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Transcranial HIFU

Transcranial HIFU therapy has the advantage of being non-invasive and thus allows thetreatment of patients for whom operation are not safe. Accuracy is typically of the order of a millimeter. In addition, temperature elevation used in thermal ablation can be measured with dedicated MRI sequences to verify the proper course of the treatment.
The non-ionizing nature of this approach is an advantage in terms of simplicity of implementation and integration. The absence of radiation allows repeated treatments if necessary, unlike radiotherapy treatments.
Note the potential benefits of the procedure on the developing brain of children, more sensitive to ionizing radiation(Goske et al. 2008)(Duffner et al. 1993). The impact in terms of public health and comfort for the patient could be very beneficial, especially because such equipment helps overcome potential risks of both surgery (infection, bleeding, etc.) and ionizing radiation (radioprotection, etc.) and also because its cost is expected to be lower than stereotactic radiosurgery.
Recently, the first clinical trials with a frequency of 660 kHz have been performed with a system developed by Insightec to address different pathologies of the brain. They used a hemispherical HIFU probe, which distributes the energy over the largest skull surface possible but consequently limits the position of the probe in regard to the head and can cause large angles between the axis of the elements and the normal of the skull surface. Coupling is performed with water without any membrane between the probe and the head along the beam path, for better transmission. It is attached to a stereotactic frame and can be translated. Aberration correction is performed using a CTderived model of the skull and based on ray tracings between the elements of the array and the target, taking into account the skull thickness.
In 2009, a first clinical trial on glioblastomas was performed on three patients using this system. However the maximum temperatures reached after 20 s emissions were too low (C 42 ° , 48 ° C and 51 ° C for each patient ) to generate a significant treatment effect (McDannold et al. 2010).

Influence of the human skull on displacement profiles

To investigate the influence of the human skull bone on the displacement profiles, hydrophone measurements were performed on twelve human skulls. The skulls were extracted from 12 fresh human cadavers at the “Institut d’Anatomie UFR Biomédicale des Saints-Pères Université René Descartes”, Paris and were lent to the authors for the duration of the study. All the specimens fulfilled the “Centre du Don des Corps” criteria and had given their informed consent before death. The 512 element therapeutic probe was used in a water tank and a hydrophone (HNC-0400, Onda Corporation) was placed at its geometrical focus with stepped motors. The skulls had been used in previous study on the evaluation of the precision of the treatment for targeting the thalamic nucleus ventro-intermedius (VIM) implicated in essential tremor(Chauvet et al. 2013). The geometrical focus was set to the same location it is intended to be in the first clinical target envisioned with the prototype used in this study: the VIM. Skulls were mounted on a stereotactic frame and placed between the probe and the hydrophone. The hydrophone was then scanned (FOV size: 6×6×12 mm3, resolution 0.375×0.375×2 mm3) to record the intensity field in the presence of the skull. Intensities were measured with and without skull aberration correction. Skull aberration correction was achieved by hydrophone-based time reversal:
i. a ten cycle 1MHz signal was first emitted by the hydrophone.
ii. after propagation through the skull bone, the distorted wave front was recorded on the therapeutic array; the wave front was then time reversed in order to compensate for the diffraction and refraction effects induced by the skull bone: each transducer was driven by an independent electronic channel capable of generating the temporally inverted signal stored in memory.
iii. time reversed signals where re-emitted in order to focus back through the skull towards the initial position.

Keyhole and MR ARFI: simulations

Numerical simulations were performed to determine the effect of the keyhole method on phase images containing a two-dimensional Gaussian profile f(x, y). In the following, the x and y axes denote the readout and PE (keyhole) axis respectively. The Gaussian profile was characterized by spreads {σx, σy} and was centered at a given position {x0, y0}. Simulated data were generated in two ways. First, the impact of the keyhole sampling on a dynamic Gaussian object of amplitude A0 was studied. Magnitude images of the Gaussian profile were produced for {σx, σy} = {1, 1} or {1, 4} pixels, A0 = 1 (a.u.), {x0, y0} = {49, 49} and with Nx×Ny = 96×96 points. Simulated keyhole (magnitude) images were generated for every even keyhole range 􀟜�y, i.e., by replacing pairs of lines, one on each edge of k-space with zeroes, and this repeatedly until 􀟜�y = 0.
Secondly, the two-dimensional Gaussian profile was encoded into the background phase of an experimental image, as would occur in a realistic MR ARFI experiment. A spherical phantom filled with doped water (17 cm diameter, Siemens Healthcare, Erlangen, Germany) was used to generate a background image. A spinecho sequence was implemented with a FOV of 192×192 mm using an isotropic resolution of 2 mm (matrix size = 96×96). The slice was approximately positioned at the center of the sphere, resulting in a ~17 cm in-plane disc image. In order to remove background phase variations, two acquisitions were performed and only the phase difference image, combined with one of the two magnitude images, was considered in the simulations. As in the previous case, the Gaussian profile was arbitrarily positioned and inserted with spreads {σx, σy} = {1, 1} or {1, 4} pixels. For the sake of clarity, we have denoted by φ0 (in radians) the amplitude of the Gaussian profile encoded into the phase. This second category of simulations was achieved with φ0 = 1 rad. The keyhole acquisitions were simulated by replacing the outer k-space lines of the synthetic phase images by the corresponding lines taken from the initial experimental set of raw data. Again, this was achieved for every even keyhole range 􀟜�y.

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Ultrasound sequence and calibration

The ultrasound sequence used is based on the protocol of Tufail et al.(Y. Tufail et al. 2011), with a slightly higher center frequency of 320 kHz instead of 300 kHz; this corresponds to a peak in the transducer spectrum and a longer total sonication duration of 250 ms instead of 100ms, which was found to be more efficient. The detailed parameters are as follows: ultrasound frequency was 320 KHz, number of cycles was 75 per pulse (pulse duration = 230 μs), pulse repetition frequency (PRF) was 2 KHz (duty-cycle=50%) and the total burst duration was 250 ms. Only the pressure was changed in this study to identify the threshold, and ranged from 0.4 MPa to 1 MPa peak pressure. In order to build such sequence, two generators were used (AFG3101, Tektronix, Melrose, MA); a 75 Watt amplifier (75A250A, Amplifier Research, Souderton, PA) was then used to deliver the required power to the transducer and the input voltage of the transducer was monitored using an oscilloscope (TDS2022B, Tektronix, Melrose, MA) and voltage probe (P6139A, Tektronix, Melrose, MA). The transducer was calibrated with a custom built heterodyne interferometer(Royer, Dubois, and Fink 1992) in degassed water. The heterodyne interferometer uses a laser beam to detect the small vibration of the ultrasound wave on a mylar membrane which is then converted to pressure.

Table of contents :

1.1 Introduction
1.2 HIFU transcrâniens
1.3 Objectif de la thèse
1.4 Localisation des ultrasons par MR ARFI
1.5 Neuromodulation sur les rats
1.6 Neuromodulation sur singe éveillé
2.1 Introduction
2.2 Transcranial HIFU
3.1 Introduction
3.3 Influence of the human skull on displacement profiles
3.4 Keyhole
3.5 Keyhole and MR ARFI: simulations
3.6 Ex-vivo experiments
3.7 Results
3.7.1 Simulated data
3.7.2 Experimental MR ARFI data
3.7.3 Experimental evaluation of the influence of the skull on the intensity profile
3.8 Discussion
3.9 Conclusion
4.1 Introduction
4.2 Experimental setup
4.3 Ultrasound sequence and calibration
4.4 Preliminary experiments
4.5 Animal preparation and ultrasound neuromodulation protocol
4.6 Numerical simulation of the experimental setup
4.7 Results
4.7.1 Ultrasound pressure calibration through the half skulls
4.7.2 Ultrasound neuromodulation experiments
4.7.3 Pressure threshold
4.7.4 Acoustic numerical simulation of the experiment
4.8 Discussion
4.9 Conclusion
5.1 Introduction
5.1.1 Frontal Eye Field
5.1.2 Antisaccade
5.1.3 Objectives
5.2 Focused ultrasound
5.3 Task
5.4 Experimental protocols
5.5 Surgical procedure
5.6 Data analysis and presentation
5.7 Results
5.7.1 Focused ultrasound-modulated antisaccade latencies
5.7.2 Focused ultrasound Effect on Antisaccade Error Rate and Amplitude
5.8 Discussion
5.9 Conclusion


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