

Abstract

Recent studies have demonstrated the feasibility of transcranial high-intensity focused ultrasound (HIFU) therapy in the brain using adaptive focusing techniques. However, the complexity of the procedures imposes provision of accurate targeting, monitoring and control of this emerging therapeutic modality in order to ensure the safety of the treatment and avoid potential damaging effects of ultrasound on healthy tissues. For these purposes, a complete workflow and setup for HIFU treatment under magnetic resonance (MR) guidance is proposed and implemented in rats. For the first time, tissue displacements induced by the acoustic radiation force are detected in vivo in brain tissues and measured quantitatively using motion-sensitive MR sequences. Such a valuable target control prior to treatment assesses the quality of the focusing pattern in situ and enables us to estimate the acoustic intensity at focus. This MR-acoustic radiation force imaging is then correlated with conventional MR-thermometry sequences which are used to follow the temperature changes during the HIFU therapeutic session. Last, pre- and post-treatment magnetic resonance elastography (MRE) datasets are acquired and evaluated as a new potential way to non-invasively control the stiffness changes due to the presence of thermal necrosis. As a proof of concept, MR-guided HIFU is performed in vitro in turkey breast samples and in vivo in transcranial rat brain experiments. The experiments are conducted using a dedicated MR-compatible HIFU setup in a high-field MRI scanner (7 T). Results obtained on rats confirmed that both the MR localization of the US focal point and the pre- and post-HIFU measurement of the tissue stiffness, together with temperature control during HIFU are feasible and valuable techniques for efficient monitoring of HIFU in the brain. Brain elasticity appears to be more sensitive to the presence of oedema than to tissue necrosis.

Figure 1

A dedicated experimental setup (A) for rat HIFU investigations ensures the positioning of the transducer against the animal head and limits motion artefacts due to respiration. It also enables to steer the US beam in the rat brain in order to target a desired location. The piezoelectric US single element transducer is placed on top of the shaved head (B).

Figure 2

Normalized pressure field created by a 1.5MHz circular focused transducer with F=D=25mm. The focal spot dimensions at −6dB are 1 by 1 by 8 mm.

Figure 3

The radiation force induced displacements are mapped in 1 to 5 slices oriented perpendicularly to the US beam. 75Hz sinusoidal Motion Sensitizing Gradients (MSG) are added to a standard multislice spin echo sequence in the slice selection direction to encode the displacements along the US beam (A). US are switched on during the third quarter of each MSG period to optimize the motion encoding and keep the US duty cycle as low as possible. For the elastography acquisition, a piezoelectric bending plate coupled to the skull generates 400Hz sinusoidal motion in the brain. The 3D displacement field is mapped in 30 adjacent slices. 400 Hz MSG are added to a standard multislice spin echo sequence (B). 8 different delays d are sequentially recorded for each of the 3 gradient axes so that to cover one full excitation cycle.

Figure 4

Simulated displacement profiles along the central line in the focal plane at 4 different times after the beginning of the 3ms US emission (main frame): 1ms (solid line), 3ms (broken line), 5ms (dotted line) and 7ms (mixed line). Simulations were done assuming a density of 1000kg/m³, a speed of sound of 1540m/s, an attenuation factor of 6Np/m/MHz, a peak pressure value of 2.66MPa, a shear velocity of 1.5m/s and a shear viscosity of 1Pa.s. The time profile of the maximum displacement at the focus for a 3ms pulse is given in the top right corner.

Figure 5

Evolution of the sensitivity to motion S (blue line) and the normalized amplitude of the displacement at the end of the Motion Sensitizing Gradients (green line) as a function of the US pulse duration (given in fraction of MSG periods). A 3ms burst duration (corresponding to 0.225 T) was experimentally found as an optimum. Simulations were done assuming a density of 1000kg/m³, a speed of sound of 1540m/s, an attenuation factor of 6Np/m/MHz, a peak pressure value of 2.66MPa, a shear velocity of 1.5m/s and a shear viscosity of 1Pa.s.

Figure 6

Experimental MR phases obtained in the rat brain (green circles) for different voltages on the transducer. The pressure values are the estimated ones according to the calibration of the transducer in a water tank. Simulated maximum MR phase signal for different acoustic pressure (dotted line). Simulations were done assuming a density of 1000kg/m³, a speed of sound of 1540m/s, an attenuation factor of 6Np/m/MHz, a shear velocity of 1.5m/s and a shear viscosity of 1Pa.s. Simulations are in good agreement with the experimental results.

Figure 7

The full protocol was performed in a turkey breast sample: The focal point corresponds to the maximum displacement in the coronal slice corresponding to the focal plane (A). The thermometry map (B) at the end of a 35 seconds HIFU session is clearly correlated with the radiation force map (A). The time profile of the absolute temperature at focus is given on image C (green circles) in degree Celsius together with the corresponding simulated data (blue line). The elastography maps before (D) and after (E) the HIFU session show an increased stiffness at the focal point several minutes after HIFU. The scale for elasticity is given in kPa. Image F presents a post-treatment cut of the necrosed sample along the beam axis.

Figure 8

Validation of the proposed protocol in the rat brain in vivo. Magnitude image from the MR-ARFI sequence in the coronal plane corresponding to the focal plane of the HIFU transducer (A). Corresponding motion encoded phase image allowing the accurate localization of the US focal spot and the quantitative calibration of the sent pressure with limited sent energy (B). The focal spot can also be imaged along the beam as shown on axial images (magnitude E, phase F). Map of the temperature elevation (C) in the same coronal slice as (B) during an HIFU session after 100s. Temperature in °C at the focus (D) as a function of time (green circles) together with the results of finite difference simulations of the same experiment with (red dashed line) and without (blue solid line) considering the perfusion term in eq(6). Axial T2 image immediately after the HIFU session (G). The red arrow indicates early inflammatory response of the cortex and the skin in contact with the heated skull.

Figure 9

Evolution of the T2 hypersignal and elasticity in the plane of maximum heating. Left column: T2 axial images at four time steps: before HIFU, after 3, 14 and 21 days. Red arrows indicate abnormal T2 hyposignals. Middle and right columns: corresponding MRE magnitudes slices and reconstructed elasticity maps μ(kPa). Red arrows indicate the abnormally soft region.

Figure 10

Right: Horizontal histology slice around the location of the T2 hyposignal on figure 9. Left: Microscopic view of the thermally induced lesion showing macrophage necrosis and astroglyosis.