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Kullervo Hynynen - One of the best experts on this subject based on the ideXlab platform.
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Technical Principles and Clinical Workflow of Transcranial MR-guided Focused Ultrasound.
Stereotactic and functional neurosurgery, 2020Co-Authors: Ying Meng, Clement Hamani, Kullervo Hynynen, Yuexi Huang, Ryan M. Jones, Benjamin Davidson, Christopher B. Pople, Shanan Surendrakumar, Nir LipsmanAbstract:Transcranial MR-guided Focused Ultrasound (MRgFUS) is a rapidly developing technology in neuroscience for manipulating brain structure and function without open surgery. The effectiveness of transcranial MRgFUS for thermoablation is well established, and the technique is actively employed worldwide for movement disorders including essential tremor. A growing number of centers are also investigating the potential of microbubble-mediated Focused Ultrasound-induced opening of the blood-brain barrier (BBB) for targeted drug delivery to the brain. Here, we provide a technical overview of the principles, clinical workflow, and operator considerations of transcranial MRgFUS procedures for both thermoablation and BBB opening.
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First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided Focused Ultrasound
Nature Communications, 2019Co-Authors: Agessandro Abrahao, Clement Hamani, Ying Meng, Sandra E. Black, Isabelle Aubert, Yuexi Huang, Chinthaka Heyn, Maheleth Llinas, Todd Mainprize, Kullervo HynynenAbstract:MR-Focused Ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients. MR-guided Focused Ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS.
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First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided Focused Ultrasound
Nature communications, 2019Co-Authors: Agessandro Abrahao, Clement Hamani, Ying Meng, Sandra E. Black, Isabelle Aubert, Yuexi Huang, Chinthaka Heyn, Maheleth Llinas, Todd Mainprize, Kullervo HynynenAbstract:MR-guided Focused Ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS. MR-Focused Ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.
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Blood-Brain Barrier Opening in Alzheimer's Disease Using MR-guided Focused Ultrasound
Neurosurgery, 2019Co-Authors: Ying Meng, Zahra Shirzadi, Chris Heyn, Gwen S Smith, Clement Hamani, Kullervo Hynynen, Bradley J Macintosh, Sandra E. Black, Isabelle Aubert, Nir LipsmanAbstract:Abstract INTRODUCTION The blood-brain barrier (BBB) represents a significant restriction to therapeutic delivery to the central nervous system. Several techniques are available to circumvent the BBB, however Focused Ultrasound does so noninvasively and under image-guidance. MR-guided Focused Ultrasound (MRgFUS) in combination with intravenous microbubbles has been shown in animal models to transiently open the BBB, enhance biological therapeutics, and lead to greater reductions in Alzheimer disease (AD) pathology. Leveraging this preclinical data, we test, for the first time, whether MRgFUS induced increase in BBB permeability is safe, feasible, and repeatable in patients with early-to-moderate AD. METHODS Five patients with AD (mean age 66.2, mean MMSE 22.6) were recruited to this phase I open-label study. Two MRgFUS procedures targeting the right dorsolateral prefrontal cortex were performed 1-mo apart. [18F]-florbetaben PET was used to confirm amyloid deposition at the target site before the procedure. Patients were followed for 3 mo. Safety was assessed by the number and quality of adverse events. Feasibility was qualitatively assessed by gadolinium contrast extravasation in the target immediately and 1-d postprocedure. Resting state functional MRIs (rs-fMRIs) and [18F]-florbetaben PET were additionally acquired as exploratory measures. RESULTS Immediate gadolinium extravasation after MRgFUS demonstrated increased BBB permeability. This resolved the morning after. BBB open was uniform and achievable on all occasions. Opening the BBB did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at 3 mo compared to baseline. [18F]-florbetaben PET analysis suggested no group-wise changes in amyloid deposition at the target postsonication. There was a significant temporary decrease in functional connectivity in the ipsilateral frontoparietal network, with no additional long-term changes in frontoparietal or default mode network. CONCLUSION Our results provide the basis for the next investigation of MRgFUS as a potential novel treatment and therapeutic delivery strategy for patients with Alzheimer's disease. Exploratory analysis of advanced imaging further suggests Ultrasound is capable of noninvasive neuromodulation.
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Resting state functional connectivity changes after MR-guided Focused Ultrasound mediated blood-brain barrier opening in patients with Alzheimer's disease.
NeuroImage, 2019Co-Authors: Ying Meng, Zahra Shirzadi, Clement Hamani, Bradley J Macintosh, Sandra E. Black, Karim Mithani, Alex Kiss, Allison Bethune, Chinthaka Heyn, Kullervo HynynenAbstract:MR-guided Focused Ultrasound (MRgFUS) can temporarily permeabilize the blood-brain barrier (BBB), noninvasively, to allow therapeutics access to the central nervous system. However, its secondary and potential neuromodulation effects are not well understood. We aimed to characterize the functional impact of MRgFUS BBB opening in human subjects, based on the phase I trial in patients with Alzheimer's disease. We analyzed for changes in bilateral frontoparietal networks in resting state functional MRI from five subjects after BBB opening in the right frontal lobe. We found a transient functional connectivity decrease within only the ipsilateral frontoparietal network that was recovered by the next day. Additionally, baseline to month three comparisons did not reveal any significant differences from matched-controls from the Alzheimer's Disease Neuroimaging Initiative. Overall, MRgFUS may transiently affect neurologic function, but the functional organization is restored at one day and remains unchanged at three months. This first in human data has implications for the development of MRgFUS as a drug delivery platform to pathologic brain tissue and potential use for non-invasive neuromodulation.
Rares Salomir - One of the best experts on this subject based on the ideXlab platform.
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Mild hyperthermia by MR-guided Focused Ultrasound in an ex vivo model of osteolytic bone tumour: optimization of the spatio-temporal control of the delivered temperature
Journal of Translational Medicine, 2019Co-Authors: Pauline C. Guillemin, Rares Salomir, Orane Lorton, Thomas Zilli, Lindsey A. Crowe, Stéphane Desgranges, Xavier Montet, Sylvain Terraz, Raymond Miralbell, Sana BoudabbousAbstract:Background Magnetic resonance guided Focused Ultrasound was suggested for the induction of deep localized hyperthermia adjuvant to radiation- or chemotherapy. In this study we are aiming to validate an experimental model for the induction of uniform temperature elevation in osteolytic bone tumours, using the natural acoustic window provided by the cortical breakthrough. Materials and methods Experiments were conducted on ex vivo lamb shank by mimicking osteolytic bone tumours. The cortical breakthrough was exploited to induce hyperthermia inside the medullar cavity by delivering acoustic energy from a phased array HIFU transducer. MR thermometry data was acquired intra-operatory using the proton resonance frequency shift (PRFS) method. Active temperature control was achieved via a closed-loop predictive controller set at 6 °C above the baseline. Several beam geometries with respect to the cortical breakthrough were investigated. Numerical simulations were used to further explain the observed phenomena. Thermal safety of bone heating was assessed by cross-correlating MR thermometry data with the measurements from a fluoroptic temperature sensor inserted in the cortical bone. Results Numerical simulations and MR thermometry confirmed the feasibility of spatio-temporal uniform hyperthermia (± 0.5 °C) inside the medullar cavity using a fixed focal point sonication. This result was obtained by the combination of several factors: an optimal positioning of the focal spot in the plane of the cortical breakthrough, the direct absorption of the HIFU beam at the focal spot, the “acoustic oven effect” yielded by the beam interaction with the bone, and a predictive temperature controller. The fluoroptical sensor data revealed no heating risks for the bone and adjacent tissues and were in good agreement with the PRFS thermometry from measurable voxels adjacent to the periosteum. Conclusion To our knowledge, this is the first study demonstrating the feasibility of MR-guided Focused Ultrasound hyperthermia inside the medullar cavity of bones affected by osteolytic tumours. Our results are considered a promising step for combining adjuvant mild hyperthermia to external beam radiation therapy for sustained pain relief in patients with symptomatic bone metastases.
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Mild hyperthermia by MR-guided Focused Ultrasound in an ex vivo model of osteolytic bone tumour: optimization of the spatio-temporal control of the delivered temperature.
Journal of translational medicine, 2019Co-Authors: Pauline C. Guillemin, Orane Lorton, Thomas Zilli, Lindsey A. Crowe, Stéphane Desgranges, Xavier Montet, Sylvain Terraz, Raymond Miralbell, Laura Gui, Rares SalomirAbstract:Magnetic resonance guided Focused Ultrasound was suggested for the induction of deep localized hyperthermia adjuvant to radiation- or chemotherapy. In this study we are aiming to validate an experimental model for the induction of uniform temperature elevation in osteolytic bone tumours, using the natural acoustic window provided by the cortical breakthrough. Experiments were conducted on ex vivo lamb shank by mimicking osteolytic bone tumours. The cortical breakthrough was exploited to induce hyperthermia inside the medullar cavity by delivering acoustic energy from a phased array HIFU transducer. MR thermometry data was acquired intra-operatory using the proton resonance frequency shift (PRFS) method. Active temperature control was achieved via a closed-loop predictive controller set at 6 °C above the baseline. Several beam geometries with respect to the cortical breakthrough were investigated. Numerical simulations were used to further explain the observed phenomena. Thermal safety of bone heating was assessed by cross-correlating MR thermometry data with the measurements from a fluoroptic temperature sensor inserted in the cortical bone. Numerical simulations and MR thermometry confirmed the feasibility of spatio-temporal uniform hyperthermia (± 0.5 °C) inside the medullar cavity using a fixed focal point sonication. This result was obtained by the combination of several factors: an optimal positioning of the focal spot in the plane of the cortical breakthrough, the direct absorption of the HIFU beam at the focal spot, the “acoustic oven effect” yielded by the beam interaction with the bone, and a predictive temperature controller. The fluoroptical sensor data revealed no heating risks for the bone and adjacent tissues and were in good agreement with the PRFS thermometry from measurable voxels adjacent to the periosteum. To our knowledge, this is the first study demonstrating the feasibility of MR-guided Focused Ultrasound hyperthermia inside the medullar cavity of bones affected by osteolytic tumours. Our results are considered a promising step for combining adjuvant mild hyperthermia to external beam radiation therapy for sustained pain relief in patients with symptomatic bone metastases.
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hyperthermia by mr guided Focused Ultrasound accurate temperature control based on fast mri and a physical model of local energy deposition and heat conduction
Magnetic Resonance in Medicine, 2000Co-Authors: Rares Salomir, Frederic Vimeux, Jacco A De Zwart, N Grenier, Chrit T W MoonenAbstract:Temperature regulation in MR-guided Focused Ultrasound requires rapid MR temperature mapping and automatic feedback control of the Ultrasound output. Here, a regulation method is proposed based on a physical model of local energy deposition and heat conduction. The real-time evaluation of local temperature gradients from temperature maps is an essential element of the control system. Each time a new image is available, Ultrasound power is adjusted on-the-fly in order to obtain the desired evolution of the focal point temperature. In vitro and in vivo performance indicated fast and accurate control of temperature and a large tolerance of errors in initial estimates of Ultrasound absorption and heat conduction. When using correct estimates for the physical parameters of the model, focal point temperature was controlled within the measurement noise limit. Initial errors in absorption and diffusion parameters are compensated for exponentially with a user-defined response time, which is suggested to be on the order of 10 sec.
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hyperthermia by mr guided Focused Ultrasound accurate temperature control based on fast mri and a physical model of local energy deposition and heat conduction
Magnetic Resonance in Medicine, 2000Co-Authors: Rares Salomir, Frederic Vimeux, Jacco A De Zwart, N Grenier, Chrit T W MoonenAbstract:Temperature regulation in MR-guided Focused Ultrasound requires rapid MR temperature mapping and automatic feedback control of the Ultrasound output. Here, a regulation method is proposed based on a physical model of local energy deposition and heat conduction. The real-time evaluation of local temperature gradients from temperature maps is an essential element of the control system. Each time a new image is available, Ultrasound power is adjusted on-the-fly in order to obtain the desired evolution of the focal point temperature. In vitro and in vivo performance indicated fast and accurate control of temperature and a large tolerance of errors in initial estimates of Ultrasound absorption and heat conduction. When using correct estimates for the physical parameters of the model, focal point temperature was controlled within the measurement noise limit. Initial errors in absorption and diffusion parameters are compensated for exponentially with a user-defined response time, which is suggested to be on the order of 10 sec. Magn Reson Med 43:342–347, 2000. © 2000 Wiley-Liss, Inc.
Yuexi Huang - One of the best experts on this subject based on the ideXlab platform.
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Technical Principles and Clinical Workflow of Transcranial MR-guided Focused Ultrasound.
Stereotactic and functional neurosurgery, 2020Co-Authors: Ying Meng, Clement Hamani, Kullervo Hynynen, Yuexi Huang, Ryan M. Jones, Benjamin Davidson, Christopher B. Pople, Shanan Surendrakumar, Nir LipsmanAbstract:Transcranial MR-guided Focused Ultrasound (MRgFUS) is a rapidly developing technology in neuroscience for manipulating brain structure and function without open surgery. The effectiveness of transcranial MRgFUS for thermoablation is well established, and the technique is actively employed worldwide for movement disorders including essential tremor. A growing number of centers are also investigating the potential of microbubble-mediated Focused Ultrasound-induced opening of the blood-brain barrier (BBB) for targeted drug delivery to the brain. Here, we provide a technical overview of the principles, clinical workflow, and operator considerations of transcranial MRgFUS procedures for both thermoablation and BBB opening.
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First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided Focused Ultrasound
Nature Communications, 2019Co-Authors: Agessandro Abrahao, Clement Hamani, Ying Meng, Sandra E. Black, Isabelle Aubert, Yuexi Huang, Chinthaka Heyn, Maheleth Llinas, Todd Mainprize, Kullervo HynynenAbstract:MR-Focused Ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients. MR-guided Focused Ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS.
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First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided Focused Ultrasound
Nature communications, 2019Co-Authors: Agessandro Abrahao, Clement Hamani, Ying Meng, Sandra E. Black, Isabelle Aubert, Yuexi Huang, Chinthaka Heyn, Maheleth Llinas, Todd Mainprize, Kullervo HynynenAbstract:MR-guided Focused Ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS. MR-Focused Ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.
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The relevance of skull density ratio in selecting candidates for transcranial MR-guided Focused Ultrasound.
Journal of neurosurgery, 2019Co-Authors: Alexandre Boutet, Yuexi Huang, Dave Gwun, Robert Gramer, Manish Ranjan, Gavin J B Elias, David Tilden, Benjamin DavidsonAbstract:OBJECTIVETranscranial MR-guided Focused Ultrasound (MRgFUS) is a minimally invasive treatment for movement disorders. Considerable interpatient variability in skull transmission efficiency exists with the current clinical devices, which is thought to be dependent on each patient's specific skull morphology. Lower skull density ratio (SDR) values are thought to impede acoustic energy transmission across the skull, attenuating or preventing the therapeutic benefits of MRgFUS. Patients with SDR values below 0.4 have traditionally been deemed poor candidates for MRgFUS. Although considerable anecdotal evidence has suggested that SDR is a reliable determinant of procedural and clinical success, relationships between SDR and clinical outcomes have yet to be formally investigated. Moreover, as transcranial MRgFUS is becoming an increasingly widespread procedure, knowledge of SDR distribution in the general population may enable improved preoperative counseling and preparedness.METHODSA total of 98 patients who underwent MRgFUS thalamotomy at the authors' institutions between 2012 and 2018 were analyzed (cohort 1). The authors retrospectively assessed the relationships between SDR and various clinical outcomes, including tremor improvement and adverse effects, as well as procedural factors such as sonication parameters. An SDR was also prospectively obtained in 163 random emergency department patients who required a head CT scan for various clinical indications (cohort 2). Patients' age and sex were used to explore relationships with SDR.RESULTSIn the MRgFUS treatment group, 17 patients with a thalamotomy lesion had an SDR below 0.4. Patients with lower SDRs required more sonication energy; however, their low SDR did not influence their clinical outcomes. In the emergency department patient group, about one-third of the patients had a low SDR (< 0.4). SDR did not correlate with age or sex.CONCLUSIONSAlthough lower SDR values correlated with higher energy requirements during MRgFUS thalamotomy, within the range of this study population, the SDR did not appreciably impact or provide the ability to predict the resulting clinical outcomes. Sampling of the general population suggests that age and sex have no relationship with SDR. Other variables, such as local variances in bone density, should also be carefully reviewed to build a comprehensive appraisal of a patient's suitability for MRgFUS treatment.
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Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-guided Focused Ultrasound: A Clinical Safety and Feasibility Study.
Scientific reports, 2019Co-Authors: Todd Mainprize, Nir Lipsman, Ying Meng, Yuexi Huang, Allison Bethune, Chinthaka Heyn, Sarah Ironside, Ryan Alkins, Maureen Trudeau, Arjun SahgalAbstract:The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided Focused Ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of “sonicated” and “unsonicated” tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15–50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.
Nir Lipsman - One of the best experts on this subject based on the ideXlab platform.
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Technical Principles and Clinical Workflow of Transcranial MR-guided Focused Ultrasound.
Stereotactic and functional neurosurgery, 2020Co-Authors: Ying Meng, Clement Hamani, Kullervo Hynynen, Yuexi Huang, Ryan M. Jones, Benjamin Davidson, Christopher B. Pople, Shanan Surendrakumar, Nir LipsmanAbstract:Transcranial MR-guided Focused Ultrasound (MRgFUS) is a rapidly developing technology in neuroscience for manipulating brain structure and function without open surgery. The effectiveness of transcranial MRgFUS for thermoablation is well established, and the technique is actively employed worldwide for movement disorders including essential tremor. A growing number of centers are also investigating the potential of microbubble-mediated Focused Ultrasound-induced opening of the blood-brain barrier (BBB) for targeted drug delivery to the brain. Here, we provide a technical overview of the principles, clinical workflow, and operator considerations of transcranial MRgFUS procedures for both thermoablation and BBB opening.
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Blood-Brain Barrier Opening in Alzheimer's Disease Using MR-guided Focused Ultrasound
Neurosurgery, 2019Co-Authors: Ying Meng, Zahra Shirzadi, Chris Heyn, Gwen S Smith, Clement Hamani, Kullervo Hynynen, Bradley J Macintosh, Sandra E. Black, Isabelle Aubert, Nir LipsmanAbstract:Abstract INTRODUCTION The blood-brain barrier (BBB) represents a significant restriction to therapeutic delivery to the central nervous system. Several techniques are available to circumvent the BBB, however Focused Ultrasound does so noninvasively and under image-guidance. MR-guided Focused Ultrasound (MRgFUS) in combination with intravenous microbubbles has been shown in animal models to transiently open the BBB, enhance biological therapeutics, and lead to greater reductions in Alzheimer disease (AD) pathology. Leveraging this preclinical data, we test, for the first time, whether MRgFUS induced increase in BBB permeability is safe, feasible, and repeatable in patients with early-to-moderate AD. METHODS Five patients with AD (mean age 66.2, mean MMSE 22.6) were recruited to this phase I open-label study. Two MRgFUS procedures targeting the right dorsolateral prefrontal cortex were performed 1-mo apart. [18F]-florbetaben PET was used to confirm amyloid deposition at the target site before the procedure. Patients were followed for 3 mo. Safety was assessed by the number and quality of adverse events. Feasibility was qualitatively assessed by gadolinium contrast extravasation in the target immediately and 1-d postprocedure. Resting state functional MRIs (rs-fMRIs) and [18F]-florbetaben PET were additionally acquired as exploratory measures. RESULTS Immediate gadolinium extravasation after MRgFUS demonstrated increased BBB permeability. This resolved the morning after. BBB open was uniform and achievable on all occasions. Opening the BBB did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at 3 mo compared to baseline. [18F]-florbetaben PET analysis suggested no group-wise changes in amyloid deposition at the target postsonication. There was a significant temporary decrease in functional connectivity in the ipsilateral frontoparietal network, with no additional long-term changes in frontoparietal or default mode network. CONCLUSION Our results provide the basis for the next investigation of MRgFUS as a potential novel treatment and therapeutic delivery strategy for patients with Alzheimer's disease. Exploratory analysis of advanced imaging further suggests Ultrasound is capable of noninvasive neuromodulation.
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Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-guided Focused Ultrasound: A Clinical Safety and Feasibility Study.
Scientific reports, 2019Co-Authors: Todd Mainprize, Nir Lipsman, Ying Meng, Yuexi Huang, Allison Bethune, Chinthaka Heyn, Sarah Ironside, Ryan Alkins, Maureen Trudeau, Arjun SahgalAbstract:The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided Focused Ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of “sonicated” and “unsonicated” tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15–50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.
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Predicting lesion size by accumulated thermal dose in MR-guided Focused Ultrasound for essential tremor.
Medical physics, 2018Co-Authors: Yuexi Huang, Nir Lipsman, Michael L Schwartz, Andres M Lozano, Vibhor Krishna, Francesco Sammartino, Kullervo HynynenAbstract:Purpose To correlate the accumulated thermal dose (ATD) with lesion size in magnetic resonance (MR)-guided Focused Ultrasound (MRgFUS) thalamotomy to help guide future clinical treatments. Materials and methods Thirty-six patients with medication-refractory essential tremor were treated using a commercial MRgFUS brain system (ExAblate 4000, InSightec) in a 3T MR scanner (MR750, GE Healthcare). Intraoperative MR-thermometry was performed to measure the induced temperature and thermal dose distributions (thermal coefficient = -0.00909 ppm/°C). The ATD was calculated over multiple sonications with appropriate corrections for spatial-shifting artifacts. The ATD profile sizes obtained for dose values of 17, 40, 100, 200, and 240 cumulative equivalent minutes at 43°C (CEM) were correlated with the corresponding lesion sizes measured via axial T1- and T2-weighted MR images acquired 1 day post-treatment. Results Of a total of 232 included sonications, 83 required corrections for off-resonance-induced spatial-shifting artifacts (correction range = [1.1,2.2] mm). The mean lesion sizes measured on T2-weighted MR images (6.2 ± 1.3 mm, mean ± SD) were 15% larger than those measured on corresponding T1-weighted MR images (5.3 ± 1.2 mm, mean ± SD). The ATD values that provided the best correlations with the measured lesion sizes on T2- and T1-weighted MR images were 100 and 200 CEM, respectively. Conclusion The ATD was correlated with lesion size measured 1 day following MRgFUS thalamotomy for essential tremor. These data provide useful information for predicting brain lesion size and determining treatment endpoints in future clinical MRgFUS procedures.
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Low-Intensity MR-guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases.
Frontiers in oncology, 2018Co-Authors: Ying Meng, Shanan Surendrakumar, Suganth Suppiah, Luca Bigioni, Nir LipsmanAbstract:Low-intensity MR-guided Focused Ultrasound in combination with intravenously injected microbubbles is a promising platform for drug delivery to the central nervous system past the blood-brain barrier. The blood-brain barrier is a key bottleneck for cancer therapeutics via limited inter- and intracellular transport. Further, drugs that cross the blood-brain barrier when delivered in a spatially nonspecific way, result in adverse effects on normal brain tissue, or at high concentrations, result in increasing risks to peripheral organs. As such, various anti-cancer drugs that have been developed or to be developed in the future would benefit from a noninvasive, temporary, and repeatable method of targeted opening of the blood-brain barrier to treat metastatic brain diseases. MR-guided Focused Ultrasound is a potential solution to these design requirements. The safety, feasibility and preliminary efficacy of MRgFUS aided delivery have been demonstrated in various animal models. In this review, we discuss this preclinical evidence, mechanisms of Focused Ultrasound mediated blood-brain barrier opening, and translational efforts to neuro-oncology patients.
Wufan Chen - One of the best experts on this subject based on the ideXlab platform.
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Numerical optimization of a three‐channel radiofrequency coil for open, vertical‐field, MR‐guided, Focused Ultrasound surgery using the hybrid method of moment/finite difference time domain method
NMR in biomedicine, 2011Co-Authors: Xuegang Xin, Yanqiu Feng, Jijun Han, Di Wang, Qianjin Feng, Wufan ChenAbstract:The numerical optimization of a three-channel radiofrequency (RF) coil with a physical aperture for the open, vertical-field, MR-guided, Focused Ultrasound surgery (MRgFUS) system using the hybrid method of moment (MoM)/finite difference time domain (FDTD) method is reported. The numerical simulation of the current density distribution on an RF coil with a complicated irregular structure was performed using MoM. The electromagnetic field simulation containing the full coil–tissue interactions within the region of interest was accomplished using the FDTD method. Huygens' equivalent box with six surfaces smoothly connected the MoM and FDTD method. An electromagnetic model of the human pelvic region was reconstructed and loaded in the FDTD zone to optimize the three-channel RF coil and compensate for the lower sensitivity at the vertical field. In addition, the numerical MoM was used to model the resonance, decoupling and impedance matching of the RF coil in compliance with engineering practices. A prototype RF coil was constructed to verify the simulation results. The results demonstrate that the signal-to-noise ratio and the homogeneity of the B1 field were both greatly improved compared with previously published results. Copyright © 2011 John Wiley & Sons, Ltd.
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Three-channel receive-only RF coil for vertical-field MR guided Focused Ultrasound surgery
2010 International Conference of Medical Image Analysis and Clinical Application, 2010Co-Authors: Xuegang Xin, Yanqiu Feng, Jijun Han, Wufan ChenAbstract:Focused Ultrasound plays an important role in local hyperthermia treatment. Magnetic resonance imaging (MRI) can be used for monitoring temperature during a thermo-coagulation treatment of tumors. The combination of these two technologies offers great advantages for oncology treatment. Currently, only horizontal-field MR guided Focused Ultrasound systems are available clinically, but the circular magnetic field restricts the operational space during surgery. Vertical-field open MR could provide wider access to patients during the Ultrasound surgery and thus increase the potential clinical applications. A key component to facilitate such a system is the radio frequency (RF) coils. Common RF coils of vertical-field MR are not adaptive to combined system because there is no unhindered path for Ultrasound beams to pass. A special three-channel receive-only RF coil with a 27 cm aperture to pass Ultrasound beams was designed and reported first time. Phantom scan, body imaging and temperature measurements were all taken with the specially designed prototype coil. The results show that the designed coil was functionally adaptive to the vertical-field MR guided Focused Ultrasound system.
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Decoupling of multi-channels RF coil and its application to intraoperative MR-guided Focused Ultrasound device
2010 International Conference of Medical Image Analysis and Clinical Application, 2010Co-Authors: Jijun Han, Xuegang Xin, Wufan ChenAbstract:Decoupling between different elements is the key technology in the design of the RF coil. The electrical decoupling circuits should vary with different arrangement of the elements. A novel method of decoupling for the RF coil used in the intraoperative MR-guided Focused Ultrasound system was reported in the paper. The prototype RF coil was made according to the proposed decoupling method. The bench test of the coil showed that the performance of the decoupling of the coil was excellent. The images in vivo were acquired with the designed prototype RF coil.