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.

Walking naturally after spinal cord injury using a brain-spine interface.

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain-spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.

A systematic review of the effects of transcranial photobiomodulation on brain activity in humans.

In recent years, transcranial photobiomodulation (tPBM) has been developing as a promising method to protect and repair brain tissues against damages. The aim of our systematic review is to examine the results available in the literature concerning the efficacy of tPBM in changing brain activity in humans, either in healthy individuals, or in patients with neurological diseases. Four databases were screened for references containing terms encompassing photobiomodulation, brain activity, brain imaging, and human. We also analysed the quality of the included studies using validated tools. Results in healthy subjects showed that even after a single session, tPBM can be effective in influencing brain activity. In particular, the different transcranial approaches - using a focal stimulation or helmet for global brain stimulation - seemed to act at both the vascular level by increasing regional cerebral blood flow (rCBF) and at the neural level by changing the activity of the neurons. In addition, studies also showed that even a focal stimulation was sufficient to induce a global change in functional connectivity across brain networks. Results in patients with neurological disease were sparser; nevertheless, they indicated that tPBM could improve rCBF and functional connectivity in several regions. Our systematic review also highlighted the heterogeneity in the methods and results generated, together with the need for more randomised controlled trials in patients with neurological diseases. In summary, tPBM could be a promising method to act on brain function, but more consistency is needed in order appreciate fully the underlying mechanisms and the precise outcomes.

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.

The Riemannian spatial pattern method: mapping and clustering movement imagery using Riemannian geometry.

Objective. Over the last decade, Riemannian geometry has shown promising results for motor imagery classification. However, extracting the underlying spatial features is not as straightforward as for applying common spatial pattern (CSP) filtering prior to classification. In this article, we propose a simple way to extract the spatial patterns obtained from Riemannian classification: the Riemannian spatial pattern (RSP) method, which is based on the backward channel selection procedure.Approach. The RSP method was compared to the CSP approach on ECoG data obtained from a quadriplegic patient while performing imagined movements of arm articulations and fingers.Main results.Similar results were found between the RSP and CSP methods for mapping each motor imagery task with activations following the classical somatotopic organization. Clustering obtained by pairwise comparisons of imagined motor movements however, revealed higher differentiation for the RSP method compared to the CSP approach. Importantly, the RSP approach could provide a precise comparison of the imagined finger flexions which added supplementary information to the mapping results.Significance.Our new RSP method illustrates the interest of the Riemannian framework in the spatial domain and as such offers new avenues for the neuroimaging community. This study is part of an ongoing clinical trial registered with ClinicalTrials.gov, NCT02550522.

Space-Time-Frequency Multi-Sensor Analysis for Motor Cortex Localization Using Magnetoencephalography.

Brain source imaging and time frequency mapping (TFM) are commonly used in magneto/electro encephalography (M/EEG) imaging. However, these methods suffer from important limitations. Source imaging is based on an ill-posed inverse problem leading to instability of source localization solutions, has a limited capacity to localize high frequency oscillations and loses its robustness for induced responses (ill-defined trigger). The drawback of TFM is that it involves independent analysis of signals from a number of frequency bands, and from co-localized sensors. In the present article, a regression-based multi-sensor space-time-frequency analysis (MSA) approach, which integrates co-localized sensors and/or multi-frequency information, is proposed. To estimate task-specific brain activations, MSA uses cross-validated, shifted, multiple Pearson correlation, calculated from the time-frequency transformed brain signal and the binary signal of stimuli. The results are projected from the sensor space onto the cortical surface. To assess MSA performance, the proposed method was compared to the weighted minimum norm estimate (wMNE) source imaging method, in terms of spatial selectivity and robustness against an ill-defined trigger. Magnetoencephalography (MEG) recordings were performed in fourteen subjects during two motor tasks: finger tapping and elbow flexion/extension. In particular, our results show that the MSA approach provides good localization performance when compared to wMNE and statistically significant improvement of robustness against ill-defined trigger.

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.

Recursive Exponentially Weighted N-way Partial Least Squares Regression with Recursive-Validation of Hyper-Parameters in Brain-Computer Interface Applications.

A tensor-input/tensor-output Recursive Exponentially Weighted N-Way Partial Least Squares (REW-NPLS) regression algorithm is proposed for high dimension multi-way (tensor) data treatment and adaptive modeling of complex processes in real-time. The method unites fast and efficient calculation schemes of the Recursive Exponentially Weighted PLS with the robustness of tensor-based approaches. Moreover, contrary to other multi-way recursive algorithms, no loss of information occurs in the REW-NPLS. In addition, the Recursive-Validation method for recursive estimation of the hyper-parameters is proposed instead of conventional cross-validation procedure. The approach was then compared to state-of-the-art methods. The efficiency of the methods was tested in electrocorticography (ECoG) and magnetoencephalography (MEG) datasets. The algorithms are implemented in software suitable for real-time operation. Although the Brain-Computer Interface applications are used to demonstrate the methods, the proposed approaches could be efficiently used in a wide range of tasks beyond neuroscience uniting complex multi-modal data structures, adaptive modeling, and real-time computational requirements.

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.

Near-infrared light is neuroprotective in a monkey model of Parkinson disease.

OBJECTIVE: To examine whether near-infrared light (NIr) treatment reduces clinical signs and/or offers neuroprotection in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson disease. METHODS: We implanted an optical fiber device that delivered NIr (670 nm) to the midbrain of macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.5-2.1mg/kg) were made over a 5- to 7-day period, during which time the NIr device was turned on. This was then followed by a 3-week survival period. Monkeys were evaluated clinically (eg, posture, bradykinesia) and behaviorally (open field test), and their brains were processed for immunohistochemistry and stereology. RESULTS: All monkeys in the MPTP group developed severe clinical and behavioral impairment (mean clinical scores = 21-34; n = 11). By contrast, the MPTP-NIr group developed much less clinical and behavioral impairment (n = 9); some monkeys developed moderate clinical signs (mean scores = 11-15; n = 3), whereas the majority--quite remarkably--developed few clinical signs (mean scores = 1-6; n = 6). The monkeys that developed moderate clinical signs had hematic fluid in their optical fibers at postmortem, presumably limiting NIr exposure and overall clinical improvement. NIr was not toxic to brain tissue and offered neuroprotection to dopaminergic cells and their terminations against MPTP insult, particularly in animals that developed few clinical signs. INTERPRETATION: Our findings indicate NIr to be an effective therapeutic agent in a primate model of the disease and create the template for translation into clinical trials.

In vitro demonstration of focused ultrasound thrombolysis using bifrequency excitation.

Focused ultrasound involving inertial cavitation has been shown to be an efficient method to induce thrombolysis without any pharmacological agent. However, further investigation of the mechanisms involved and further optimization of the process are still required. The present work aims at studying the relevance of a bifrequency excitation compared to a classical monofrequency excitation to achieve thrombolysis without any pharmacological agent. In vitro human blood clots were placed at the focus of a piezoelectric transducer. Efficiency of the thrombolysis was assessed by weighing each clot before and after sonication. The efficiencies of mono- (550 kHz) and bifrequency (535 and 565 kHz) excitations were compared for peak power ranging from 70 W to 220 W. The thrombolysis efficiency appears to be correlated to the inertial cavitation activity quantified by passive acoustic listening. In the conditions of the experiment, the power needed to achieve 80% of thrombolysis with a monofrequency excitation is reduced by the half with a bifrequency excitation. The thermal effects of bifrequency and monofrequency excitations, studied using MR thermometry measurements in turkey muscle samples where no cavitation occurred, did not show any difference between both types of excitations when using the same power level.

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.

Respiratory-gated MRgHIFU in upper abdomen using an MR-compatible in-bore digital camera.

OBJECTIVE: To demonstrate the technical feasibility and the potential interest of using a digital optical camera inside the MR magnet bore for monitoring the breathing cycle and subsequently gating the PRFS MR thermometry, MR-ARFI measurement, and MRgHIFU sonication in the upper abdomen. MATERIALS AND METHODS: A digital camera was reengineered to remove its magnetic parts and was further equipped with a 7 m long USB cable. The system was electromagnetically shielded and operated inside the bore of a closed 3T clinical scanner. Suitable triggers were generated based on real-time motion analysis of the images produced by the camera (resolution 640 × 480 pixels, 30 fps). Respiratory-gated MR-ARFI prepared MRgHIFU ablation was performed in the kidney and liver of two sheep in vivo, under general anaesthesia and ventilator-driven forced breathing. RESULTS: The optical device demonstrated very good MR compatibility. The current setup permitted the acquisition of motion artefact-free and high resolution MR 2D ARFI and multiplanar interleaved PRFS thermometry (average SNR 30 in liver and 56 in kidney). Microscopic histology indicated precise focal lesions with sharply delineated margins following the respiratory-gated HIFU sonications. CONCLUSION: The proof-of-concept for respiratory motion management in MRgHIFU using an in-bore digital camera has been validated in vivo.

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).