Erik Dumont - Academia.edu (original) (raw)

Papers by Erik Dumont

Journal of therapeutic ultrasound, Dec 1, 2015

Background: Focused ultrasound combined with microbubble injection is capable of locally and tran... more Background: Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Magnetic resonance imaging (MRI) guidance enables to plan, monitor, and characterize the BBB disruption. Being able to precisely and remotely control the permeabilization location is of great interest to perform reproducible drug delivery protocols. Methods: In this study, we developed an MR-guided motorized focused ultrasound (FUS) system allowing the transducer displacement within preclinical MRI scanners, coupled with real-time transfer and reconstruction of MRI images, to help ultrasound guidance. Capabilities of this new device to deliver large molecules to the brain on either single locations or along arbitrary trajectories were characterized in vivo on healthy rats and mice using 1.5 MHz ultrasound sonications combined with microbubble injection. The efficacy of BBB permeabilization was assessed by injecting a gadolinium-based MR contrast agent that does not cross the intact BBB. Results: The compact motorized FUS system developed in this work fits into the 9-cm inner diameter of the gradient insert installed on our 7-T preclinical MRI scanners. MR images acquired after contrast agent injection confirmed that this device can be used to enhance BBB permeability along remotely controlled spatial trajectories of the FUS beam in both rats and mice. The two-axis motor stage enables reaching any region of interest in the rodent brain. The positioning error when targeting the same anatomical location on different animals was estimated to be smaller than 0.5 mm. Finally, this device was demonstrated to be useful for testing BBB opening at various acoustic pressures (0.2, 0.4, 0.7, and 0.9 MPa) in the same animal and during one single ultrasound session. Conclusions: Our system offers the unique possibility to move the transducer within a high magnetic field preclinical MRI scanner, thus enabling the delivery of large molecules to virtually any rodent brain area in a non-invasive manner. It results in time-saving and reproducibility and could be used to either deliver drugs over large parts of the brain or test different acoustic conditions on the same animal during the same session, therefore reducing physiological variability.

Ultrasound in Medicine and Biology, Mar 1, 2022

The blood-brain barrier (BBB) is the most important obstacle to delivery of therapeutics to the c... more The blood-brain barrier (BBB) is the most important obstacle to delivery of therapeutics to the central nervous system. Low-intensity pulsed focused ultrasound (FUS) in combination with microbubbles applied under magnetic resonance imaging (MRI) control provides a non-invasive and safe technique for BBB opening (BBBo). In rodent models, however, settings and application protocols differ significantly. Depending on the strain and size, important variables include ultrasound attenuation and sound field distortion caused by the skull. We examined the ultrasound attenuation of the skull of Wistar rats using a targeted FUS system. By modifying the transducer elements and by varying and simulating the acoustic field of the FUS system, we measured a skull attenuation of about 60%. To evaluate potential application of the targeted FUS system in genetically modified animals with increased sensitivity to brain hemorrhage caused by vascular dysfunction, we assessed safety in healthy animals. Histological and MRI analyses of the central nervous system revealed an increase in the number and severity of hyperacute bleeds with focal pressure. At a pressure of 0.4 MPa, no bleeds were induced, albeit at the cost of a weaker hyperintense MRI signal post BBBo. These results indicate a relationship between pressure and the dimension of permeabilization.

2022 IEEE International Ultrasonics Symposium (IUS), Oct 10, 2022

Nucleation and Atmospheric Aerosols, 2017

Focused ultrasound combined with microbubbles injection has shown its potential to transiently di... more Focused ultrasound combined with microbubbles injection has shown its potential to transiently disrupt the Blood Brain Barrier (BBB), allowing the delivery of large molecules to the Central Nervous System (CNS). However, the phenomenon has still to be investigated as the optimal parameters remain unknown up to date. To do so, we developed a new MR-guided motorized system, allowing the displacement of the transducer within preclinical magnets in order to choose the location of the opening. We demonstrated the capabilities of our system by opening the BBB along arbitrary trajectories. We also show the existence of an acoustic pressure threshold for BBB disruption estimated at about 0.3 MPa at 1.5 MHz by testing different acoustic conditions on the same animal. Finally, we investigated the BBB opening efficiency with the duty cycle. We proved that the disruption was greater with higher duty cycle.

Magnetic Resonance (MR)-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for... more Magnetic Resonance (MR)-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for controlling hyperthermia and local drug delivery. In this work, we developed a system capable of controlled tissue heating using proportional-integral-derivative (PID) feedback control combined with 7T MR thermometry for temperature feedback. MR thermometry was validated by an optical temperature probe. We have measured and simulated MR estimates of transient ultrasound-induced heating in a tofu phantom and performed controlled heating studies in an in vivo Met-1 mouse tumor. MR thermometry estimates agreed with fiber optic temperature measurements within 1°C, and simulations of heating in a tofu phantom were in agreement with the MR temperature measurement. MR-Acoustic Radiation Force Imaging (ARFI) was used to detect micron-scale displacement caused by acoustic radiation for beam localization in the absence of heating. The MRgFUS system developed here demonstrates adequate spatial and thermal accuracy for image-guided hyperthermia applications in small animals.

Physics in Medicine and Biology, Apr 20, 2017

Non-invasive, quantitative methods to assess the properties of biological tissues are needed for ... more Non-invasive, quantitative methods to assess the properties of biological tissues are needed for many therapeutic and tissue engineering applications. Magnetic resonance elastography (MRE) has historically relied on external vibration to generate periodic shear waves. In order to focally assess a biomaterial or to monitor the response to ablative therapy, the interrogation of a specific region of interest by a focused beam is desirable and transient MRE (t-MRE) techniques have previously been developed to accomplish this goal. Also, strategies employing a series of discrete ultrasound pulses directed to increasing depths along a single line-of-sight have been designed to generate a quasi-planar shear wave. Such 'supersonic' excitations have been applied for ultrasound elasticity measurements. The resulting shear wave is higher in amplitude than that generated from a single excitation and the properties of the media are simply visualized and quantified due to the quasiplanar wave geometry and the opportunity to generate the wave at the site of interest. Here for the first time, we extend the application of supersonic methods by developing a protocol for supersonic transient magnetic resonance elastography (sst-MRE) using an MR-guided focused ultrasound system capable of therapeutic ablation. We apply the new protocol to quantify tissue elasticity in vitro using biologically-relevant inclusions and tissue-mimicking phantoms, compare the results with elasticity maps acquired with ultrasound shear wave elasticity imaging (US-SWEI), and validate both methods with mechanical testing. We found that a modified time-offlight (TOF) method efficiently quantified shear modulus from sst-MRE data, and both the TOF and local inversion methods result in similar maps based on US-SWEI. With a three-pulse excitation, the proposed sst-MRE protocol was capable of visualizing quasi-planar shear waves propagating away from the excitation location and detecting differences in shear modulus of 1 kPa. The techniques demonstrated here have potential application in real-time in vivo lesion detection and monitoring, with particular significance for image-guided interventions.

We present here a new method to study the diffusion process of Gadolinium-based MRI Contrast Agen... more We present here a new method to study the diffusion process of Gadolinium-based MRI Contrast Agents within the brain extracellular space after ultrasound-induced Blood-Brain Barrier permeabilization. Four compounds were tested (MultiHance, Gadovist, Dotarem and AGuIX). By estimating the Free Diffusion Coefficients from in vitro studies, and the Apparent Diffusion Coefficients from in vivo experiments, an evaluation of the tortuosity (λ) in the right striatum of 11 Sprague-Dawley rats has been performed. The values of λ are in agreement with literature and demonstrate that the chosen permeabilization protocol maintains the integrity of brain tissue.

2017 IEEE International Ultrasonics Symposium (IUS), Sep 1, 2017

Transcranial focused ultrasound (FUS) is a noninvasive technique for therapy and study of brain n... more Transcranial focused ultrasound (FUS) is a noninvasive technique for therapy and study of brain neural activation. Here we report on the design and characterization of a new MR-guided FUS transducer for neuromodulation in nonhuman primates at 650kHz. Focus size and grating lobes during electronic steering were quantified using hydrophone measurements in water and a three-axis stage. Pressure output vs. power was characterized and shown to agree with design simulations.

Biochemical Journal, May 1, 1999

Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling ... more Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling for insulin analogues having slower dissociation kinetics than insulin itself. A plausible explanation in molecular terms of this timing-dependent specificity is lacking. We show here that if signalling is transmitted through a single effector, binding coincidentally with hormone to the insulin receptor and whose association and dissociation kinetics are slow relative to the hormone dissociation rate, the resulting biological effect is predicted to be dependent on hormone-binding kinetics. However, known primary effector molecules associating with the insulin receptor bind and interact rapidly with the receptor, contrary to the assumptions of the

Experimental and Clinical Endocrinology & Diabetes, Jul 15, 2009

Investigative Radiology, Nov 1, 2000

effect of iodinated high-viscosity contrast medium in the rat kidney: A diffusion-weighted MRI fe... more effect of iodinated high-viscosity contrast medium in the rat kidney: A diffusion-weighted MRI feasibility study. Invest Radiol 2000;35:647-652. RATIONALE AND OBJECTIVES. To assess the abilities of dynamic diffusion-weighted MRI to demonstrate the effects in vivo of a high-viscosity iodinated contrast agent on medullary and cortical blood flow in the rat kidney. METHODS. Dynamic diffusion-weighted, echoplanar MR images obtained from five b-value single-shot acquisitions and their isotropic apparent diffusion coefficient maps were obtained from nine rats anesthetized by pentobarbital sedation, before and after intravenous injection of a high-viscosity, dimeric iso-osmolar iodinated contrast medium (iodixanol), and compared with those obtained from four control rats that received saline. RESULTS. The mean baseline apparent diffusion coefficient values were 1.64 ؎ 0.05 ؋ 10 ؊3 mm 2 /s for the cortex and 1.75 ؎ 0.06 ؋ 10 ؊3 mm 2 /s for the medulla. In the iodixanol group, a significant decrease in renal diffusion was observed at 12 minutes and lasted at least until 24 minutes. The decrease in diffusion occurred earlier for the cortex and lasted less than for the medulla. There was no significant modification in diffusion over time in the control group. CONCLUSIONS. This preliminary experience in rats shows that dynamic diffusion-weighted MRI can be used to study noninvasively the in vivo renal hemodynamic response after injection of iodinated contrast.

Contrast Media & Molecular Imaging, Dec 1, 2019

Journal of Neurosurgery, Jul 1, 2022

OBJECTIVE Surgery can be highly effective for the treatment of medically intractable, neurologica... more OBJECTIVE Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage. METHODS Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB. RESULTS Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure. CONCLUSIONS These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.

Osteoarthritis implies a progressive degeneration of the whole joint. Cartilage is particularly a... more Osteoarthritis implies a progressive degeneration of the whole joint. Cartilage is particularly affected, with inflammation playing a pivotal role1. In recent years, cartilage regeneration has been pursued through several bioengineering strategies and using different stem cell types2-6. Adipose -derived mesenchymal stromal cells (ASCs) constitute an intriguing and minimally invasive option. However, the use of ASCs for cartilage regeneration is hampered by a relatively inefficient expression of key chondrogenic markers7. Thus, new strategies to boost both in situ targeting and chondrogenesis of ASCs are highly desirable. Here we show that ASCs embedded in a nanocomposite hydrogel including piezoelectric nanomaterials and graphene oxide nanoflakes, and stimulated with ultrasound waves with precisely controlled parameters (1 MHz and 250 mW/cm2, for 5 min once every two days for a period of 10 days) dramatically boost cell chondrogenic commitment. Furthermore, this stimulation regimen ...

IEEE Transactions on Biomedical Engineering, Mar 1, 2021

Objective:This paper presents and evaluates a breast-specific magnetic resonance guided focused u... more Objective:This paper presents and evaluates a breast-specific magnetic resonance guided focused ultrasound (MRgFUS) system. A first-in-human evaluation demonstrates the novel hardware, a sophisticated tumor targeting algorithm and a volumetric magnetic resonance imaging (MRI) protocol.Methods:At the time of submission, N=10 patients with non-palpable T0 stage breast cancer have been treated with the breast MRgFUS system. The described tumor targeting algorithm is evaluated both with a phantom test and in vivo during the breast MRgFUS treatments. Treatments were planned and monitored using volumetric MR-acoustic radiation force imaging (MR-ARFI) and temperature imaging (MRTI).Results:Successful technical treatments were achieved in 80% of the patients. All patients underwent the treatment with no sedation and 60% of participants had analgesic support. The total MR treatment time ranged from 73 to 114 minutes. Mean error between desired and achieved targeting in a phantom was 2.9±1.8 mm while 6.2±1.9 mm was achieved in patient studies, assessed either with MRTI or MR-ARFI measurements. MRTI and MR-ARFI were successful in 60% and 70% of patients, respectively.Conclusion:The targeting accuracy allows the accurate placement of the focal spot using electronic steering capabilities of the transducer. The use of both volumetric MRTI and MR-ARFI provides complementary treatment planning and monitoring information during the treatment, allowing the treatment of all breast anatomies, including homogeneously fatty breasts.

Proceedings of Meetings on Acoustics, 2017

Low-frequency ultrasound imaging using compressed-parametric ultrasound with application of synth... more Low-frequency ultrasound imaging using compressed-parametric ultrasound with application of synthetic aperture focusing

Medical Physics, Mar 11, 2010

MR thermometry based on the proton resonance frequency shift ͑PRFS͒ is the most commonly used met... more MR thermometry based on the proton resonance frequency shift ͑PRFS͒ is the most commonly used method for the monitoring of thermal therapies. As the chemical shift of water protons is temperature dependent, the local temperature variation ͑relative to an initial baseline͒ may be calculated from time-dependent phase changes in gradient-echo ͑GRE͒ MR images. Dynamic phase shift in GRE images is also produced by time-dependent changes in the magnetic bulk susceptibility of tissue. Gas bubbles ͑known as "white cavitation"͒ are frequently visualized near the RF electrode in ultrasonography-guided radio frequency ablation ͑RFA͒. This study aimed to investigate RFA-induced cavitation's effects by using simultaneous ultrasonography and MRI, to both visualize the cavitation and quantify the subsequent magnetic susceptibility-mediated errors in concurrent PRFS MR-thermometry ͑MRT͒ as well as to propose a first-order correction for the latter errors. Methods: RF heating in saline gels and in ex vivo tissues was performed with MR-compatible bipolar and monopolar electrodes inside a 1.5 T MR clinical scanner. Ultrasonography simultaneous to PRFS MRT was achieved using a MR-compatible phased-array ultrasonic transducer. PRFS MRT was performed interleaved in three orthogonal planes and compared to measurements from fluoroptic sensors, under low and, respectively, high RFA power levels. Control experiments were performed to isolate the main source of errors in standard PRFS thermometry. Results: Ultrasonography, MRI and digital camera pictures clearly demonstrated generation of bubbles every time when operating the radio frequency equipment at therapeutic powers ͑ജ30 W͒. Simultaneous bimodal ͑ultrasonography and MRI͒ monitoring of high power RF heating demonstrated a correlation between the onset of the PRFS-thermometry errors and the appearance of bubbles around the applicator. In an ex vivo study using a bipolar RF electrode under low power level ͑5 W͒, the MR measured temperature curves accurately matched the reference fluoroptic data. In similar ex vivo studies when applying higher RFA power levels ͑30 W͒, the correlation plots of MR thermometry versus fluoroptic data showed large errors in PRFS-derived temperature ͑up to 45°C absolute deviation, positive or negative͒ depending not only on fluoroptic tip position but also on the RF electrode orientation relative to the B 0 axis. Regions with apparent decrease in the PRFS-derived temperature maps as much as 30°C below the initial baseline were visualized during RFA high power application. Ex vivo data were corrected assuming a Gaussian dynamic source of susceptibility, centered in the anode/cathode gap of the RF bipolar electrode. After correction, the temperature maps recovered the revolution symmetry pattern predicted by theory and matched the fluoroptic data within 4.5°C mean offset. Conclusions: RFA induces dynamic changes in magnetic bulk susceptibility in biological tissue, resulting in large and spatially dependent errors of phase-subtraction-only PRFS MRT and unexploitable thermal dose maps. These thermometry artifacts were strongly correlated with the appearance of transient cavitation. A first-order dynamic model of susceptibility provided a useful method for minimizing these artifacts in phantom and ex vivo experiments.

NMR in Biomedicine, Apr 7, 2016

Boiling histotripsy (BH) is a new high intensity focused ultrasound (HIFU) ablation technique to ... more Boiling histotripsy (BH) is a new high intensity focused ultrasound (HIFU) ablation technique to mechanically fragmentize soft tissue into submicrometer fragments. So far, ultrasound has been used for BH treatment guidance and evaluation. The in vivo histopathological effects of this treatment are largely unknown. Here, we report on an MR guided BH method to treat subcutaneous tumors in a mouse model. The treatment effects of BH were evaluated one hour and four days later with MRI and histopathology, and compared with the effects of thermal HIFU (T-HIFU). The lesions caused by BH were easily detected with T2 w imaging as a hyper-intense signal area with a hypo-intense rim. Histopathological evaluation showed that the targeted tissue was completely disintegrated and that a narrow transition zone (<200 µm) containing many apoptotic cells was present between disintegrated and vital tumor tissue. A high level of agreement was found between T2 w imaging and H&E stained sections, making T2 w imaging a suitable method for treatment evaluation during or directly after BH. After T-HIFU, contrast enhanced imaging was required for adequate detection of the ablation zone. On histopathology, an ablation zone with concentric layers was seen after T-HIFU. In line with histopathology, contrast enhanced MRI revealed that after BH or T-HIFU perfusion within the lesion was absent, while after BH in the transition zone some micro-hemorrhaging appeared. Four days after BH, the transition zone with apoptotic cells was histologically no longer detectable, corresponding to the absence of a hypo-intense rim around the lesion in T2 w images. This study demonstrates the first results of in vivo BH on mouse tumor using MRI for treatment guidance and evaluation and opens the way for more detailed investigation of the in vivo effects of BH. Copyright © 2016 John Wiley & Sons, Ltd.

Journal of therapeutic ultrasound, Dec 1, 2015

Background: Focused ultrasound combined with microbubble injection is capable of locally and tran... more Background: Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Magnetic resonance imaging (MRI) guidance enables to plan, monitor, and characterize the BBB disruption. Being able to precisely and remotely control the permeabilization location is of great interest to perform reproducible drug delivery protocols. Methods: In this study, we developed an MR-guided motorized focused ultrasound (FUS) system allowing the transducer displacement within preclinical MRI scanners, coupled with real-time transfer and reconstruction of MRI images, to help ultrasound guidance. Capabilities of this new device to deliver large molecules to the brain on either single locations or along arbitrary trajectories were characterized in vivo on healthy rats and mice using 1.5 MHz ultrasound sonications combined with microbubble injection. The efficacy of BBB permeabilization was assessed by injecting a gadolinium-based MR contrast agent that does not cross the intact BBB. Results: The compact motorized FUS system developed in this work fits into the 9-cm inner diameter of the gradient insert installed on our 7-T preclinical MRI scanners. MR images acquired after contrast agent injection confirmed that this device can be used to enhance BBB permeability along remotely controlled spatial trajectories of the FUS beam in both rats and mice. The two-axis motor stage enables reaching any region of interest in the rodent brain. The positioning error when targeting the same anatomical location on different animals was estimated to be smaller than 0.5 mm. Finally, this device was demonstrated to be useful for testing BBB opening at various acoustic pressures (0.2, 0.4, 0.7, and 0.9 MPa) in the same animal and during one single ultrasound session. Conclusions: Our system offers the unique possibility to move the transducer within a high magnetic field preclinical MRI scanner, thus enabling the delivery of large molecules to virtually any rodent brain area in a non-invasive manner. It results in time-saving and reproducibility and could be used to either deliver drugs over large parts of the brain or test different acoustic conditions on the same animal during the same session, therefore reducing physiological variability.

Ultrasound in Medicine and Biology, Mar 1, 2022

The blood-brain barrier (BBB) is the most important obstacle to delivery of therapeutics to the c... more The blood-brain barrier (BBB) is the most important obstacle to delivery of therapeutics to the central nervous system. Low-intensity pulsed focused ultrasound (FUS) in combination with microbubbles applied under magnetic resonance imaging (MRI) control provides a non-invasive and safe technique for BBB opening (BBBo). In rodent models, however, settings and application protocols differ significantly. Depending on the strain and size, important variables include ultrasound attenuation and sound field distortion caused by the skull. We examined the ultrasound attenuation of the skull of Wistar rats using a targeted FUS system. By modifying the transducer elements and by varying and simulating the acoustic field of the FUS system, we measured a skull attenuation of about 60%. To evaluate potential application of the targeted FUS system in genetically modified animals with increased sensitivity to brain hemorrhage caused by vascular dysfunction, we assessed safety in healthy animals. Histological and MRI analyses of the central nervous system revealed an increase in the number and severity of hyperacute bleeds with focal pressure. At a pressure of 0.4 MPa, no bleeds were induced, albeit at the cost of a weaker hyperintense MRI signal post BBBo. These results indicate a relationship between pressure and the dimension of permeabilization.

2022 IEEE International Ultrasonics Symposium (IUS), Oct 10, 2022

Nucleation and Atmospheric Aerosols, 2017

Focused ultrasound combined with microbubbles injection has shown its potential to transiently di... more Focused ultrasound combined with microbubbles injection has shown its potential to transiently disrupt the Blood Brain Barrier (BBB), allowing the delivery of large molecules to the Central Nervous System (CNS). However, the phenomenon has still to be investigated as the optimal parameters remain unknown up to date. To do so, we developed a new MR-guided motorized system, allowing the displacement of the transducer within preclinical magnets in order to choose the location of the opening. We demonstrated the capabilities of our system by opening the BBB along arbitrary trajectories. We also show the existence of an acoustic pressure threshold for BBB disruption estimated at about 0.3 MPa at 1.5 MHz by testing different acoustic conditions on the same animal. Finally, we investigated the BBB opening efficiency with the duty cycle. We proved that the disruption was greater with higher duty cycle.

Magnetic Resonance (MR)-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for... more Magnetic Resonance (MR)-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for controlling hyperthermia and local drug delivery. In this work, we developed a system capable of controlled tissue heating using proportional-integral-derivative (PID) feedback control combined with 7T MR thermometry for temperature feedback. MR thermometry was validated by an optical temperature probe. We have measured and simulated MR estimates of transient ultrasound-induced heating in a tofu phantom and performed controlled heating studies in an in vivo Met-1 mouse tumor. MR thermometry estimates agreed with fiber optic temperature measurements within 1°C, and simulations of heating in a tofu phantom were in agreement with the MR temperature measurement. MR-Acoustic Radiation Force Imaging (ARFI) was used to detect micron-scale displacement caused by acoustic radiation for beam localization in the absence of heating. The MRgFUS system developed here demonstrates adequate spatial and thermal accuracy for image-guided hyperthermia applications in small animals.

Physics in Medicine and Biology, Apr 20, 2017

Non-invasive, quantitative methods to assess the properties of biological tissues are needed for ... more Non-invasive, quantitative methods to assess the properties of biological tissues are needed for many therapeutic and tissue engineering applications. Magnetic resonance elastography (MRE) has historically relied on external vibration to generate periodic shear waves. In order to focally assess a biomaterial or to monitor the response to ablative therapy, the interrogation of a specific region of interest by a focused beam is desirable and transient MRE (t-MRE) techniques have previously been developed to accomplish this goal. Also, strategies employing a series of discrete ultrasound pulses directed to increasing depths along a single line-of-sight have been designed to generate a quasi-planar shear wave. Such 'supersonic' excitations have been applied for ultrasound elasticity measurements. The resulting shear wave is higher in amplitude than that generated from a single excitation and the properties of the media are simply visualized and quantified due to the quasiplanar wave geometry and the opportunity to generate the wave at the site of interest. Here for the first time, we extend the application of supersonic methods by developing a protocol for supersonic transient magnetic resonance elastography (sst-MRE) using an MR-guided focused ultrasound system capable of therapeutic ablation. We apply the new protocol to quantify tissue elasticity in vitro using biologically-relevant inclusions and tissue-mimicking phantoms, compare the results with elasticity maps acquired with ultrasound shear wave elasticity imaging (US-SWEI), and validate both methods with mechanical testing. We found that a modified time-offlight (TOF) method efficiently quantified shear modulus from sst-MRE data, and both the TOF and local inversion methods result in similar maps based on US-SWEI. With a three-pulse excitation, the proposed sst-MRE protocol was capable of visualizing quasi-planar shear waves propagating away from the excitation location and detecting differences in shear modulus of 1 kPa. The techniques demonstrated here have potential application in real-time in vivo lesion detection and monitoring, with particular significance for image-guided interventions.

We present here a new method to study the diffusion process of Gadolinium-based MRI Contrast Agen... more We present here a new method to study the diffusion process of Gadolinium-based MRI Contrast Agents within the brain extracellular space after ultrasound-induced Blood-Brain Barrier permeabilization. Four compounds were tested (MultiHance, Gadovist, Dotarem and AGuIX). By estimating the Free Diffusion Coefficients from in vitro studies, and the Apparent Diffusion Coefficients from in vivo experiments, an evaluation of the tortuosity (λ) in the right striatum of 11 Sprague-Dawley rats has been performed. The values of λ are in agreement with literature and demonstrate that the chosen permeabilization protocol maintains the integrity of brain tissue.

2017 IEEE International Ultrasonics Symposium (IUS), Sep 1, 2017

Transcranial focused ultrasound (FUS) is a noninvasive technique for therapy and study of brain n... more Transcranial focused ultrasound (FUS) is a noninvasive technique for therapy and study of brain neural activation. Here we report on the design and characterization of a new MR-guided FUS transducer for neuromodulation in nonhuman primates at 650kHz. Focus size and grating lobes during electronic steering were quantified using hydrophone measurements in water and a three-axis stage. Pressure output vs. power was characterized and shown to agree with design simulations.

Biochemical Journal, May 1, 1999

Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling ... more Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling for insulin analogues having slower dissociation kinetics than insulin itself. A plausible explanation in molecular terms of this timing-dependent specificity is lacking. We show here that if signalling is transmitted through a single effector, binding coincidentally with hormone to the insulin receptor and whose association and dissociation kinetics are slow relative to the hormone dissociation rate, the resulting biological effect is predicted to be dependent on hormone-binding kinetics. However, known primary effector molecules associating with the insulin receptor bind and interact rapidly with the receptor, contrary to the assumptions of the

Experimental and Clinical Endocrinology & Diabetes, Jul 15, 2009

Investigative Radiology, Nov 1, 2000

effect of iodinated high-viscosity contrast medium in the rat kidney: A diffusion-weighted MRI fe... more effect of iodinated high-viscosity contrast medium in the rat kidney: A diffusion-weighted MRI feasibility study. Invest Radiol 2000;35:647-652. RATIONALE AND OBJECTIVES. To assess the abilities of dynamic diffusion-weighted MRI to demonstrate the effects in vivo of a high-viscosity iodinated contrast agent on medullary and cortical blood flow in the rat kidney. METHODS. Dynamic diffusion-weighted, echoplanar MR images obtained from five b-value single-shot acquisitions and their isotropic apparent diffusion coefficient maps were obtained from nine rats anesthetized by pentobarbital sedation, before and after intravenous injection of a high-viscosity, dimeric iso-osmolar iodinated contrast medium (iodixanol), and compared with those obtained from four control rats that received saline. RESULTS. The mean baseline apparent diffusion coefficient values were 1.64 ؎ 0.05 ؋ 10 ؊3 mm 2 /s for the cortex and 1.75 ؎ 0.06 ؋ 10 ؊3 mm 2 /s for the medulla. In the iodixanol group, a significant decrease in renal diffusion was observed at 12 minutes and lasted at least until 24 minutes. The decrease in diffusion occurred earlier for the cortex and lasted less than for the medulla. There was no significant modification in diffusion over time in the control group. CONCLUSIONS. This preliminary experience in rats shows that dynamic diffusion-weighted MRI can be used to study noninvasively the in vivo renal hemodynamic response after injection of iodinated contrast.

Contrast Media & Molecular Imaging, Dec 1, 2019

Journal of Neurosurgery, Jul 1, 2022

OBJECTIVE Surgery can be highly effective for the treatment of medically intractable, neurologica... more OBJECTIVE Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage. METHODS Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB. RESULTS Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure. CONCLUSIONS These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.

Osteoarthritis implies a progressive degeneration of the whole joint. Cartilage is particularly a... more Osteoarthritis implies a progressive degeneration of the whole joint. Cartilage is particularly affected, with inflammation playing a pivotal role1. In recent years, cartilage regeneration has been pursued through several bioengineering strategies and using different stem cell types2-6. Adipose -derived mesenchymal stromal cells (ASCs) constitute an intriguing and minimally invasive option. However, the use of ASCs for cartilage regeneration is hampered by a relatively inefficient expression of key chondrogenic markers7. Thus, new strategies to boost both in situ targeting and chondrogenesis of ASCs are highly desirable. Here we show that ASCs embedded in a nanocomposite hydrogel including piezoelectric nanomaterials and graphene oxide nanoflakes, and stimulated with ultrasound waves with precisely controlled parameters (1 MHz and 250 mW/cm2, for 5 min once every two days for a period of 10 days) dramatically boost cell chondrogenic commitment. Furthermore, this stimulation regimen ...

IEEE Transactions on Biomedical Engineering, Mar 1, 2021

Objective:This paper presents and evaluates a breast-specific magnetic resonance guided focused u... more Objective:This paper presents and evaluates a breast-specific magnetic resonance guided focused ultrasound (MRgFUS) system. A first-in-human evaluation demonstrates the novel hardware, a sophisticated tumor targeting algorithm and a volumetric magnetic resonance imaging (MRI) protocol.Methods:At the time of submission, N=10 patients with non-palpable T0 stage breast cancer have been treated with the breast MRgFUS system. The described tumor targeting algorithm is evaluated both with a phantom test and in vivo during the breast MRgFUS treatments. Treatments were planned and monitored using volumetric MR-acoustic radiation force imaging (MR-ARFI) and temperature imaging (MRTI).Results:Successful technical treatments were achieved in 80% of the patients. All patients underwent the treatment with no sedation and 60% of participants had analgesic support. The total MR treatment time ranged from 73 to 114 minutes. Mean error between desired and achieved targeting in a phantom was 2.9±1.8 mm while 6.2±1.9 mm was achieved in patient studies, assessed either with MRTI or MR-ARFI measurements. MRTI and MR-ARFI were successful in 60% and 70% of patients, respectively.Conclusion:The targeting accuracy allows the accurate placement of the focal spot using electronic steering capabilities of the transducer. The use of both volumetric MRTI and MR-ARFI provides complementary treatment planning and monitoring information during the treatment, allowing the treatment of all breast anatomies, including homogeneously fatty breasts.

Proceedings of Meetings on Acoustics, 2017

Low-frequency ultrasound imaging using compressed-parametric ultrasound with application of synth... more Low-frequency ultrasound imaging using compressed-parametric ultrasound with application of synthetic aperture focusing

Medical Physics, Mar 11, 2010

MR thermometry based on the proton resonance frequency shift ͑PRFS͒ is the most commonly used met... more MR thermometry based on the proton resonance frequency shift ͑PRFS͒ is the most commonly used method for the monitoring of thermal therapies. As the chemical shift of water protons is temperature dependent, the local temperature variation ͑relative to an initial baseline͒ may be calculated from time-dependent phase changes in gradient-echo ͑GRE͒ MR images. Dynamic phase shift in GRE images is also produced by time-dependent changes in the magnetic bulk susceptibility of tissue. Gas bubbles ͑known as "white cavitation"͒ are frequently visualized near the RF electrode in ultrasonography-guided radio frequency ablation ͑RFA͒. This study aimed to investigate RFA-induced cavitation's effects by using simultaneous ultrasonography and MRI, to both visualize the cavitation and quantify the subsequent magnetic susceptibility-mediated errors in concurrent PRFS MR-thermometry ͑MRT͒ as well as to propose a first-order correction for the latter errors. Methods: RF heating in saline gels and in ex vivo tissues was performed with MR-compatible bipolar and monopolar electrodes inside a 1.5 T MR clinical scanner. Ultrasonography simultaneous to PRFS MRT was achieved using a MR-compatible phased-array ultrasonic transducer. PRFS MRT was performed interleaved in three orthogonal planes and compared to measurements from fluoroptic sensors, under low and, respectively, high RFA power levels. Control experiments were performed to isolate the main source of errors in standard PRFS thermometry. Results: Ultrasonography, MRI and digital camera pictures clearly demonstrated generation of bubbles every time when operating the radio frequency equipment at therapeutic powers ͑ജ30 W͒. Simultaneous bimodal ͑ultrasonography and MRI͒ monitoring of high power RF heating demonstrated a correlation between the onset of the PRFS-thermometry errors and the appearance of bubbles around the applicator. In an ex vivo study using a bipolar RF electrode under low power level ͑5 W͒, the MR measured temperature curves accurately matched the reference fluoroptic data. In similar ex vivo studies when applying higher RFA power levels ͑30 W͒, the correlation plots of MR thermometry versus fluoroptic data showed large errors in PRFS-derived temperature ͑up to 45°C absolute deviation, positive or negative͒ depending not only on fluoroptic tip position but also on the RF electrode orientation relative to the B 0 axis. Regions with apparent decrease in the PRFS-derived temperature maps as much as 30°C below the initial baseline were visualized during RFA high power application. Ex vivo data were corrected assuming a Gaussian dynamic source of susceptibility, centered in the anode/cathode gap of the RF bipolar electrode. After correction, the temperature maps recovered the revolution symmetry pattern predicted by theory and matched the fluoroptic data within 4.5°C mean offset. Conclusions: RFA induces dynamic changes in magnetic bulk susceptibility in biological tissue, resulting in large and spatially dependent errors of phase-subtraction-only PRFS MRT and unexploitable thermal dose maps. These thermometry artifacts were strongly correlated with the appearance of transient cavitation. A first-order dynamic model of susceptibility provided a useful method for minimizing these artifacts in phantom and ex vivo experiments.

NMR in Biomedicine, Apr 7, 2016

Boiling histotripsy (BH) is a new high intensity focused ultrasound (HIFU) ablation technique to ... more Boiling histotripsy (BH) is a new high intensity focused ultrasound (HIFU) ablation technique to mechanically fragmentize soft tissue into submicrometer fragments. So far, ultrasound has been used for BH treatment guidance and evaluation. The in vivo histopathological effects of this treatment are largely unknown. Here, we report on an MR guided BH method to treat subcutaneous tumors in a mouse model. The treatment effects of BH were evaluated one hour and four days later with MRI and histopathology, and compared with the effects of thermal HIFU (T-HIFU). The lesions caused by BH were easily detected with T2 w imaging as a hyper-intense signal area with a hypo-intense rim. Histopathological evaluation showed that the targeted tissue was completely disintegrated and that a narrow transition zone (<200 µm) containing many apoptotic cells was present between disintegrated and vital tumor tissue. A high level of agreement was found between T2 w imaging and H&E stained sections, making T2 w imaging a suitable method for treatment evaluation during or directly after BH. After T-HIFU, contrast enhanced imaging was required for adequate detection of the ablation zone. On histopathology, an ablation zone with concentric layers was seen after T-HIFU. In line with histopathology, contrast enhanced MRI revealed that after BH or T-HIFU perfusion within the lesion was absent, while after BH in the transition zone some micro-hemorrhaging appeared. Four days after BH, the transition zone with apoptotic cells was histologically no longer detectable, corresponding to the absence of a hypo-intense rim around the lesion in T2 w images. This study demonstrates the first results of in vivo BH on mouse tumor using MRI for treatment guidance and evaluation and opens the way for more detailed investigation of the in vivo effects of BH. Copyright © 2016 John Wiley & Sons, Ltd.