In the case of infinite media without boundaries, this equation admits solutions of the form This equation is used in Chapter 5 in the optimized design of a new phased array transducer.
Clinical status of focused ultrasound procedures
Background: Thermal Ablation
RF and MW ablation use probe-mounted temperature sensors that provide only rough estimates of the temperature in the treatment volume [47]. A detailed consideration of essential tremor and fibroid ablation with HIFU is discussed in the following paragraphs.
Essential Tremor: Ablation of the thalamus
Surgical options are RF ablation or deep brain stimulation (DBS), both of which target the Vim nucleus in the thalamus, which is a central relay in neural motor control. Additionally, 6% of patients in the HIFU trial appeared to have cranial tissue that transmitted sound less efficiently than others, making it difficult to achieve the ablative temperature.
Uterine Fibroid Ablation
However, retrospective analysis suggests that FUS ablation is equally effective for both RF and UAE with fewer associated risks. FUS treatments had the lowest rate of complications but also lower treatment efficacy and increased need for retreatment compared to RF and UAE.
Pre-clinical and research stage FUS
Background - Cavitation
Acceleration of heating is thought to work through the scattering of the primary acoustic wave via viscoelastic and acoustic effects that create viscous shear flows at the bubble-tissue interfaces and the generation of energy at higher harmonics of the transmitted frequency which are preferentially absorbed in most tissues. [16]. [67]. When the PNP is large enough, during expansion, the interior of the gas bubble becomes so weak that it can no longer resist the pressure of the surrounding environment and will collapse violently via 'inertial cavitation', producing local liquid jets and waves impacts that can damage or destroy nearby structures [68].
Mild hyperthermia
Cavitation has been observed in HIFU and used to improve thermal therapy by increasing the rate of temperature increase in the target. It has been repeatedly observed that the transition from 0% to 100% cavitation probability follows a steep sigmoid curve that occurs rapidly as the PNP approaches the cavitation threshold.
FUS Neuromodulation
Indirect effect - Activation of drug carriers and opening of the BBB: An alternative method of modulating neural activity in the brain is through spatially targeted delivery of pharmacological agents beyond the endothelial layer known as the blood-brain barrier (BBB). BBB selectivity allows it to play a critical role in maintaining homeostasis, but also limits the potential for pharmacological targets in the brain.
REVIEW OF TRANSDUCERS AND IMAGE GUIDANCE
Transducer Materials
For many years, the primary implementation of PZT transducers was piezoceramics, which are single, continuous bulk crystal masses. First, multiple vibrational modes occur across the bulk crystal mass and part of the energy is converted into lateral waves along the surface, reducing the longitudinal wave output [94] .
Phased-array Transducer Design
- Imaging vs. Therapeutic Arrays
- Spherically-focused arrays
Geometry, element distribution, and packing density affect sound power and control capabilities, as discussed in the text. Secondary maxima in the transmission field (often synonymous with gratings in the focused ultrasound literature) can cause heating in non-target regions in hyperthermia.
Deep Brain
The simultaneous limitations of a large radius of curvature for non-invasive deep tissue sonication and a focal length ratio between 0.5 - 1.0 for efficient focal gain without grating lobes lead to large area transducers (Figure 2.2). In 1999, Daum and Hynynen presented a 256-element spherical cap array for ablation with a radius of curvature of 10 cm and focal length 0.83.
The surface area was close to 100% covered with equal area elements, the element spacing was nearly periodic and chosen to allow safe electronic control within a 1x1 cm^2 area around the natural focus while maintaining the grating lobes < 10% of the focal pressure [ 106 ].
Body
Sparse arrays
Sparse spherical arrays have also received significant attention as a way to achieve large aperture capabilities with a cost-effective number of elements. Furthermore, if the same active area is distributed over a small number of large elements, vs.
Image Guidance
- Selective Targeting with Focused Ultrasound
Their system used 16 MR-localized tracking coils rigidly attached to a transducer with a 5-DOF in-bore positioning system and, after calibration with pilot heating scans, had an average targeting accuracy of 2.1 mm [117]. They measured the location of the acoustic fountain created by the focus at several motor positions and marked these locations within MR coordinates using an MR-visible mechanical transfer plate that provides registration between the motor position and the focus in MR.
Passive Optical Tracking
- Background
- Optically Tracked Focused Ultrasound
For MR-independent calibration, a caterpillar was attached to a copper rod, the length equal to the radius of curvature of the transducer (ROC), and a rotation test was performed to determine the approximate focal spot offset. The tracker was then mounted on the back of the transducer so that the displacement vector could be used to predict focus.
REDUCTION OF CAVITATION IN MULTI-FOCAL MILD HYPERTHERMIA
Introduction
Summary
Multi-focal sonications used four points equally spaced on a ring of either 4 mm or 8 mm diameter. Results: Multi-focal sonication generated distinct foci visible in MRI thermal maps in both phantoms and porcine and only visible in PAM images in phantoms.
Background: Cavitation in Thermal HIFU
The multi-focal methods used in our study can deliver mild hyperthermia in the absence of cavitation and may be preferable in cases where mechanical cavitation may impede dose delivery. This chapter compares the effect of single and multifocal continuous wave (CW) HIFU on heating while quantifying cavitation activity.
Methods
- Multi-focal sonication
- Passive Acoustic Mapping (PAM)
- Probe alignment and registration
- MR Temperature Mapping
- Sample Preparation
- Phantom and pork sonications
- Data Analysis
The US imaging plane was roughly aligned with the HIFU focal plane in the following manner. Both broadband noise and total variance were compared with a PAM-derived measure of cavitation, which we expressed as the mean pixel value of a reconstructed PAM image (i.e., the mean of a reconstructed image ).
Results
- Multi-focal sonications generated distinct foci
- PAM imaged simultaneous cavitation nuclei
- PAM correlated with standard cavitation metrics
- Multi-focal sonication reduced cavitation
- Multi-focal sonications reduce peak heat
The PAM technique was able to resolve foci in single- and multifocal ultrasound treatments in the phantom. Although cavitation activity was always highest initially with the single-focus beam, the 4-mm multifocal beam had similar mean variance to the single-focus beam.
Discussion
- Summary of results
- PAM imaging of multi-focal cavitation
- Temporal evolution of cavitation
- Diffuse heating with multi-focal ultrasound
- Study limitations
- Potential applications
Standard cavitation data (broadband noise level and channel variance) correlated linearly with mean PAM image values, and multifocal sonifications generated less cavitation activity and more diffuse heating. In Figure 3.5a, transient bursts superimposed on exponential decay can be seen in the single-focal channel variance curves, but not to the same extent in the multifocal curves.
Conclusion
Thermally sensitive liposomal carriers loaded with doxorubicin have been used preclinically with ultrasound-induced hyperthermia to effectively treat several cancer models [70]-[74].
OPTICALLY-TRACKED FUS IN TRANSCRANIAL NEUROMODULATION
Introduction
The results of ray mapping from the internal cranial cavity are presented in Chapter 5, but the hydrophone tracking presented in this chapter is relevant to these results. The calibrated system has been used in in vivo MR ARFI ultrasonography in the rhesus macaque monkey, and—to our knowledge—the displacement maps presented in this chapter represent the first of their kind from transcranial FUS in a large (non-rodent) live mammalian head.
Summary
The accuracy (TRE) of the method was assessed by multi-slice MR thermometry in phantoms and shown to be within the range of conventional optically guided surgery. The new approach enabled two unprecedented experimental techniques: real-time projection of the estimated FUS beam shape during aiming, and beam mapping along the inner surface of an ex vivo skull.
Methods
- Materials
Transducer (T) Reference (R)
Pivot
All MR scans were performed on a Philips 7T machine using a custom single-channel surface coil and threaded housing attached to the transducer cone at the port. All phantom ultrasound treatments were in a tissue-mimicking gel. Figure 4.2 Coordinate systems involved in projecting beam voxels into MR image space.
3-axis motor stage (M)
In the first two rounds of calibration experiments, a small 3D printed tracker and a metal tracker from NDI (removed before each scan) were used as reference and target trackers, respectively (Figure 4.1b). Acoustic voxels are defined by motor phase (M), recorded at the tracked position of the hydrophone tip, and converted to transducer coordinates (T).
Transducer (T)
Donut-shaped MR-visible reference markers were used for image registration (MM3003, IZI Medical Products). At the scanner, these acoustic voxels are projected into the MR scan volume (S) after fiducial registration.
Tracked hydrophone
An NDI Polaris Vicra tracking system was used for all optical guidance (Northern Digital Inc., Waterloo, Ontario, CA), with two sets of rigid body trackers.
MR scan volume (S)
Projected beam map
- Calibration and Optically Tracked Beam Mapping
- MR-guided Experiment Setup
- Registration and Targeting
- Sonication in Phantoms to Measure TRE
- Sonications in vivo
- Acoustic Radiation Force Imaging (ARFI)
- Data Analysis
The transducer+cone+tracker assembly was then joined on the side of the water tank. The calibrated tracer was mounted on the back of the transducer and the second tracer was fixed to it.
802 kHz 250 kHz
Results
Bundle maps (Figure 4.3) show that the H115 in the coupling cone is focused about 1 cm beyond the cone opening. As shown in Figure 4.6, the bias correction did not appear to completely correct the errors observed in Round 1, but instead rotated the error to a different axis.
Animal 1, Coronal Animal 2, Coronal
Animal 2, SagittalAnimal 1, Transverse
Discussion
- Tracking Accuracy and Error Sources
Several donut-shaped fiducials were difficult to access with the tracked probe, which may have resulted in repeated localization errors. An error in the configuration of one or both optically tracked bodies may also have contributed to the observed bias.
TargetBias
TRE distribution
In vivo ARFI
The two main reasons are likely to be aberration through the skull and geometric scaling differences between THRIVE and ARFI scans. Scaling/distortion between superimposed THRIVE and ARFI scans was clearly visible based on the shape of the skull and head in the two scans.
Conclusions
The distance from the predicted focus is difficult to estimate because of how spread out the observed spot was and because ARFI scans are 2D (single-slice). The new calibration was used to prospectively estimate the primary direction of acoustic propagation in MR coordinates within 1.43˚ uncertainty, enabling the alignment of gradient directions for MR ARFI.
DESIGN OF A NEW PHASED-ARRAY
- Introduction
- Summary
- Methods
- Design Simulations
- Fabrication
- Output
- Transcranial FUS
- Results
- Array coverage percentage and steering
- Output measurements
- Transcranial Evaluation
- Discussion
- Transducer Design
However, the needle tip is prone to damage, making it challenging to safely navigate the hydrophone in close proximity to the skull (i.e. the cortical area we want to stimulate). The location of the transducer along the sonication axis (approximate motor x direction) was recorded and used for the K-wave simulation shown (right).
Simulation Free field
Using simulations and knowledge gained from previous work, we designed a new randomized, relatively Figure 5.9 Pressure maps in a slice of the focal plane of a collection of 3D hydrophones using an optical tracking setup, showing a free-field scan without the skull part (left) and the corresponding scan for ex -vivo skull without aberration correction (in the middle). The actual transducer azimuth rotation, off-axis alignment, and skull parameters were unknown for the simulation.
The acoustic transparency of this skull piece at 650 kHz was consistent with expectations, although it is not necessarily representative of the biological variability encountered in living subjects.
To Transducer
Transcranial
Transducer Output
Driving the transducer at other frequencies would result in poor conversion to acoustic power, although it may still be possible for the low-pressure, low-duty-cycle pulses used in neuromodulation.
Transcranial Performance
Transverse ProfileAxial Profile
To Transducer
Conclusions
The transducer and generator system are MR compatible and can deliver a wide pressure range. Focus can be controlled over the range of the somatosensory cortex of non-human primates and a focal beam can be maintained transcranially.
CONCLUSIONS
Original Contributions
Future Directions
- Feedback controlled multi-focusing
- Real-time transcranial beam prediction
- Phased-array aberration correction
Additionally, the tool can be useful for validating acoustic models and parameters, which tend to be most sensitive near boundaries. Phase aberration correction with the new transducer should be implemented for cortical macaque targets.
BIBLIOGRAPHY
Chapiro, “Three-dimensional quantitative assessment of lesion response to treatment of uterine fibroids with MR-guided high-intensity focused ultrasound,” Acad. Westphalen, "Clinical applications of high-intensity focused ultrasound with magnetic resonance (MRgHIFU): present and future", J.
