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Magnetic resonance imaging-guided focused ultrasound to increase localized blood-spinal cord barrier permeability

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Neural Regeneration Research 2017年第12期12卷 2045-2049页

作者： Allison H.Payne Gregory W.Hawryluk Yoshimi Anzai Henrik Odéen Megan A.Ostlie Ethan C.Reichert Amanda J.Stump Satoshi Minoshima Donna J.Cross Department of Radiology and Imaging Sciences University of Utah Salt Lake City UT USA Department of Neurosurgery University of Utah Salt Lake City UT USA

Spinal cord injury（SCI） affects thousands of people every year in the USA, and most patients are left with some permanent paralysis. Therapeutic options are limited and only modestly affect outcome. To address this issue, we used magnetic resonance imaging-guided focused ultrasound（MRg FUS） as a non-invasive approach to increase permeability in the blood-spinal cord barrier（BSCB）. We hypothesize that localized, controlled sonoporation of the BSCB by MRg FUS will aid delivery of therapeutics to the injury. Here, we report our preliminary findings for the ability of MRg FUS to increase BSCB permeability in the thoracic spinal cord of a normal rat model. First, an excised portion of normal rat spinal column was used to characterize the acoustic field and to estimate the insertion losses that could be expected in an MRg FUS blood spinal cord barrier opening. Then, in normal rats, MRg FUS was applied in combination with intravenously administered microbubbles to the spinal cord region. Permeability of the BSCB was indicated as signal enhancement by contrast administered prior to T1-weighted magnetic resonance imaging and verified by Evans blue dye. Neurological testing using the Basso, Beattie, and Breshnahan scale and the ladder walk was normal in 8 of 10 rats tested. Two rats showed minor impairment indicating need for further refinement of parameters. No gross tissue damage was evident by histology. In this study, we have opened successfully the blood spinal cord barrier in the thoracic region of the normal rat spine using magnetic resonance-guided focused ultrasound combined with microbubbles.

关键词： focused ultrasound spinal cord magnetic resonance imaging contrast-enhanced blood-spinalcord barrier

Magnetic resonance imaging biomarkers for pulsed focused ultrasound treatment of pancreatic ductal adenocarcinoma

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World Journal of Gastroenterology 2020年第9期26卷 904-917页

作者： Ezekiel Maloney Yak-Nam Wang Ravneet Vohra Helena Son Stella Whang Tatiana Khokhlova Joshua Park Kayla Gravelle Stephanie Totten Joo Ha Hwang Donghoon Lee Department of Radiology University of WashingtonSeattleWA 98195United States Applied Physics Laboratory University of WashingtonSeattleWA 98195United States Division of Gastroenterology University of WashingtonSeattle 98195WAUnited States Division of Gastroenterology&Hepatology Stanford University School of MedicineRedwood CityCA 94063United States

BACKGROUND The robust fibroinflammatory stroma characteristic of pancreatic ductal adenocarcinoma(PDA)impedes effective drug delivery.Pulsed focused ultrasound(pFUS)can disrupt this stroma and has improved survival in an early clinical trial.Non-invasive methods to characterize pFUS treatment effects are desirable for advancement of this promising treatment modality in larger clinical trials.AIM To identify promising,non-invasive pre-clinical imaging methods to characterize acute pFUS treatment effects for in vivo models of PDA.METHODS We utilized quantitative magnetic resonance imaging methods at 14 tesla in three mouse models of PDA(subcutaneous,orthotopic and transgenic-KrasLSLG12D/+,Trp53LSL-R172H/+,Cre or“KPC”)to assess immediate tumor response to pFUS treatment(VIFU 2000 Alpinion Medical Systems;475 W peak electric power,1 ms pulse duration,1 Hz,duty cycle 0.1%)vs sham therapy,and correlated our results with histochemical data.These pFUS treatment parameters were previously shown to enhance tumor permeability to chemotherapeutics.T1 and T2 relaxation maps,high(126,180,234,340,549)vs low(7,47,81)b-value apparent diffusion coefficient(ADC)maps,magnetization transfer ratio(MTR)maps,and chemical exchange saturation transfer(CEST)maps for the amide proton spectrum(3.5 parts per million or“ppm”)and the glycosaminoglycan spectrum(0.5-1.5 ppm)were generated and analyzed pre-treatment,and immediately post-treatment,using ImageJ.Animals were sacrificed immediately following post-treatment imaging.The whole-tumor was selected as the region of interest for data analysis and subsequent statistical analysis.T-tests and Pearson correlation were used for statistical inference.RESULTS Mean high-b value ADC measurements increased significantly with pFUS treatment for all models.Mean glycosaminoglycan CEST and T2 measurements decreased significantly post-treatment for the KPC group.Mean MTR and amide CEST values increased significantly for the KPC group.Hyaluronic acid focal intensities in the treated regions were significant

关键词： Pancreatic adenocarcinoma Multiparametric magnetic resonance imaging focused ultrasound

Vulvar Rejuvenation Using High-Intensity focused ultrasound (HIFU): Fundamentals and Technique

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Journal of Biosciences and Medicines 2022年第12期10卷 239-252页

作者： Fábio dos Santos Borges Mylana Almeida de Carvalho Carla Barreto Silva de Cerqueira Tais Andrade Cravo Monteiro Isabelle Maria Almeida e Benevides Adriele Machado Dantas Thiago Gusmão da Silva Carolina Barreto Ribeiro Martins dos Santos Estácio de Sá University Rio de Janeiro Brazil IDE Faculty—Institute for Educational Development Salvador Brazil Longevitat Clinic—Advanced Aesthetics Salvador Brazi FAINOR Independent College of the Northeast Vitória da Conquista Brazil UFBA Federal University of Bahia Salvador Brazil

Background: The unaesthetic appearance of the female intimate area (vulva, “mound of venus” and perianal region) is a triggering factor of negative psychological responses, embarrassment, anxiety and insecurity in many women. Using rejuvenating equipment for vaginal structure or for the intimate area as a whole is already widespread in the literature, and High-Intensity focused ultrasound (HIFU) has proven to be very effective in the clinical practice of many professionals. This study, therefore, aims to describe the fundamentals and applicability that guide the use of HIFU in vulvar rejuvenation. Materials and Methods: Exploratory research was carried out, presented in a narrative review, to highlight the action of HIFU in female intimate rejuvenation. The review explored scientific articles published and available in the following databases: MEDLINE (Medical Literature Analysis and Retrieval System Online), PubMed (National Library of Medicine), SCIELO (Scientific Electronic Library Online), and LILACS (Latin Literature American and the Caribbean in Health Sciences). In addition, some clinical findings obtained through a retrospective analysis of medical records were added to describe the authors’ clinical experience in the use of focused ultrasound (HIFU) for vulvar rejuvenation. Results: We verified that the tissues of female external genitalia respond very well to the stimuli of the focused sound waves of the HIFU, being able to produce immediate and lasting results through isolated applications or in association with intradermotherapy or other therapeutic resources. Conclusion: We conclude that using High Intensity focused ultrasound aimed at vulvar rejuvenation is safely indicated and assures excellent aesthetic results at the end of the treatment because similarly to other treatment techniques, the thermal stimuli of HIFU are also able to produce an excellent therapeutic response in the dermal tissue of the female intimate area, promoting intense neocollagenesis and generating great aesthetic improvement.

关键词： Intimate Aesthetics Vulvar Rejuvenation Vaginal Rejuvenation HIFU focused ultrasound Micro focused ultrasound and Cosmetic Gynecology

Nonlinear propagation of focused ultrasound in layered biological tissues based on angular spectrum approach

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Chinese Physics B 2005年第8期14卷 1594-1599页

作者：朱晓峰周琳章东龚秀芬 StateKeyLaboratoryofModernAcoustics InstituteofAcousticsNanjingUniversityNanjing210093China

Nonlinear propagation of focused ultrasound in layered biological tissues is theoretically studied by using the angular spectrum approach (ASA), in which an acoustic wave is decomposed into its angular spectrum, and the distribution of nonlinear acoustic fields is calculated in arbitrary planes normal to the acoustic axis. Several biological tissues are used as specimens inserted into the focusing region illuminated by a focused piston source. The second harmonic components within or beyond the biological specimens are numerically calculated. Validity of the theoretical model is examined by measurements. This approach employing the fast Fourier transformation gives a clear visualization of the focused ultrasound, which is helpful for nonlinear ultrasonic imaging.

关键词： focused ultrasound second harmonic imaging angular spectrum approach

Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice,an AD model

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Translational Neurodegeneration 2022年第1期11卷 31-45页

作者： Chanho Kong Eun-Jeong Yang Jaewoo Shin Junwon Park Si-Hyun Kim Seong-Wook Park Won Seok Chang Chang-Han Lee Hyunju Kim Hye-Sun Kim Jin Woo Chang Department of Neurosurgery Yonsei University College of Medicine50 Yonsei-RoSeodaemun-GuSeoulRepublic of Korea Department of Pharmacology College of MedicineSeoul National University103 DaehakroJongro-GuSeoulRepublic of Korea Neuroscience Research Center College of MedicineSeoul National University103 DaehakroJongro-GuSeoulRepublic of Korea Department of Biomedical Sciences College of MedicineSeoul National University103 DaehakroJongro-GuSeoulRepublic of Korea Bundang Hospital Seoul National University College of MedicineBundang-GuSungnamRepublic of Korea.

Background:Aducanumab(Adu),which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid,has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose(10 mg/kg)of the drug in Alzheimer’s disease(AD)clinical trials.The purpose of this study was to investigate the effects of a lower dose of Adu(3 mg/kg)with enhanced delivery via focused ultrasound(FUS)in an AD mouse model.Methods:The FUS with microbubbles opened the blood-brain barrier(BBB)of the hippocampus for the delivery of Adu.The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly.Y-maze test,Brdu labeling,and immunohistochemical experimental methods were employed in this study.In addition,RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals.Results:The FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains.The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone.Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice.Furthermore,RNA sequencing identified that 4 enriched canonical pathways including phagosome formation,neuroinflammation signaling,CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment.Conclusion:In conclusion,the enhanced delivery of a low dose of Adu(3 mg/kg)via FUS decreases amyloid deposits and attenuates cognitive function deficits.FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery.We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.

关键词： Aducanumab Alzheimer’s disease focused ultrasound Transcriptome profiling

Extensive frontal focused ultrasound Check for updates mediated blood-brain barrier opening for the treatment of Alzheimer's disease:a proof-of-concept study

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Translational Neurodegeneration 2021年第4期10卷 573-583页

作者： So Hee Park Kyoungwon Baik Seun Jeon Won Seok Chang Byoung Seok Ye Jin Woo Chang Brain Research Institute Department of NeurosurgeryYonsei University College of MedicineSeoulKorea Department of Neurology Yonsei University College of MedicineSeoulKorea

Background:focused ultrasound(FUS)-mediated blood-brain barrier(BBB)opening has shown efficacy in removal of amyloid plaque and improvement of cognitive functions in preclinical studies,but this is rarely reported in clinical studies.This study was conducted to evaluate the safety,feasibility and potential benefits of repeated extensive BBB opening.Methods:In this open-label,prospective study,six patients with Alzheimer's disease(AD)were enrolled at Severance Hospital in Korea between August 2020 and September 2020.Five of them completed the study.FUS-mediated BBB opening,targeting the bilateral frontal lobe regions over 20 cm^(3),was performed twice at three-month intervals.Magnetic resonance imaging,^(18)F-Florbetaben(FBB)positron emission tomography,Caregiver-Administered Neuropsychiatric Inventory(CGA-NPI)and comprehensive neuropsychological tests were performed before and after the procedures.Results:FUS targeted a mean volume of 21.1±2.7 cm^(3)and BBB opening was confirmed at 95.7%±9.4%of the targeted volume.The frontal-to-other cortical region FBB standardized uptake value ratio at 3 months after the procedure showed a slight decrease,which was statistically significant,compared to the pre-procedure value(-1.6%,0.986 vs 1.002,P=0.043).The CGA-NPI score at 2 weeks after the second procedure significantly decreased compared to baseline(2.2±3.0 vs 8.6±6.0,P=0.042),but recovered after 3 months(5.2±5.8 vs 8.6±6.0,P=0.89).No adverse effects were observed.Conclusions:The repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD.In addition,the BBB opening is potentially beneficial for amyloid removal in AD patients.

关键词： Alzheimer disease focused ultrasound Blood-brain barrier Amyloid beta-peptides

ultrasound imaging and evaluation of lesion induced by High Intensity focused ultrasound

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Chinese Journal of Acoustics 2006年第2期25卷 104-115页

作者： ZHONG Hui WAN Mingxi JIANG Yifeng WANG Supin The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Department of Biomedical Engineering School of Life Science and Technology Xi'an Jiaotong University Xi'an 710049

The present study was to investigate the differential imaging method for detecting HIFU （High Intensity focused ultrasound）-induced lesions and the estimation of variation of attenuation for lesion evaluation with log spectral difference algorithm. Experiment results of bovine muscle and liver in vitro were acquired. Several algorithms for lesion detection - Absolute Difference （AD）, Sum Absolute Differences （SAD） and Sum Squared Differences （SSD） - were analyzed with several window sizes and threshold values. Then three attenuation parameters were compared to evaluate the degree of tissue damage. It was found that variation of the mean attenuation △a^- was an effective parameter to evaluate lesions.

关键词： focused ultrasound threshold values in vitro

Novel drug-delivery approaches to the blood-brain barrier

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Neuroscience Bulletin 2015年第2期31卷 257-264页

作者： Xiaoqing Wang Xiaowen Yu William Vaughan Mingyuan Liu Yangtai Guan Department of Neurology Changhai Hospital Second Military Medical University Stem Cells and Medical Research Center Second Military Medical University Department of Gerontology Changhai Hospital Second Military Medical University Department of Genetics Yale University

The blood-brain barrier （BBB） maintains homeostasis by blocking toxic molecules from the circulation, but drugs are blocked at the same time. When the dose is increased to enhance the drug concentration in the central nervous system, there are side-effects on peripheral organs. In recent years, genetic therapeutic agents and small molecules have been used in various strategies to penetrate the BBB while minimizing the damage to systemic organs. In this review, we describe several representative methods to circumvent or cross the BBB, including chemical and physical strategies.

关键词： drug delivery blood-brain barrier nanoparticles focused ultrasound

Current surgical treatments for Parkinson's disease and potential therapeutic targets

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Neural Regeneration Research 2018年第8期13卷 1342-1345页

作者： Darrin J.Lee Robert F.Dallapiazza Philippe De Vloo Andres M.Lozano Division of Neurosurgery Toronto Western Hospital Department of Surgery University of Toronto

Currently, the most common surgical treatment for Parkinson＇s disease is deep brain stimulation（DBS）. This treatment strategy is typically reserved for bradykinesia, rigidity and tremor in patients who no longer respond to medication in a predictable manner or who suffer medication-induced dyskinesias. In addition to DBS, ablative procedures like radiofrequency, radiosurgery and focused ultrasound are also utilized for select tremor symptoms. In this review, we discuss evolving surgical techniques, targets, and emerging technology. In addition, we evaluate potential paradigm shifts in treatment, including gene therapy, immunotherapy and cell transplantation. While these new techniques and treatment options are still in their infancy, advances in Parkinson＇s disease treatment are rapidly expanding.

关键词： Parkinson＇s disease deep brain stimulation pallidotomy thalamotomy focused ultrasound gene therapy immunotherapy cell transplantation