Focal cooling: An alternative treatment for drug-resistant epilepsy in a mesial temporal lobe epilepsy primate model-A preliminary study.

OBJECTIVE: Focal cooling is emerging as a relevant therapy for drug-resistant epilepsy (DRE). However, we lack data on its effectiveness in controlling seizures that originate in deep-seated areas like the hippocampus. We present a thermoelectric solution for focal brain cooling that specifically targets these brain structures. METHODS: A prototype implantable device was developed, including temperature sensors and a cannula for penicillin injection to create an epileptogenic zone (EZ) near the cooling tip in a non-human primate model of epilepsy. The mesial temporal lobe was targeted with repeated penicillin injections into the hippocampus. Signals were recorded from an sEEG (Stereoelectroencephalography) lead placed 2 mm from the EZ. Once the number of seizures had stabilized, focal cooling was applied, and temperature and electroclinical events were monitored using a customized detection algorithm. Tests were performed on two Macaca fascicularis monkeys at three temperatures. RESULTS: Hippocampal seizures were observed 40-120 min post-injection, their duration and frequency stabilized at around 120 min. Compared to the control condition, a reduction in the number of hippocampal seizures was observed with cooling to 21°C (Control: 4.34 seizures, SD 1.704 per 20 min vs Cooling to 21°C: 1.38 seizures, SD 1.004 per 20 min). The effect was more pronounced with cooling to 17°C, resulting in an almost 80% reduction in seizure frequency. Seizure duration and number of interictal discharges were unchanged following focal cooling. After several months of repeated penicillin injections, hippocampal sclerosis was observed, similar to that recorded in humans. In addition, seizures were identified by detecting temperature variations of 0.3°C in the EZ correlated with the start of the seizures. SIGNIFICANCE: In epilepsy therapy, the ultimate aim is total seizure control with minimal side effects. Focal cooling of the EZ could offer an alternative to surgery and to existing neuromodulation devices.

Long-term stability of the chronic epidural wireless recorder WIMAGINE in tetraplegic patients.

Objective.The evaluation of the long-term stability of ElectroCorticoGram (ECoG) signals is an important scientific question as new implantable recording devices can be used for medical purposes such as Brain-Computer Interface (BCI) or brain monitoring.Approach.The long-term clinical validation of wireless implantable multi-channel acquisition system for generic interface with neurons (WIMAGINE), a wireless 64-channel epidural ECoG recorder was investigated. The WIMAGINE device was implanted in two quadriplegic patients within the context of a BCI protocol. This study focused on the ECoG signal stability in two patients bilaterally implanted in June 2017 (P1) and in November 2019 (P2).Methods. The ECoG signal was recorded at rest prior to each BCI session resulting in a 32 month and in a 14 month follow-up for P1 and P2 respectively. State-of-the-art signal evaluation metrics such as root mean square (RMS), the band power (BP), the signal to noise ratio (SNR), the effective bandwidth (EBW) and the spectral edge frequency (SEF) were used to evaluate stability of signal over the implantation time course. The time-frequency maps obtained from task-related motor activations were also studied to investigate the long-term selectivity of the electrodes.Mainresults.Based on temporal linear regressions, we report a limited decrease of the signal average level (RMS), spectral distribution (BP) and SNR, and a remarkable steadiness of the EBW and SEF. Time-frequency maps obtained during motor imagery, showed a high level of discrimination 1 month after surgery and also after 2 years.Conclusions.The WIMAGINE epidural device showed high stability over time. The signal evaluation metrics of two quadriplegic patients during 32 months and 14 months respectively provide strong evidence that this wireless implant is well-suited for long-term ECoG recording.Significance.These findings are relevant for the future of implantable BCIs, and could benefit other patients with spinal cord injury, amyotrophic lateral sclerosis, neuromuscular diseases or drug-resistant epilepsy.

An exoskeleton controlled by an epidural wireless brain-machine interface in a tetraplegic patient: a proof-of-concept demonstration.

BACKGROUND: Approximately 20% of traumatic cervical spinal cord injuries result in tetraplegia. Neuroprosthetics are being developed to manage this condition and thus improve the lives of patients. We aimed to test the feasibility of a semi-invasive technique that uses brain signals to drive an exoskeleton. METHODS: We recruited two participants at Clinatec research centre, associated with Grenoble University Hospital, Grenoble, France, into our ongoing clinical trial. Inclusion criteria were age 18-45 years, stability of neurological deficits, a need for additional mobility expressed by the patient, ambulatory or hospitalised monitoring, registration in the French social security system, and signed informed consent. The exclusion criteria were previous brain surgery, anticoagulant treatments, neuropsychological sequelae, depression, substance dependence or misuse, and contraindications to magnetoencephalography (MEG), EEG, or MRI. One participant was excluded because of a technical problem with the implants. The remaining participant was a 28-year-old man, who had tetraplegia following a C4-C5 spinal cord injury. Two bilateral wireless epidural recorders, each with 64 electrodes, were implanted over the upper limb sensorimotor areas of the brain. Epidural electrocorticographic (ECoG) signals were processed online by an adaptive decoding algorithm to send commands to effectors (virtual avatar or exoskeleton). Throughout the 24 months of the study, the patient did various mental tasks to progressively increase the number of degrees of freedom. FINDINGS: Between June 12, 2017, and July 21, 2019, the patient cortically controlled a programme that simulated walking and made bimanual, multi-joint, upper-limb movements with eight degrees of freedom during various reach-and-touch tasks and wrist rotations, using a virtual avatar at home (64·0% [SD 5·1] success) or an exoskeleton in the laboratory (70·9% [11·6] success). Compared with microelectrodes, epidural ECoG is semi-invasive and has similar efficiency. The decoding models were reusable for up to approximately 7 weeks without recalibration. INTERPRETATION: These results showed long-term (24-month) activation of a four-limb neuroprosthetic exoskeleton by a complete brain-machine interface system using continuous, online epidural ECoG to decode brain activity in a tetraplegic patient. Up to eight degrees of freedom could be simultaneously controlled using a unique model, which was reusable without recalibration for up to about 7 weeks. FUNDING: French Atomic Energy Commission, French Ministry of Health, Edmond J Safra Philanthropic Foundation, Fondation Motrice, Fondation Nanosciences, Institut Carnot, Fonds de Dotation Clinatec.

CEST-MRI for glioma pH quantification in mouse model: Validation by immunohistochemistry.

In glioma, the acidification of the extracellular tumor microenvironment drives proliferation, angiogenesis, immunosuppression, invasion and chemoresistance. Therefore, quantification of glioma extracellular pH (pHe) is of crucial importance. This study is focused on the application of the YbHPDO3A (ytterbium 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane) probe for in vivo glioma pHe quantification using chemical exchange saturation transfer (CEST)-MRI and its correlation with tumor metabolism assessed by immunohistochemistry. The U87 glioma mouse model was used (n = 18) and MRI performed at 4.7 T. CEST-MRI of YbHPDO3A solutions at different pH values showed two resolved CEST spectra at 71 ppm and 99 ppm, both sensitive to pH variations, allowing therefore calculation of the ratiometric curve for in vivo pH quantification. In vivo MRI sequences consisted of T2w for tumor localization, T2w * to assess YbHPDO3A biodistribution by exploiting its magnetic susceptibility effect and CEST for glioma pHe mapping. T2w * images show that YbHPDO3A extravasates in tumor in regions with damaged blood-brain barrier. The pHe is calculated only in these regions. Hematoxylin/eosin histology and Ki-67, CA-IX (carbonic anhydrase 9) and NHE-1 immunohistochemical staining were performed; their expression rates were compared with the in vivo pHe values. On the basis of the cell proliferation marker Ki-67, two groups were defined: one group with a lower mitotic index (MI% < 20% = mean value) and a mean pHe value of 7.00 (low-proliferation/high-pH group) and the other with MI% > 20% and an acidic pHe of 6.6 (high-proliferation/low-pH group). CA-IX and NHE-1 were over-expressed in the high-proliferation/low-pH group (CA-IX, 92 ± 7% versus 30 ± 13%; NHE-1, 84 ± 8% versus 35 ± 11%), indicating an acidic/hypoxic microenvironment. These immunohistochemical results are consistent with our pHe mapping (Pearson correlation coefficient > 0.70) and provide evidence for the feasibility of the CEST-MRI method with the YbHPDO3A probe for glioma pHe quantification at 4.7 T. Importantly, the YbHPDO3A probe has similar chemical and biological properties to the clinically approved MRI contrast agent GdHPDO3A. This makes the method promising for a clinical translation.

Hybrid ultrasound-MR guided HIFU treatment method with 3D motion compensation.

PURPOSE: Treatments using high-intensity focused ultrasound (HIFU) in the abdominal region remain challenging as a result of respiratory organ motion. A novel method is described here to achieve 3D motion-compensated ultrasound (US) MR-guided HIFU therapy using simultaneous ultrasound and MRI. METHODS: A truly hybrid US-MR-guided HIFU method was used to plan and control the treatment. Two-dimensional ultrasound was used in real time to enable tracking of the motion in the coronal plane, whereas an MR pencil-beam navigator was used to detect anterior-posterior motion. Prospective motion compensation of proton resonance frequency shift (PRFS) thermometry and HIFU electronic beam steering were achieved. RESULTS: The 3D prospective motion-corrected PRFS temperature maps showed reduced intrascan ghosting artifacts, a high signal-to-noise ratio, and low geometric distortion. The k-space data yielded a consistent temperature-dependent PRFS effect, matching the gold standard thermometry within approximately 1°C. The maximum in-plane temperature elevation ex vivo was improved by a factor of 2. Baseline thermometry acquired in volunteers indicated reduction of residual motion, together with an accuracy/precision of near-harmonic referenceless PRFS thermometry on the order of 0.5/1.0°C. CONCLUSIONS: Hybrid US-MR-guided HIFU ablation with 3D motion compensation was demonstrated ex vivo together with a stable referenceless PRFS thermometry baseline in healthy volunteer liver acquisitions. Magn Reson Med 79:2511-2523, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

In vivo quantification of magnetically labelled cells by MRI relaxometry.

Cellular MRI, which visualizes magnetically labelled cells (cells*), is an active research field for in vivo cell therapy and tracking. The simultaneous relaxation rate measurements (R2 *, R2 , R1 ) are the basis of a quantitative cellular MRI method proposed here. U937 cells were labelled with Molday ION Rhodamine B, a bi-functional superparamagnetic and fluorescent nanoparticle (U937*). U937* viability and proliferation were not affected in vitro. In vitro relaxometry was performed in a cell concentration range of [2.5 × 104 -108 ] cells/mL. These measurements show the existence of complementary cell concentration intervals where these rates vary linearly. The juxtaposition of these intervals delineates a wide cell concentration range over which one of the relaxation rates in a voxel of an in vivo image can be converted into an absolute cell concentration. The linear regime was found at high concentrations for R1 in the range of [106 - 2 × 108 ] cells/mL, at intermediate concentrations for R2 in [2.5 × 105 - 5 × 107 ] cells/mL and at low concentrations for R2 * in [8 × 104 - 5 × 106 ] cells/mL. In vivo relaxometry was performed in a longitudinal study, with labelled U937 cells injected into a U87 glioma mouse model. Using in vitro data, maps of in vivo U937* concentrations were obtained by converting one of the in vivo relaxation rates to cell concentration maps. MRI results were compared with the corresponding optical images of the same brains, showing the usefulness of our method to accurately follow therapeutic cell biodistribution in a longitudinal study. Results also demonstrate that the method quantifies a large range of magnetically labelled cells*. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of a higher dose of near-infrared light on clinical signs and neuroprotection in a monkey model of Parkinson's disease.

We have reported previously that intracranial application of near-infrared light (NIr) - when delivered at the lower doses of 25J and 35J - reduces clinical signs and offers neuroprotection in a subacute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease. In this study, we explored whether a higher NIr dose (125J) generated beneficial effects in the same MPTP monkey model (n=15). We implanted an NIr (670nm) optical fibre device within a midline region of the midbrain in macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.8-2.1mg/kg) were made over a five day period, during which time the NIr device was turned on and left on continuously throughout the ensuing three week survival period. Monkeys were evaluated clinically and their brains processed for immunohistochemistry and stereology. Our results showed that the higher NIr dose did not have any toxic impact on cells at the midbrain implant site. Further, this NIr dose resulted in a higher number of nigral tyrosine hydroxylase immunoreactive cells when compared to the MPTP group. However, the higher NIr dose monkeys showed little evidence for an increase in mean clinical score, number of nigral Nissl-stained cells and density of striatal tyrosine hydroxylase terminations. In summary, the higher NIr dose of 125J was not as beneficial to MPTP-treated monkeys as compared to the lower doses of 25J and 35J, boding well for strategies of NIr dose delivery and device energy consumption in a future clinical trial.

A nonparametric temperature controller with nonlinear negative reaction for multi-point rapid MR-guided HIFU ablation.

Magnetic resonance-guided high intensity focused ultrasound (MRgHIFU) is a noninvasive method for thermal ablation, which exploits the capabilities of magnetic resonance imaging (MRI) for excellent visualization of the target and for near real-time thermometry. Oncological quality of ablation may be obtained by volumetric sonication under automatic feedback control of the temperature. For this purpose, a new nonparametric (i.e., model independent) temperature controller, using nonlinear negative reaction, was designed and evaluated for the iterated sonication of a prescribed pattern of foci. The main objective was to achieve the same thermal history at each sonication point during volumetric MRgHIFU. Differently sized linear and circular trajectories were investigated ex vivo and in vivo using a phased-array HIFU transducer. A clinical 3T MRI scanner was used and the temperature elevation was measured in five slices simultaneously with a voxel size of 1 ×1 ×5 mm(3) and temporal resolution of 4 s. In vivo results indicated a similar thermal history of each sonicated focus along the prescribed pattern, that was 17.3 ± 0.5 °C as compared to 16 °C prescribed temperature elevation. The spatio-temporal control of the temperature also enabled meaningful comparison of various sonication patterns in terms of dosimetry and near-field safety. The thermal build-up tended to drift downwards in the HIFU transducer with a circular scan.

An experimental model to investigate the targeting accuracy of MR-guided focused ultrasound ablation in liver.

BACKGROUND: Magnetic Resonance-guided High Intensity Focused Ultrasound (MRgHIFU) is a hybrid technology that aims to offer non-invasive thermal ablation of targeted tumors or other pathological tissues. Acoustic aberrations and non-linear wave propagating effects may shift the focal point significantly away from the prescribed (or, theoretical) position. It is therefore mandatory to evaluate the spatial accuracy of ablation for a given HIFU protocol and/or device. We describe here a method for producing a user-defined ballistic target as an absolute reference marker for MRgHIFU ablations. METHODS: The investigated method is based on trapping a mixture of MR contrast agent and histology stain using radiofrequency (RF) ablation causing cell death and coagulation. A dedicated RF-electrode was used for the marker fixation as follows: a RF coagulation (4 W, 15 seconds) and injection of the mixture followed by a second RF coagulation. As a result, the contrast agent/stain is encapsulated in the intercellular space. Ultrasonography imaging was performed during the procedure, while high resolution T1w 3D VIBE MR acquisition was used right after to identify the position of the ballistic marker and hence the target tissue. For some cases, after the marker fixation procedure, HIFU volumetric ablations were produced by a phased-array HIFU platform. First ex vivo experiments were followed by in vivo investigation on four rabbits in thigh muscle and six pigs in liver, with follow-up at Day 7. RESULTS: At the end of the procedure, no ultrasound indication of the marker's presence could be observed, while it was clearly visible under MR and could be conveniently used to prescribe the HIFU ablation, centered on the so-created target. The marker was identified at Day 7 after treatment, immediately after animal sacrifice, after 3 weeks of post-mortem formalin fixation and during histology analysis. Its size ranged between 2.5 and 4 mm. CONCLUSIONS: Experimental validation of this new ballistic marker method was performed for liver MRgHIFU ablation, free of any side effects (e.g. no edema around the marker, no infection, no bleeding). The study suggests that the absolute reference marker had ultrasound conspicuity below the detection threshold, was irreversible, MR-compatible and MR-detectable, while also being a well-established histology staining technique.

Real-time method for motion-compensated MR thermometry and MRgHIFU treatment in abdominal organs.

PURPOSE: Magnetic resonance-guided high-intensity focused ultrasound is considered to be a promising treatment for localized cancer in abdominal organs such as liver, pancreas, or kidney. Abdominal motion, anatomical arrangement, and required sustained sonication are the main challenges. METHODS: MR acquisition consisted of thermometry performed with segmented gradient-recalled echo echo-planar imaging, and a segment-based one-dimensional MR navigator parallel to the main axis of motion to track the organ motion. This tracking information was used in real-time for: (i) prospective motion correction of MR thermometry and (ii) HIFU focal point position lock-on target. Ex vivo experiments were performed on a sheep liver and a turkey pectoral muscle using a motion demonstrator, while in vivo experiments were conducted on two sheep liver. RESULTS: Prospective motion correction of MR thermometry yielded good signal-to-noise ratio (range, 25 to 35) and low geometric distortion due to the use of segmented EPI. HIFU focal point lock-on target yielded isotropic in-plane thermal build-up. The feasibility of in vivo intercostal liver treatment was demonstrated in sheep. CONCLUSION: The presented method demonstrated in moving phantoms and breathing sheep accurate motion-compensated MR thermometry and precise HIFU focal point lock-on target using only real-time pencil-beam navigator tracking information, making it applicable without any pretreatment data acquisition or organ motion modeling.

Experimental methods for improved spatial control of thermal lesions in magnetic resonance-guided focused ultrasound ablation.

Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU, or MRgFUS) is a hybrid technology that was developed to provide efficient and tolerable thermal ablation of targeted tumors or other pathologic tissues, while preserving the normal surrounding structures. Fast 3-D ablation strategies are feasible with the newly available phased-array HIFU transducers. However, unlike fixed heating sources for interstitial ablation (radiofrequency electrode, microwave applicator, infra-red laser applicator), HIFU uses propagating waves. Therefore, the main challenge is to avoid thermo-acoustical adverse effects, such as energy deposition at reflecting interfaces and thermal drift of the focal lesion toward the near field. We report here our investigations on some novel experimental solutions to solve, or at least to alleviate, these generally known tolerability problems in HIFU-based therapy. Online multiplanar MR thermometry was the main investigational tool extensively used in this study to identify the problems and to assess the efficacy of the tested solutions. We present an improved method to cancel the beam reflection at the exit window (i.e., tissue-to-air interface) by creating a multilayer protection, to dissipate the residual HIFU beam by bulk scattering. This study evaluates selective de-activation of transducer elements to reduce the collateral heating at bone surfaces in the far field, mainly during automatically controlled volumetric ablation. We also explore, using hybrid US/MR simultaneous imaging, the feasibility of using disruptive boiling at the focus, both as a far-field self-shielding technique and as an enhanced ablation strategy (i.e., boiling core controlled HIFU ablation).

Magnetic resonance-guided shielding of prefocal acoustic obstacles in focused ultrasound therapy: application to intercostal ablation in liver.

OBJECTIVES: The treatment of liver cancer is a major public health issue because the liver is a frequent site for both primary and secondary tumors. Rib heating represents a major obstacle for the application of extracorporeal focused ultrasound to liver ablation. Magnetic resonance (MR)-guided external shielding of acoustic obstacles (eg, the ribs) was investigated here to avoid unwanted prefocal energy deposition in the pathway of the focused ultrasound beam. MATERIALS AND METHODS: Ex vivo and in vivo (7 female sheep) experiments were performed in this study. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) was performed using a randomized 256-element phased-array transducer (f∼1 MHz) and a 3-T whole-body clinical MR scanner. A physical mask was inserted in the prefocal beam pathway, external to the body, to block the energy normally targeted on the ribs. The effectiveness of the reflecting material was investigated by characterizing the efficacy of high-intensity focused ultrasound beam reflection and scattering on its surface using Schlieren interferometry. Before high-intensity focused ultrasound sonication, the alignment of the protectors with the conical projections of the ribs was required and achieved in multiple steps using the embedded graphical tools of the MR scanner. Multiplanar near real-time MR thermometry (proton resonance frequency shift method) enabled the simultaneous visualization of the local temperature increase at the focal point and around the exposed ribs. The beam defocusing due to the shielding was evaluated from the MR acoustic radiation force impulse imaging data. RESULTS: Both MR thermometry (performed with hard absorber positioned behind a full-aperture blocking shield) and Schlieren interferometry indicated a very good energy barrier of the shielding material. The specific temperature contrast between rib surface (spatial average) and focus, calculated at the end point of the MRgHIFU sonication, with protectors vs no protectors, indicated an important reduction of the temperature elevation at the ribs' surface, typically by 3.3 ± 0.4 in vivo. This was translated into an exponential reduction in thermal dose by several orders of magnitude. The external shielding covering the full conical shadow of the ribs was more effective when the protectors could be placed close to the ribs' surface and had a tendency to lose its efficiency when placed further from the ribs. Hepatic parenchyma was safely ablated in vivo using this rib-sparing strategy and single-focus independent sonications. CONCLUSIONS: A readily available, MR-compatible, effective, and cost-competitive method for rib protection in transcostal MRgHIFU was validated in this study, using specific reflective strips. The current approach permitted safe intercostal ablation of small volumes (0.7 mL) of liver parenchyma.

Experimental investigation of MRgHIFU sonication with interleaved electronic and mechanical displacement of the focal point for transrectal prostate application.

High intensity focused ultrasound (HIFU) under MRI guidance may provide minimally invasive treatment for localized prostate cancer. In this study, ex vivo and in vivo experiments were performed using a prostate-dedicated endorectal phased array (16 circular elements arranged on a truncated spherical cap of radius 60 mm) and a translation-rotation mechanical actuator in order to evaluate the lesion formation and the potential interest of dual-modality (electronic and mechanical) interleaved displacement of the focus for volumetric sonication paradigms. Different sonication sequences, including elementary lesions, line scan, slice sweeping and volume sonications, were investigated with a clinical 1.5 T MR scanner. Two orthogonal planes (axial and sagittal) were simultaneously monitored using rapid MR thermometry (PRFS method) and the temperature and thermal dose maps were displayed in real time. No RF interferences were detected in MR acquisition during sonications. The shape of the thermal lesions in vivo was examined at day 5 post-treatment by MRI follow-up (T2w sequence and Gd-T1w-TFE) and postmortem histological analysis. This study suggests that electronic displacement of the focus (along the ultrasound propagation axis) interleaved with mechanical X-Z translations and rotation around B(0) can be a suitable modality to treat patient-specific sizes and shapes of a pathologic tissue. The electronic displacement of focus (achieved in less than 0.1 s) is an order of magnitude faster than the mechanical motion of the HIFU device (1 s latency). As an example, for an in vivo volumetric sonication with foci between 32 and 47 mm (7 successive line scans, 11 lines/slice, 4 foci/line) with applied powers between 17.4 and 39.1 Wac, a total duration of sonication of 408.1 s was required to ablate a volume of approximately 5.7 cm(3) (semi-chronic lesion measured at day 5), while the maximum temperature elevation reached was 30 °C. While electronic focusing is necessary to speed up the procedure, one should consider as a potential drawback the non-negligible risk for generating secondary lobes with full steering in 3D. Reference-free PRFS thermometry accurately removed the effects of B(o) dynamic perturbation in the vicinity of the moving transducer. Therefore, the dual-modality volumetric sonication paradigm represents a cost-effective technological compromise to induce the desired shape of the lesion in the prostate through the limited endorectal space, in a reasonable period of time and without side effects.

ARFI-prepared MRgHIFU in liver: simultaneous mapping of ARFI-displacement and temperature elevation, using a fast GRE-EPI sequence.

MR acoustic radiation force imaging (ARFI) is an elegant adjunct to MR-guided high intensity focused ultrasound for treatment planning and optimization, permitting in situ assessment of the focusing and targeting quality. The thermal effect of high intensity focused ultrasound pulses associated with ARFI measurements is recommended to be monitored on line, in particular when the beam crosses highly absorbent structures or interfaces (e.g., bones or air-filled cavities). A dedicated MR sequence is proposed here, derived from a segmented gradient echo-echo planar imaging kernel by adding a bipolar motion encoding gradient with interleaved alternating polarities. Temporal resolution was reduced to 2.1 s, with in-plane spatial resolution of 1 mm. MR-ARFI measurements were executed during controlled animal breathing, with trans-costal successively steered foci, to investigate the spatial modulation of the focus intensity and the targeting offset. ARFI-induced tissue displacement measurements enabled the accurate localization, in vivo, of the high intensity focused ultrasound focal point in sheep liver, with simultaneous monitoring of the temperature elevation. ARFI-based precalibration of the focal point position was immediately followed by trans-costal MR-guided high intensity focused ultrasound ablation, monitored with a conventional proton resonance frequency shift MR thermometry sequence. The latter MR thermometry sequence had spatial resolution and geometrical distortion identical with the ARFI maps, hence no coregistration was required.

Reference-free PRFS MR-thermometry using near-harmonic 2-D reconstruction of the background phase.

Proton resonance frequency shift (PRFS) MR thermometry (MRT) is the generally preferred method for monitoring thermal ablation, typically implemented with gradient-echo (GRE) sequences. Standard PRFS MRT is based on the subtraction of a temporal reference phase map and is, therefore, intrinsically sensitive to tissue motion (including deformation) and to external perturbation of the magnetic field. Reference-free (or reference-less) PRFS MRT has been previously described by Rieke and was based on a 2-D polynomial fit performed on phase data from outside the heated region, to estimate the background phase inside the region of interest. While their approach was undeniably a fundamental progress in terms of robustness against tissue motion and magnetic perturbations, the underlying mathematical formalism requires a thick unheated border and may be subject to numerical instabilities with high order polynomials. A novel method of reference-free PRFS MRT is described here, using a physically consistent formalism, which exploits mathematical properties of the magnetic field in a homogeneous or near-homogeneous medium. The present implementation requires as input the MR GRE phase values along a thin, nearly-closed and unheated border. This is a 2-D restriction of a classic Dirichlet problem, working on a slice per slice basis. The method has been validated experimentally by comparison with the "ground truth" data, considered to be the standard PRFS method for static ex vivo tissue. "Zero measurement" of the gradient-echo phase baseline was performed in healthy volunteer liver with rapid acquisition (300 ms/image). In vivo data acquired in sheep liver during MR-guided high intensity focused ultrasound (MRgHIFU) sonication were post-processed as proof of applicability in a therapeutic scenario. Bland and Altman mean absolute difference between the novel method and the "ground truth" thermometry in ex vivo static tissue ranged between 0.069 °C and 0.968 °C, compared to the inherent "white" noise SD of 0.23 °C. The accuracy and precision of the novel method in volunteer liver were found to be on average 0.13 °C and respectively 0.65 °C while the inherent "white" noise SD was on average 0.51 °C. The method was successfully applied to large ROIs, up to 6.2 cm inner diameter, and the computing time per slice was systematically less than 100 ms using C++. The current limitations of reference-free PRFS thermometry originate mainly from the need to provide a nearly-closed border, where the MR phase is artifact-free and the tissue is unheated, plus the potential need to reposition that border during breathing to track the motion of the anatomic zone being monitored.A reference-free PRFS thermometry method based on the theoretical framework of harmonic functions is described and evaluated here. The computing time is compatible with online monitoring during local thermotherapy. The current reference-free MRT approach expands the workflow flexibility, eliminates the need for respiratory triggers, enables higher temporal resolution, and is insensitive to unique-event motion of tissue.

An MR-compliant phased-array HIFU transducer with augmented steering range, dedicated to abdominal thermotherapy.

A novel architecture for a phased-array high intensity focused ultrasound (HIFU) device was investigated, aiming to increase the capabilities of electronic steering without reducing the size of the elementary emitters. The principal medical application expected to benefit from these developments is the time-effective sonication of large tumours in moving organs. The underlying principle consists of dividing the full array of transducers into multiple sub-arrays of different resonance frequencies, with the reorientation of these individual emitters, such that each sub-array can focus within a given spatial zone. To enable magnetic resonance (MR) compatibility of the device and the number of output channels from the RF generator to be halved, a passive spectral multiplexing technique was used, consisting of parallel wiring of frequency-shifted paired piezoceramic emitters with intrinsic narrow-band response. Two families of 64 emitters (circular, 5 mm diameter) were mounted, with optimum efficiency at 0.96 and 1.03 MHz, respectively. Two different prototypes of the HIFU device were built and tested, each incorporating the same two families of emitters, but differing in the shape of the rapid prototyping plastic support that accommodated the transducers (spherical cap with radius of curvature/aperture of 130 mm/150 mm and, respectively, 80 mm/110 mm). Acoustic measurements, MR-acoustic radiation force imaging (ex vivo) and MR-thermometry (ex vivo and in vivo) were used for the characterization of the prototypes. Experimental results demonstrated an augmentation of the steering range by 80% along one preferentially chosen axis, compared to a classic spherical array of the same total number of elements. The electric power density provided to the piezoceramic transducers exceeded 50 W cm(-2) CW, without circulation of coolant water. Another important advantage of the current approach is the versatility of reshaping the array at low cost.

Endocavitary thermal therapy by MRI-guided phased-array contact ultrasound: experimental and numerical studies on the multi-input single-output PID temperature controller's convergence and stability.

PURPOSE: Endocavitary high intensity contact ultrasound (HICU) may offer interesting therapeutic potential for fighting localized cancer in esophageal or rectal wall. On-line MR guidance of the thermotherapy permits both excellent targeting of the pathological volume and accurate preoperatory monitoring of the temperature elevation. In this article, the authors address the issue of the automatic temperature control for endocavitary phased-array HICU and propose a tailor-made thermal model for this specific application. The convergence and stability of the feedback loop were investigated against tuning errors in the controller's parameters and against input noise, through ex vivo experimental studies and through numerical simulations in which nonlinear response of tissue was considered as expected in vivo. METHODS: An MR-compatible, 64-element, cooled-tip, endorectal cylindrical phased-array applicator of contact ultrasound was integrated with fast MR thermometry to provide automatic feedback control of the temperature evolution. An appropriate phase law was applied per set of eight adjacent transducers to generate a quasiplanar wave, or a slightly convergent one (over the circular dimension). A 2D physical model, compatible with on-line numerical implementation, took into account (1) the ultrasound-mediated energy deposition, (2) the heat diffusion in tissue, and (3) the heat sink effect in the tissue adjacent to the tip-cooling balloon. This linear model was coupled to a PID compensation algorithm to obtain a multi-input single-output static-tuning temperature controller. Either the temperature at one static point in space (situated on the symmetry axis of the beam) or the maximum temperature in a user-defined ROI was tracked according to a predefined target curve. The convergence domain in the space of controller's parameters was experimentally explored ex vivo. The behavior of the static-tuning PID controller was numerically simulated based on a discrete-time iterative solution of the bioheat transfer equation in 3D and considering temperature-dependent ultrasound absorption and blood perfusion. RESULTS: The intrinsic accuracy of the implemented controller was approximately 1% in ex vivo trials when providing correct estimates for energy deposition and heat diffusivity. Moreover, the feedback loop demonstrated excellent convergence and stability over a wide range of the controller's parameters, deliberately set to erroneous values. In the extreme case of strong underestimation of the ultrasound energy deposition in tissue, the temperature tracking curve alone, at the initial stage of the MR-controlled HICU treatment, was not a sufficient indicator for a globally stable behavior of the feedback loop. Our simulations predicted that the controller would be able to compensate for tissue perfusion and for temperature-dependent ultrasound absorption, although these effects were not included in the controller's equation. The explicit pattern of acoustic field was not required as input information for the controller, avoiding time-consuming numerical operations. CONCLUSIONS: The study demonstrated the potential advantages of PID-based automatic temperature control adapted to phased-array MR-guided HICU therapy. Further studies will address the integration of this ultrasound device with a miniature RF coil for high resolution MRI and, subsequently, the experimental behavior of the controller in vivo.