Time-dependent change of blood flow in the prostate treated with high-intensity focused ultrasound.

Science.gov (United States)

Shoji, Sunao; Tonooka, Akiko; Hashimoto, Akio; Nakamoto, Masahiko; Tomonaga, Tetsuro; Nakano, Mayura; Sato, Haruhiro; Terachi, Toshiro; Koike, Junki; Uchida, Toyoaki

2014-09-01

Avascular areas on contrast-enhanced magnetic resonance imaging have been considered to be areas of localized prostate cancer successfully treated by high-intensity focused ultrasound. However, the optimal timing of magnetic resonance imaging has not been discussed. The thermal effect of high-intensity focused ultrasound is degraded by regional prostatic blood flow. Conversely, the mechanical effect of high-intensity focused ultrasound (cavitation) is not affected by blood flow, and can induce vessel damage. In this series, the longitudinal change of blood flow on contrast-enhanced magnetic resonance imaging was observed from postoperative day 1 to postoperative day 14 in 10 patients treated with high-intensity focused ultrasound. The median rates of increase in the non-enhanced volume of the whole gland, transition zone and peripheral zone from postoperative day 1 to postoperative day 14 were 36%, 39%, and 34%, respectively. In another pathological analysis of the prostate tissue of 17 patients immediately after high-intensity focused ultrasound without neoadjuvant hormonal therapy, we observed diffuse coagulative degeneration and partial non-coagulative prostate tissue around arteries with vascular endothelial cell detachment. These observations on contrast-enhanced magnetic resonance imaging support a time-dependent change of the blood flow in the prostate treated with high-intensity focused ultrasound. Additionally, our pathological findings support the longitudinal changes of these magnetic resonance imaging findings. Further large-scale studies will investigate the most appropriate timing of contrast-enhanced magnetic resonance imaging for evaluation of the effectiveness of high-intensity focused ultrasound for localized prostate cancer. © 2014 The Japanese Urological Association.

Improved survival in rats with glioma using MRI-guided focused ultrasound and microbubbles to disrupt the blood-brain barrier and deliver Doxil

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Aryal, Muna; Zhi Zhang, Yong; Vykhodtseva, Natalia; Park, Juyoung; Power, Chanikarn; McDannold, Nathan

2012-02-01

Blood-brain-barrier (BBB) limits the transportation of most neuropeptides, proteins (enzymes, antibodies), chemotherapeutic agents, and genes that have therapeutic potential for the treatment of brain diseases. Different methods have been used to overcome this limitation, but they are invasive, non-targeted, or require the development of new drugs. We have developed a method that uses MRI-guided focused ultrasound (FUS) combined with circulating microbubbles to temporarily open BBB in and around brain tumors to deliver chemotherapy agents. Here, we tested whether this noninvasive technique could enhance the effectiveness of a chemotherapy agent (Doxil). Using 690 kHz FUS transducer and microbubble (Definity), we induced BBB disruption in intracranially-implanted 9L glioma tumors in rat's brain in three weekly sessions. Animals who received BBB disruption and Doxil had a median survival time of 34.5 days, which was significantly longer than that found in control animals which is 16, 18.5, 21 days who received no treatment, BBB disruption only and Doxil only respectively This work demonstrates that FUS technique has promise in overcoming barriers to drug delivery, which are particularly stark in the brain due to the BBB.

Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles

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Downs, Matthew E.; Buch, Amanda; Karakatsani, Maria Eleni; Konofagou, Elisa E.; Ferrera, Vincent P.

2015-10-01

Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

Ultrasound effects on brain-targeting mannosylated liposomes: in vitro and blood-brain barrier transport investigations.

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Zidan, Ahmed S; Aldawsari, Hibah

2015-01-01

Delivering drugs to intracerebral regions can be accomplished by improving the capacity of transport through blood-brain barrier. Using sertraline as model drug for brain targeting, the current study aimed at modifying its liposomal vesicles with mannopyranoside. Box-Behnken design was employed to statistically optimize the ultrasound parameters, namely ultrasound amplitude, time, and temperature, for maximum mannosylation capacity, sertraline entrapment, and surface charge while minimizing vesicular size. Moreover, in vitro blood-brain barrier transport model was established to assess the transendothelial capacity of the optimized mannosylated vesicles. Results showed a dependence of vesicular size, mannosylation capacity, and sertraline entrapment on cavitation and bubble implosion events that were related to ultrasound power amplitude, temperature. However, short ultrasound duration was required to achieve >90% mannosylation with nanosized vesicles (ultrasound parameters of 65°C, 27%, and 59 seconds for ultrasound temperature, amplitude, and time were elucidated to produce 81.1%, 46.6 nm, and 77.6% sertraline entrapment, vesicular size, and mannosylation capacity, respectively. Moreover, the transendothelial ability was significantly increased by 2.5-fold by mannosylation through binding with glucose transporters. Hence, mannosylated liposomes processed by ultrasound could be a promising approach for manufacturing and scale-up of brain-targeting liposomes.

Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening

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Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel

2016-01-01

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood–brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood–brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo. PMID:27278929

High intensity focused ultrasound technology, its scope and applications in therapy and drug delivery.

Science.gov (United States)

Phenix, Christopher Peter; Togtema, Melissa; Pichardo, Samuel; Zehbe, Ingeborg; Curiel, Laura

2014-01-01

Ultrasonography is a safe, inexpensive and wide-spread diagnostic tool capable of producing real-time non-invasive images without significant biological effects. However, the propagation of higher energy, intensity and frequency ultrasound waves through living tissues can induce thermal, mechanical and chemical effects useful for a variety of therapeutic applications. With the recent development of clinically approved High Intensity Focused Ultrasound (HIFU) systems, therapeutic ultrasound is now a medical reality. Indeed, HIFU has been used for the thermal ablation of pathological lesions; localized, minimally invasive ultrasound-mediated drug delivery through the transient formation of pores on cell membranes; the temporary disruption of skin and the blood brain barrier; the ultrasound induced break-down of blood clots; and the targeted release of drugs using ultrasound and temperature sensitive drug carriers. This review seeks to engage the pharmaceutical research community by providing an overview on the biological effects of ultrasound as well as highlighting important therapeutic applications, current deficiencies and future directions.

Impact of Focused Ultrasound-enhanced Drug Delivery on Survival in Rats with Glioma

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Treat, Lisa Hsu; Zhang, Yongzhi; McDannold, Nathan; Hynynen, Kullervo

2009-04-01

Malignancies of the brain remain difficult to treat with chemotherapy because the selective permeability of the blood-brain barrier (BBB) blocks many potent agents from reaching their target. Previous studies have illustrated the feasibility of drug and antibody delivery across the BBB using MRI-guided focused ultrasound. In this study, we investigated the impact of focused ultrasound-enhanced delivery of doxorubicin on survival in rats with aggressive glioma. Sprague-Dawley rats were implanted with 9 L gliosarcoma cells in the brain. Eight days after implantation, each rat received one of the following: (1) no treatment (control), (2) a single treatment with microbubble-enhanced MRI-guided focused ultrasound (FUS only), (3) a single treatment with i.v. liposomal doxorubicin (DOX only), or (4) a single treatment with microbubble-enhanced MRI-guided focused ultrasound and concurrent i.v. injections of liposomal doxorubicin (FUS+DOX). The survival time from implantation to death or euthanasia was recorded. We observed a modest but significant increase in median survival time in rats treated with combined MRI-guided focused ultrasound chemotherapy, compared to chemotherapy alone (p0.10). Our study demonstrates for the first time a therapeutic benefit achieved with ultrasound-enhanced drug delivery across the blood-brain barrier. This confirmation of efficacy in an in vivo tumor model indicates that targeted drug delivery using MRI-guided focused ultrasound has the potential to have a major impact on the treatment of patients with brain tumors and other neurological disorders.

Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers

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Tsai, Chih-Hung; Zhang, Jia-Wei; Liao, Yi-Yi; Liu, Hao-Li

2016-04-01

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a

Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual-frequency piezoelectric transducers

International Nuclear Information System (INIS)

Tsai, Chih-Hung; Zhang, Jia-Wei; Liao, Yi-Yi; Liu, Hao-Li

2016-01-01

Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood-brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast-enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB-opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra-operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a

Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study.

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Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-04-28

Transcranial MRI-guided focused ultrasound is a rapidly advancing method for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). The method's main advantages are that it is both targeted and noninvasive, and that it can be easily repeated. Studies have shown that liposomal doxorubicin (Lipo-DOX), a chemotherapy agent with promise for tumors in the central nervous system, can be delivered into the brain across BBB. However, prior studies have suggested that doxorubicin can be significantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of Lipo-DOX administered after FUS-induced BBB disruption (FUS-BBBD) induces severe adverse events in the normal brain tissues. First, we used fluorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD to ensure that a clinically relevant doxorubicin concentration was achieved in the brain. Next, we performed three weekly sessions with FUS-BBBD±Lipo-DOX administration. Five to twelve targets were sonicated each week, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., 2013). Five rats received three weekly sessions where i.v. injected Lipo-DOX was combined with FUS-BBBD; an additional four rats received FUS-BBBD only. Animals were euthanized 70days from the first session and brains were examined in histology. We found that clinically-relevant concentrations of doxorubicin (4.8±0.5μg/g) were delivered to the brain with the sonication parameters (0.69MHz; 0.55-0.81MPa; 10ms bursts; 1Hz PRF; 60s duration), microbubble concentration (Definity, 10μl/kg), and the administered Lipo-DOX dose (5.67mg/kg) used. The resulting concentration of Lipo-DOX was reduced by 32% when it was injected 10min after the last sonication compared to cases where the agent was

Development, Characterization, and Implementation of a System for Focused Ultrasound-Mediated Blood-Brain Barrier Opening in Mice

Science.gov (United States)

Valdez, Michael Aaron

The blood-brain barrier BBB refers to the set of specialized endothelial cells that line the vasculature in the brain and effectively control movement of molecules into and out of the brain. While necessary for proper brain function, the BBB blocks 98% of drugs from entering the brain and is the most significant barrier to developing therapies for neurodegenerative diseases. Active transport allows some specific molecules to cross the BBB, but therapeutic development using this route has had limited success. A number of techniques have been used to bypass the BBB, but are often highly invasive and ineffective. Over the last two decades, a minimally invasive technique to transiently open the BBB has been under development that utilizes transcranial focused ultrasound (FUS) in combination with intravascular microbubble contrast agents. This method is often carried out in conjunction with magnetic resonance imaging (MRI) to guide and assess BBB opening and has been referred to as MRI guided FUS (MRgFUS). Because of the utility of mouse models of neurological disease and the exploratory nature of MRgFUS, systems that allow BBB opening in mice are a useful and necessary tool to develop and evaluate this method for clinical application. In this dissertation project, a custom built, cost-effective FUS system for opening the BBB in mice was developed, with the objective of using this device to deliver therapeutics to the brain. Being a custom device, it was necessary to evaluate the ultrasound output, verify in vivo safety, and anticipate the therapeutic effect. The scope of the work herein consists of the design, construction, and evaluation of system that fulfills these requirements. The final constructed system cost was an order of magnitude less than any commercially available MRgFUS system. At this low price point, the hardware could allow the implementation of the methodology in many more research areas than previously possible. Additionally, to anticipate the

Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain

International Nuclear Information System (INIS)

Arvanitis, Costas D; McDannold, Nathan; Livingstone, Margaret S

2013-01-01

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation—the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood–brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood–brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that

Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging.

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O'Reilly, Meaghan Anne; Jones, Ryan Matthew; Barrett, Edward; Schwab, Anthony; Head, Elizabeth; Hynynen, Kullervo

2017-01-01

Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits. Methods: Aged dogs naturally accumulate plaques and show associated cognitive declines. Low-frequency ultrasound was used to open the BBB unilaterally in aged beagles (9-11yrs, n=10) in accordance with institutionally approved protocols. Animals received either a single treatment or four weekly treatments. Magnetic resonance imaging(MRI) was used to guide the treatments and assess the tissue effects. The animals underwent neurological testing during treatment follow-up, and a follow-up MRI exam 1 week following the final treatment. Results: The permeability of the BBB was successfully increased in all animals (mean enhancement: 19±11% relative to untreated hemisphere). There was a single adverse event in the chronic treatment group that resolved within 24 hrs. Follow-up MRI showed the BBB to be intact with no evidence of tissue damage in all animals. Histological analysis showed comparable levels of microhemorrhage between the treated and control hemispheres in the prefrontal cortex (single/repeat treatment: 1.0±1.4 vs 0.4±0.5/5.2±1.8 vs. 4.0±2.0). No significant differences were observed in beta-amyloid load (single/repeat: p=0.31/p=0.98) although 3/5 animals in each group showed lower Aβ loads in the treated hemisphere. Conclusion: Whole-hemisphere opening of the BBB was well tolerated in the aged large animal brain. The treatment volumes and frequencies

[Focused ultrasound therapy: current status and potential applications in neurosurgery].

Science.gov (United States)

Dervishi, E; Aubry, J-F; Delattre, J-Y; Boch, A-L

2013-12-01

High Intensity Focused Ultrasound (HIFU) therapy is an innovative approach for tissue ablation, based on high intensity focused ultrasound beams. At the focus, HIFU induces a temperature elevation and the tissue can be thermally destroyed. In fact, this approach has been tested in a number of clinical studies for the treatment of several tumors, primarily the prostate, uterine, breast, bone, liver, kidney and pancreas. For transcranial brain therapy, the skull bone is a major limitation, however, new adaptive techniques of phase correction for focusing ultrasound through the skull have recently been implemented by research systems, paving the way for HIFU therapy to become an interesting alternative to brain surgery and radiotherapy. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The impact of standing wave effects on transcranial focused ultrasound disruption of the blood-brain barrier in a rat model

International Nuclear Information System (INIS)

O'Reilly, Meaghan A; Huang Yuexi; Hynynen, Kullervo

2010-01-01

Microbubble-mediated disruption of the blood-brain barrier (BBB) for targeted drug delivery using focused ultrasound shows great potential as a therapy for a wide range of brain disorders. This technique is currently at the pre-clinical stage and important work is being conducted in animal models. Measurements of standing waves in ex vivo rat skulls were conducted using an optical hydrophone and a geometry dependence was identified. Standing waves could not be eliminated through the use of swept frequencies, which have been suggested to eliminate standing waves. Definitive standing wave patterns were detected in over 25% of animals used in a single study. Standing waves were successfully eliminated using a wideband composite sharply focused transducer and a reduced duty cycle. The modified pulse parameters were used in vivo to disrupt the BBB in a rat indicating that, unlike some other bioeffects, BBB disruption is not dependent on standing wave conditions. Due to the high variability of standing waves and the inability to correctly estimate in situ pressures given standing wave conditions, attempts to minimize standing waves should be made in all future work in this field to ensure that results are clinically translatable.

In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice

International Nuclear Information System (INIS)

Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E

2010-01-01

The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity (registered) microbubbles (mean diameter range: 1.1-3.3 μm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 μm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity (registered) microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without

In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice

Energy Technology Data Exchange (ETDEWEB)

Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E, E-mail: ek2191@columbia.ed [Department of Biomedical Engineering, Columbia University, New York, NY (United States)

2010-10-21

The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity (registered) microbubbles (mean diameter range: 1.1-3.3 {mu}m, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 {mu}m in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity (registered) microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected

In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice.

Science.gov (United States)

Tung, Yao-Sheng; Vlachos, Fotios; Choi, James J; Deffieux, Thomas; Selert, Kirsten; Konofagou, Elisa E

2010-10-21

The in vivo cavitation response associated with blood-brain barrier (BBB) opening as induced by transcranial focused ultrasound (FUS) in conjunction with microbubbles was studied in order to better identify the underlying mechanism in its noninvasive application. A cylindrically focused hydrophone, confocal with the FUS transducer, was used as a passive cavitation detector (PCD) to identify the threshold of inertial cavitation (IC) in the presence of Definity® microbubbles (mean diameter range: 1.1-3.3 µm, Lantheus Medical Imaging, MA, USA). A vessel phantom was first used to determine the reliability of the PCD prior to in vivo use. A cerebral blood vessel was simulated by generating a cylindrical channel of 610 µm in diameter inside a polyacrylamide gel and by saturating its volume with microbubbles. The microbubbles were sonicated through an excised mouse skull. Second, the same PCD setup was employed for in vivo noninvasive (i.e. transdermal and transcranial) cavitation detection during BBB opening. After the intravenous administration of Definity® microbubbles, pulsed FUS was applied (frequency: 1.525 or 1.5 MHz, peak-rarefactional pressure: 0.15-0.60 MPa, duty cycle: 20%, PRF: 10 Hz, duration: 1 min with a 30 s interval) to the right hippocampus of twenty-six (n = 26) mice in vivo through intact scalp and skull. T1 and T2-weighted MR images were used to verify the BBB opening. A spectrogram was generated at each pressure in order to detect the IC onset and duration. The threshold of BBB opening was found to be at a 0.30 MPa peak-rarefactional pressure in vivo. Both the phantom and in vivo studies indicated that the IC pressure threshold had a peak-rarefactional amplitude of 0.45 MPa. This indicated that BBB opening may not require IC at or near the threshold. Histological analysis showed that BBB opening could be induced without any cellular damage at 0.30 and 0.45 MPa. In conclusion, the cavitation response could be detected without craniotomy in mice

Focused ultrasound-mediated noninvasive blood-brain barrier modulation: preclinical examination of efficacy and safety in various sonication parameters.

Science.gov (United States)

Shin, Jaewoo; Kong, Chanho; Cho, Jae Sung; Lee, Jihyeon; Koh, Chin Su; Yoon, Min-Sik; Na, Young Cheol; Chang, Won Seok; Chang, Jin Woo

2018-02-01

OBJECTIVE The application of pharmacological therapeutics in neurological disorders is limited by the ability of these agents to penetrate the blood-brain barrier (BBB). Focused ultrasound (FUS) has recently gained attention for its potential application as a method for locally opening the BBB and thereby facilitating drug delivery into the brain parenchyma. However, this method still requires optimization to maximize its safety and efficacy for clinical use. In the present study, the authors examined several sonication parameters of FUS influencing BBB opening in small animals. METHODS Changes in BBB permeability were observed during transcranial sonication using low-intensity FUS in 20 adult male Sprague-Dawley rats. The authors examined the effects of FUS sonication with different sonication parameters, varying acoustic pressure, center frequency, burst duration, microbubble (MB) type, MB dose, pulse repetition frequency (PRF), and total exposure time. The focal region of BBB opening was identified by Evans blue dye. Additionally, H & E staining was used to identify blood vessel damage. RESULTS Acoustic pressure amplitude and burst duration were closely associated with enhancement of BBB opening efficiency, but these parameters were also highly correlated with tissue damage in the sonicated region. In contrast, MB types, MB dose, total exposure time, and PRF had an influence on BBB opening without conspicuous tissue damage after FUS sonication. CONCLUSIONS The study aimed to identify these influential conditions and provide safety and efficacy values for further studies. Future work based on the current results is anticipated to facilitate the implementation of FUS sonication for drug delivery in various CNS disease states in the near future.

Neuronavigation-guided focused ultrasound-induced blood-brain barrier opening: A preliminary study in swine

Science.gov (United States)

Liu, Hao-Li; Tsai, Hong-Chieh; Lu, Yu-Jen; Wei, Kuo-Chen

2012-11-01

FUS-induced BBB opening is a promising technique for noninvasive and local delivery of drugs into the brain. Here we propose the novel use of a neuronavigation system to guide the FUS-induced BBB opening procedure, and investigate its feasibility in vivo in large animals. We developed an interface between the neuronavigator and FUS to allow guidance of the focal energy produced by the FUS transducer. The system was tested in 29 pigs by more than 40 sonication procedures and evaluated by MRI. Gd-DTPA concentration was quantitated in vivo by MRI R1 relaxometry and compared by ICP-OES assay. Brain histology after FUS exposure was investigated by HE and TUNEL staining. Neuronavigation could successfully guide the focal beam with comparable precision to neurosurgical stereotactic procedures (2.3 ± 0.9 mm). FUS pressure of 0.43 MPa resulted in consistent BBB-opening. Neuronavigation-guided BBB-opening increased Gd-DTPA deposition by up to 1.83 mM (140% increase). MR relaxometry demonstrated high correlation to ICP-OES measurements (r2 = 0.822), suggesting that Gd-DTPA deposition can be directly measured by imaging. Neuronavigation could provide sufficient precision for guiding FUS to temporally and locally open the BBB. Gd-DTPA deposition in the brain could be quantified by MR relaxometry, providing a potential tool for the in vivo quantification of therapeutic agents in CNS disease treatment.

Molecules of various pharmacologically-relevant sizes can cross the ultrasound-induced blood-brain barrier opening in vivo.

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Choi, James J; Wang, Shougang; Tung, Yao-Sheng; Morrison, Barclay; Konofagou, Elisa E

2010-01-01

Focused ultrasound (FUS) is hereby shown to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened blood-brain barrier (BBB). A complete examination on the size of the FUS-induced BBB opening, the spatial distribution of the delivered agents and its dependence on the agent's molecular weight were imaged and quantified using fluorescence microscopy. BBB opening in mice (n=13) was achieved in vivo after systemic administration of microbubbles and subsequent application of pulsed FUS (frequency: 1.525MHz, peak-rarefactional pressure in situ: 570 kPa) to the left murine hippocampus through the intact skin and skull. BBB-impermeant, fluorescent-tagged dextrans at three distinct molecular weights spanning over several orders of magnitude were systemically administered and acted as model therapeutic compounds. First, dextrans of 3 and 70 kDa were delivered trans-BBB while 2000 kDa dextran was not. Second, compared with 70 kDa dextran, a higher concentration of 3 kDa dextran was delivered through the opened BBB. Third, the 3 and 70 kDa dextrans were both diffusely distributed throughout the targeted brain region. However, high concentrations of 70 kDa dextran appeared more punctated throughout the targeted region. In conclusion, FUS combined with microbubbles opened the BBB sufficiently to allow passage of compounds of at least 70 kDa, but not greater than 2000 kDa into the brain parenchyma. This noninvasive and localized BBB opening technique could, thus, provide a unique means for the delivery of compounds of several magnitudes of kDa that include agents with shown therapeutic promise in vitro but whose in vivo translation has been hampered by their associated BBB impermeability. (E-mail: ek2191@columbia.edu).

Pulsed focused ultrasound combined with micro-bubble contrast agent can open the blood-brain barrier of gliblastoma patients and improve the efficacy of Temozolomide treatment

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Qian DONG

2017-06-01

Full Text Available Objective This research examined the effect of microbubble contrast agent plus ultrasound on the permeability of blood-brain barrier, and explored whether it affects the efficacy of chemotherapeutic drugs on cerebral glioblastoma. Methods Wistar rats were divided into three groups to find the optimal concentration of ultrasonic contrast agent. To identify the best ultrasound mode that affected the permeability of blood brain barrier, we employed transmission electron microscopy for study of brain ultrastructure. Western blotting was used to detect the tight junction protein claudin-5. Evans blue staining of brain tissues was utilized to identify the best ultrasonic contrast agent concentration and mode. Rat glioma cells (line 9L were injected into Wistar rats. After temozolomide chemotherapy, the tumor size was measured and the tumor marker GFAP in serum was detected by ELISA. Results The best contrast agent concentration which increases permeability of BBB in rats was found to be 1ml/kg and the best ultrasound mode was intermittently- triggered pulses lasting for 10min (with interval was set at 400ms. More Evans blue passed the blood-brain barrier in ultrasonic cavitation effect group than in control group (P<0.05. After temozolomide chemotherapy, more tumor marker GFAP was detected in ultrasonic cavitation effect group than in control group (P<0.05. Conclusion The permeability of BBB was increased and more temozolomide went through BBB when the rats were subjected to intermittently triggered ultrasonic pulses and were injected at contrast agent at 1ml/kg, which could help to achieve better therapeutic efficacy for glioblastoma. DOI: 10.11855/j.issn.0577-7402.2017.05.06

Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening.

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Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C; Konofagou, Elisa E

2015-12-07

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r(2)  =  0.77); (2) the permeability of the opened BBB (r(2)  =  0.82); (3) the likelihood of safe opening (P  cavitation dose was correlated with the resulting BBB permeability (r(2)  =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug

Design of patient-specific focused ultrasound arrays for non-invasive brain therapy with increased trans-skull transmission and steering range

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Hughes, Alec; Hynynen, Kullervo

2017-09-01

The use of a phased array of ultrasound transducer elements to sonicate through the skull has opened the way for new treatments and the delivery of therapeutics beyond the blood-brain barrier. The limited steering range of current clinical devices, particularly at higher frequencies, limits the regions of the brain that are considered treatable by ultrasound. A new array design is introduced that allows for high levels of beam steering and increased transmission throughout the brain. These improvements are achieved using concave transducers normal to the outer-skull surface in a patient-specific configuration to target within the skull, so that the far-field of each beam is within the brain. It is shown that by using pulsed ultrasound waves timed to arrive in-phase at the desired target, sufficient levels of acoustic energy are delivered for blood-brain barrier opening throughout the brain.

Optimization of the Ultrasound-Induced Blood-Brain Barrier Opening

OpenAIRE

Konofagou, Elisa E.

2012-01-01

Current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly non-invasive, transient, and regionally selective brain drug delivery method. The brain is particularly difficult to deliver drugs to because of the blood-brain barrier (BBB). The impermeability of the BBB is due to the tight junctions connecting adjacent endothelial cells and highly regulatory transport systems of the endothelial cell membranes. The main function of the BBB is ion and vol...

Focused ultrasound in ophthalmology

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Silverman RH

2016-09-01

Full Text Available Ronald H Silverman1,2 1Department of Ophthalmology, Columbia University Medical Center, 2F.L. Lizzi Center for Biomedical Engineering, Riverside Research, New York, NY, USA Abstract: The use of focused ultrasound to obtain diagnostically significant information about the eye goes back to the 1950s. This review describes the historical and technological development of ophthalmic ultrasound and its clinical application and impact. Ultrasound, like light, can be focused, which is crucial for formation of high-resolution, diagnostically useful images. Focused, single-element, mechanically scanned transducers are most common in ophthalmology. Specially designed transducers have been used to generate focused, high-intensity ultrasound that through thermal effects has been used to treat glaucoma (via cilio-destruction, tumors, and other pathologies. Linear and annular transducer arrays offer synthetic focusing in which precise timing of the excitation of independently addressable array elements allows formation of a converging wavefront to create a focus at one or more programmable depths. Most recently, linear array-based plane-wave ultrasound, in which the array emits an unfocused wavefront and focusing is performed solely on received data, has been demonstrated for imaging ocular anatomy and blood flow. While the history of ophthalmic ultrasound extends back over half-a-century, new and powerful technologic advances continue to be made, offering the prospect of novel diagnostic capabilities. Keywords: ophthalmic ultrasound, ultrasound biomicroscopy (UBM, high-intensity focused ultrasound (HIFU, ultrafast imaging, Doppler imaging 

Noninvasive Blood-Brain Barrier Opening in Live Mice

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Choi, James J.; Pernot, Mathieu; Small, Scott; Konofagou, Elisa E.

2006-05-01

Most therapeutic agents cannot be delivered to the brain because of brain's natural defense: the Blood-Brain Barrier (BBB). It has recently been shown that Focused Ultrasound (FUS) can produce reversible and localized BBB opening in the brain when applied in the presence of ultrasound contrast agents post-craniotomy in rabbits [1]. However, a major limitation of ultrasound in the brain is the strong phase aberration and attenuation of the skull bone, and, as a result, no study of trans-cranial ultrasound-targeted drug treatment in the brain in vivo has been reported as of yet. In this study, the feasibility of BBB opening in the hippocampus of wildtype mice using FUS through the intact skull and skin was investigated. In order to investigate the effect of the skull, simulations of ultrasound wave propagation (1.5 MHz) through the skull using μCT data, and needle hydrophone measurements through an ex-vivo skull were made. The pressure field showed minimal attenuation (18% of the pressure amplitude) and a well-focused pattern through the left and right halves of the parietal bone. In experiments in vivo, the brains of four mice were sonicated through intact skull and skin. Ultrasound sonications (burst length: 20 ms; duty cycle: 20%; acoustic pressure range: 2.0 to 2.7 MPa) was applied 5 times for 30 s per shot with a 30 s delay between shots. Prior to sonication, ultrasound contrast agents (Optison; 10 μL) were injected intravenously. Contrast material enhanced high resolution MR Imaging (9.4 Tesla) was able to distinguish opening of large vessels in the region of the hippocampus. These results demonstrate the feasibility of locally opening the BBB in the mouse hippocampus using focused ultrasound through intact skull and skin. Future investigations will deal with optimization and reproducibility of the technique as well as application on Alzheimer's-model mice.

Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

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Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

2014-01-01

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB. PMID:24462453

Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

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Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-03-01

Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary to use a larger MRI contrast agent to effectively evaluate the sonication-induced enhanced permeabilization in large/late-stage tumors when a large drug carrier such as a liposome is used.

Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening

International Nuclear Information System (INIS)

Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C; Konofagou, Elisa E

2015-01-01

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r 2   =  0.77); (2) the permeability of the opened BBB (r 2   =  0.82); (3) the likelihood of safe opening (P  <  0.05, safe opening compared to cases of damage; P  <  0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r 2   =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response

Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening

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Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C.; Konofagou, Elisa E.

2015-12-01

Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r2  =  0.77) (2) the permeability of the opened BBB (r2  =  0.82) (3) the likelihood of safe opening (P  cases of damage; P  <  0.0001, no opening compared to safe opening). The inertial cavitation dose was correlated with the resulting BBB permeability (r2  =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the

Facilitation of Drug Transport across the Blood-Brain Barrier with Ultrasound and Microbubbles.

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Meairs, Stephen

2015-08-31

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood-brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer's disease is presented.

Review Paper: A Review on Brain Stimulation Using Low Intensity Focused Ultrasound

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Ehsan Rezayat

2016-07-01

Full Text Available Brain stimulation techniques are important in both basic and clinical studies. Majority of well-known brain stimulating techniques have low spatial resolution or entail invasive processes. Low intensity focused ultrasound (LIFU seems to be a proper candidate for dealing with such deficiencies. This review recapitulates studies which explored the effects of LIFU on brain structures and its function, in both research and clinical areas. Although the mechanism of LIFU action is still unclear, its different effects from molecular level up to behavioral level can be explored in animal and human brain. It can also be coupled with brain imaging assessments in future research.

Pharmacokinetic changes induced by focused ultrasound in glioma-bearing rats as measured by dynamic contrast-enhanced MRI.

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Feng-Yi Yang

Full Text Available Focused ultrasound (FUS combined with microbubbles has been shown to be a noninvasive and targeted drug delivery technique for brain tumor treatment. The purpose of this study was to measure the kinetics of Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA in glioma-bearing rats in the presence of FUS-induced blood-brain barrier disruption (BBB-D by magnetic resonance imaging (MRI. A total of ten glioma-bearing rats (9-12 weeks, 290-340 g were used in this study. Using dynamic contrast-enhanced (DCE-MRI, the spatial permeability of FUS-induced BBB-D was evaluated and the kinetic parameters were calculated by a general kinetic model (GKM. The results demonstrate that the mean Ktrans of the sonicated tumor (0.128±0.019 at 20 min and 0.103±0.023 at 24 h after sonication, respectively was significantly higher than (2.46-fold at 20 min and 1.78-fold at 24 h that of the contralateral (non-sonicated tumor (0.052±0.019 at 20 min and 0.058±0.012 at 24 h after sonication, respectively. In addition, the transfer constant Ktrans in the sonicated tumor correlated strongly with tissue EB extravasation (R = 0.95, which suggests that DCE-MRI may reflect drug accumulation in the brain. Histological observations showed no macroscopic damage except for a few small erythrocyte extravasations. The current study demonstrates that DCE-MRI can monitor the dynamics of the FUS-induced BBB-D process and constitutes a useful tool for quantifying BBB permeability in tumors.

Treatment of Movement Disorders With Focused Ultrasound

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Paul S Fishman

2017-05-01

Full Text Available Although the use of ultrasound as a potential therapeutic modality in the brain has been under study for several decades, relatively few neuroscientists or neurologists are familiar with this technology. Stereotactic brain lesioning had been widely used as a treatment for medically refractory patients with essential tremor (ET, Parkinson disease (PD, and dystonia but has been largely replaced by deep brain stimulation (DBS surgery, with advantages both in safety and efficacy. However, DBS is associated with complications including intracerebral hemorrhage, infection, and hardware malfunction. The occurrence of these complications has spurred interest in less invasive stereotactic brain lesioning methods including magnetic resonance imaging–guided high intensity–focused ultrasound (FUS surgery. Engineering advances now allow sound waves to be targeted noninvasively through the skull to a brain target. High intensities of sonic energy can create a coagulation lesion similar to that of older radiofrequency stereotactic methods, but without opening the skull, recent Food and Drug Administration approval of unilateral thalamotomy for treatment of ET. Clinical studies of stereotactic FUS for aspects of PD are underway. Moderate intensity, pulsed FUS has also demonstrated the potential to safely open the blood-brain barrier for localized delivery of therapeutics including proteins, genes, and cell-based therapy for PD and related disorders. The goal of this review is to provide basic and clinical neuroscientists with a level of understanding to interact with medical physicists, biomedical engineers, and radiologists to accelerate the application of this powerful technology to brain disease

Targeted Gene Transfer to the Brain via the Delivery of Brain-Penetrating DNA Nanoparticles with Focused Ultrasound

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Mead, Brian P.; Mastorakos, Panagiotis; Suk, Jung Soo; Klibanov, Alexander L.; Hanes, Justin; Price, Richard J.

2016-01-01

Gene therapy holds promise for the treatment of many pathologies of the central nervous system (CNS), including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracelluar matrix (ECM), which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact “brain penetrating” nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to ECM components. Here, we tested whether this combined approach could be utilized to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate localized, robust, and sustained transgene expression in the rat brain. Systemically administered DNA-BPN delivered through the BBB with FUS led to dose-dependent transgene expression only in the FUS-treated region that was evident as early as 24 h post administration and lasted for at least 28 days. In the FUS-treated region ~42% of all cells, including neurons and astrocytes, were transfected, while less than 6% were transfected in the contralateral non-FUS treated hemisphere. Importantly, this was achieved without any sign of toxicity or astrocyte activation. We conclude that the image-guided delivery of DNA-BPN with FUS and microbubbles constitutes a safe and non-invasive strategy for targeted gene therapy to the brain. PMID:26732553

Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound.

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Stavarache, Mihaela A; Petersen, Nicholas; Jurgens, Eric M; Milstein, Elizabeth R; Rosenfeld, Zachary B; Ballon, Douglas J; Kaplitt, Michael G

2018-04-27

OBJECTIVE Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain. METHODS Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses. RESULTS Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%-75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer.

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Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood-brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future.

Characterizing Focused-Ultrasound Mediated Drug Delivery to the Heterogeneous Primate Brain In Vivo with Acoustic Monitoring

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Wu, Shih-Ying; Sanchez, Carlos Sierra; Samiotaki, Gesthimani; Buch, Amanda; Ferrera, Vincent P.; Konofagou, Elisa E.

2016-11-01

Focused ultrasound with microbubbles has been used to noninvasively and selectively deliver pharmacological agents across the blood-brain barrier (BBB) for treating brain diseases. Acoustic cavitation monitoring could serve as an on-line tool to assess and control the treatment. While it demonstrated a strong correlation in small animals, its translation to primates remains in question due to the anatomically different and highly heterogeneous brain structures with gray and white matteras well as dense vasculature. In addition, the drug delivery efficiency and the BBB opening volume have never been shown to be predictable through cavitation monitoring in primates. This study aimed at determining how cavitation activity is correlated with the amount and concentration of gadolinium delivered through the BBB and its associated delivery efficiency as well as the BBB opening volume in non-human primates. Another important finding entails the effect of heterogeneous brain anatomy and vasculature of a primate brain, i.e., presence of large cerebral vessels, gray and white matter that will also affect the cavitation activity associated with variation of BBB opening in different tissue types, which is not typically observed in small animals. Both these new findings are critical in the primate brain and provide essential information for clinical applications.

Platelet activating factor induces transient blood-brain barrier opening to facilitate edaravone penetration into the brain.

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Fang, Weirong; Zhang, Rui; Sha, Lan; Lv, Peng; Shang, Erxin; Han, Dan; Wei, Jie; Geng, Xiaohan; Yang, Qichuan; Li, Yunman

2014-03-01

The blood-brain barrier (BBB) greatly limits the efficacy of many neuroprotective drugs' delivery to the brain, so improving drug penetration through the BBB has been an important focus of research. Here we report that platelet activating factor (PAF) transiently opened BBB and facilitated neuroprotectant edaravone penetration into the brain. Intravenous infusion with PAF induced a transient BBB opening in rats, reflected by increased Evans blue leakage and mild edema formation, which ceased within 6 h. Furthermore, rat regional cerebral blood flow (rCBF) declined acutely during PAF infusion, but recovered slowly. More importantly, this transient BBB opening significantly increased the penetration of edaravone into the brain, evidenced by increased edaravone concentrations in tissue interstitial fluid collected by microdialysis and analyzed by Ultra-performance liquid chromatograph combined with a hybrid quadrupole time-of-flight mass spectrometer (UPLC-MS/MS). Similarly, incubation of rat brain microvessel endothelial cells monolayer with 1 μM PAF for 1 h significantly increased monolayer permeability to (125)I-albumin, which recovered 1 h after PAF elimination. However, PAF incubation with rat brain microvessel endothelial cells for 1 h did not cause detectable cytotoxicity, and did not regulate intercellular adhesion molecule-1, matrix-metalloproteinase-9 and P-glycoprotein expression. In conclusion, PAF could induce transient and reversible BBB opening through abrupt rCBF decline, which significantly improved edaravone penetration into the brain. Platelet activating factor (PAF) transiently induces BBB dysfunction and increases BBB permeability, which may be due to vessel contraction and a temporary decline of regional cerebral blood flow (rCBF) triggered by PAF. More importantly, the PAF induced transient BBB opening facilitates neuroprotectant edaravone penetration into brain. The results of this study may provide a new approach to improve drug delivery into

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model.

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Habib Baghirov

Full Text Available The treatment of brain diseases is hindered by the blood-brain barrier (BBB preventing most drugs from entering the brain. Focused ultrasound (FUS with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma.

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model

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Baghirov, Habib; Snipstad, Sofie; Sulheim, Einar; Berg, Sigrid; Hansen, Rune; Thorsen, Frits; Mørch, Yrr; Åslund, Andreas K. O.

2018-01-01

The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma. PMID:29338016

Blood brain barrier and brain tissue injury by Gd-DTPA in uremia-induced rabbits

International Nuclear Information System (INIS)

Choi, Sun Seob; Huh, Ki Yeong; Han, Jin Yeong; Lee, Yong Chul; Eun, Choong Gi; Yang, Yeong Il

1996-01-01

An experimental study was carried out to evaluate the morphological changes in the blood brain barrier and neighbouring brain tissue caused by Gd-DTPA in uremia-induced rabbits. Bilateral renal arteries and veins of ten rabbits were ligated. Gd-DTPA(0.2mmol/kg) was intravenously injected into seven rabbits immediately after ligation. After MRI, they were sacrificed 2 or 3 days after ligation in order to observe light and electron microscopic changes in the blood brain barrier and brain tissue. MRI findings were normal, except for enhancement of the superior and inferior sagittal sinuses on T1 weighted images in uremia-induced rabbits injected with Gd-DTPA. On light microscopic examination, these rabbits showed perivascular edema and glial fibrillary acidic protein expression: electron microscopic examination showed separation of tight junctions of endothelial cells, duplication/rarefaction of basal lamina, increased lysosomes of neurons with neuronal death, demyelination of myelin, and extravasation of red blood cells. Uremia-induced rabbits injected with Gd-DTPA showed more severe changes than those without Gd-DTPA injection. Injuries to the blood brain barrier and neighbouring brain tissue were aggravated by Gd-DTPA administration in uremia-induced rabbits. These findings appear to be associated with the neurotoxicity of Gd-DTPA

Noninvasive, localized, and transient brain drug delivery using focused ultrasound and microbubbles

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Choi, James J.

In the United States, Alzheimer's disease (AD), Parkinson's disease (PD), and brain cancer caused 72,432, 19,566 and 12,886 deaths in 2006, respectively. Whereas the number of deaths due to major disorders such as heart disease, stroke, and prostate cancer have decreased since 2006, deaths attributed to AD, PD, and brain cancer have not. Treatment options for patients with CNS disorders remain limited despite significant advances in knowledge of CNS disease pathways and development of neurologically potent agents. One of the major obstacles is that the cerebral microvasculature is lined by a specialized and highly regulated blood-brain barrier (BBB) that prevents large agents from entering the brain extracellular space. The purpose of this dissertation is to design a noninvasive, localized, and transient BBB opening system using focused ultrasound (FUS) and determine ultrasound and microbubble conditions that can effectively and safely deliver large pharmacologically-relevant-sized agents to the brain. To meet this end, an in vivo mouse brain drug delivery system using a stereotactic-based targeting method was developed. FUS was applied noninvasively through the intact skin and skull, which allowed for long-term and high-throughput studies. With this system, more than 150 mice were exposed to one of 31 distinct acoustic and microbubble conditions. The feasibility of delivering a large MRI contrast agent was first demonstrated in vivo in both wild-type and transgenic Alzheimer's disease model (APP/PS1) mice. A wide range of acoustic and microbubble conditions were then evaluated for their ability to deliver agents to a target region. Interestingly, the possible design space of parameters was found to be vast and different conditions resulted in distinct spatial distributions and doses delivered. In particular, BBB opening was shown to be dependent on the microbubble diameter, acoustic pressure, pulse repetition frequency (PRF), and pulse length (PL). Each set of

Focused ultrasound treatment of abscesses induced by methicillin resistant Staphylococcus aureus: Feasibility study in a mouse model

Energy Technology Data Exchange (ETDEWEB)

Rieck, Birgit [Thunder Bay Regional Research Institute, Thunder Bay, Ontario P7B6V4 (Canada); Bates, David; Pichardo, Samuel, E-mail: spichard@lakeheadu.ca, E-mail: lcuriel@lakeheadu.ca; Curiel, Laura, E-mail: spichard@lakeheadu.ca, E-mail: lcuriel@lakeheadu.ca [Thunder Bay Regional Research Institute, Thunder Bay, Ontario P7B6V4, Canada and Lakehead University, Thunder Bay, Ontario P7B6V4 (Canada); Zhang, Kunyan [Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta T2N 1N4 (Canada); Escott, Nicholas [Department of Pathology, Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario P7B 6V4 (Canada); Mougenot, Charles [Philips Healthcare, Ontario L6C 2S3 (Canada)

2014-06-15

Purpose: To study the therapeutic effect of focused ultrasound on abscesses induced by methicillin-resistantStaphylococcus aureus (MRSA). MRSA is a major nosocomial pathogen where immunocompromised patients are prone to develop infections that are less and less responsive to regular treatments. Because of its capability to induce a rise of temperature at a very precise location, the use of focused ultrasound represents a considerable opportunity for therapy of localized MRSA-related infections. Methods: 50μl of MRSA strain USA400 bacteria suspension at a concentration of 1.32 ± 0.5 × 10{sup 5} colony forming units (cfu)/μl was injected subcutaneously in the left flank of BALB/c mice. An abscess of 6 ± 2 mm in diameter formed after 48 h. A transducer operating at 3 MHz with a focal length of 50 mm and diameter of 32 mm was used to treat the abscess. The focal point was positioned 2 mm under the skin at the abscess center. Forty-eight hours after injection four ultrasound exposures of 9 s each were applied to each abscess under magnetic resonance imaging guidance. Each exposure was followed by a 1 min pause. These parameters were based on preliminary experiments to ensure repetitive accurate heating of the abscess. Real-time estimation of change of temperature was done using water-proton resonance frequency and a communication toolbox (matMRI) developed inhouse. Three experimental groups of animals each were tested: control, moderate temperature (MT), and high temperature (HT). MT and HT groups reached, respectively, 52.3 ± 5.1 and 63.8 ± 7.5 °C at the end of exposure. Effectiveness of the treatment was assessed by evaluating the bacteria amount of the treated abscess 1 and 4 days after treatment. Myeloperoxidase (MPO) assay evaluating the neutrophil amount was performed to assess the local neutrophil recruitment and the white blood cell count was used to evaluate the systemic inflammatory response after focused ultrasound treatment. Results: Macroscopic

Focused ultrasound treatment of abscesses induced by methicillin resistant Staphylococcus aureus: Feasibility study in a mouse model

International Nuclear Information System (INIS)

Rieck, Birgit; Bates, David; Pichardo, Samuel; Curiel, Laura; Zhang, Kunyan; Escott, Nicholas; Mougenot, Charles

2014-01-01

Purpose: To study the therapeutic effect of focused ultrasound on abscesses induced by methicillin-resistantStaphylococcus aureus (MRSA). MRSA is a major nosocomial pathogen where immunocompromised patients are prone to develop infections that are less and less responsive to regular treatments. Because of its capability to induce a rise of temperature at a very precise location, the use of focused ultrasound represents a considerable opportunity for therapy of localized MRSA-related infections. Methods: 50μl of MRSA strain USA400 bacteria suspension at a concentration of 1.32 ± 0.5 × 10 5 colony forming units (cfu)/μl was injected subcutaneously in the left flank of BALB/c mice. An abscess of 6 ± 2 mm in diameter formed after 48 h. A transducer operating at 3 MHz with a focal length of 50 mm and diameter of 32 mm was used to treat the abscess. The focal point was positioned 2 mm under the skin at the abscess center. Forty-eight hours after injection four ultrasound exposures of 9 s each were applied to each abscess under magnetic resonance imaging guidance. Each exposure was followed by a 1 min pause. These parameters were based on preliminary experiments to ensure repetitive accurate heating of the abscess. Real-time estimation of change of temperature was done using water-proton resonance frequency and a communication toolbox (matMRI) developed inhouse. Three experimental groups of animals each were tested: control, moderate temperature (MT), and high temperature (HT). MT and HT groups reached, respectively, 52.3 ± 5.1 and 63.8 ± 7.5 °C at the end of exposure. Effectiveness of the treatment was assessed by evaluating the bacteria amount of the treated abscess 1 and 4 days after treatment. Myeloperoxidase (MPO) assay evaluating the neutrophil amount was performed to assess the local neutrophil recruitment and the white blood cell count was used to evaluate the systemic inflammatory response after focused ultrasound treatment. Results: Macroscopic

Time-reversal acoustics and ultrasound-assisted convection-enhanced drug delivery to the brain.

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Olbricht, William; Sistla, Manjari; Ghandi, Gaurav; Lewis, George; Sarvazyan, Armen

2013-08-01

Time-reversal acoustics is an effective way of focusing ultrasound deep inside heterogeneous media such as biological tissues. Convection-enhanced delivery is a method of delivering drugs into the brain by infusing them directly into the brain interstitium. These two technologies are combined in a focusing system that uses a "smart needle" to simultaneously infuse fluid into the brain and provide the necessary feedback for focusing ultrasound using time-reversal acoustics. The effects of time-reversal acoustics-focused ultrasound on the spatial distribution of infused low- and high-molecular weight tracer molecules are examined in live, anesthetized rats. Results show that exposing the rat brain to focused ultrasound significantly increases the penetration of infused compounds into the brain. The addition of stabilized microbubbles enhances the effect of ultrasound exposure.

MR-guided focused ultrasound. Current and future applications

International Nuclear Information System (INIS)

Trumm, C.G.; Peller, M.; Clevert, D.A.; Stahl, R.; Reiser, M.; Napoli, A.; Matzko, M.

2013-01-01

High-intensity focused ultrasound (synonyms FUS and HIFU) under magnetic resonance imaging (MRI) guidance (synonyms MRgFUS and MR-HIFU) is a completely non-invasive technology for accurate thermal ablation of a target tissue while neighboring tissues and organs are preserved. The combination of FUS with MRI for planning, (near) real-time monitoring and outcome assessment of treatment markedly enhances the safety of the procedure. The MRgFUS procedure is clinically established in particular for the treatment of symptomatic uterine fibroids, followed by palliative ablation of painful bone metastases. Furthermore, promising results have been shown for the treatment of adenomyosis, malignant tumors of the prostate, breast and liver and for various intracranial applications, such as thermal ablation of brain tumors, functional neurosurgery and transient disruption of the blood-brain barrier. (orig.) [de

[MR-guided focused ultrasound. Current and future applications].

Science.gov (United States)

Trumm, C G; Napoli, A; Peller, M; Clevert, D-A; Stahl, R; Reiser, M; Matzko, M

2013-03-01

High-intensity focused ultrasound (synonyms FUS and HIFU) under magnetic resonance imaging (MRI) guidance (synonyms MRgFUS and MR-HIFU) is a completely non-invasive technology for accurate thermal ablation of a target tissue while neighboring tissues and organs are preserved. The combination of FUS with MRI for planning, (near) real-time monitoring and outcome assessment of treatment markedly enhances the safety of the procedure. The MRgFUS procedure is clinically established in particular for the treatment of symptomatic uterine fibroids, followed by palliative ablation of painful bone metastases. Furthermore, promising results have been shown for the treatment of adenomyosis, malignant tumors of the prostate, breast and liver and for various intracranial applications, such as thermal ablation of brain tumors, functional neurosurgery and transient disruption of the blood-brain barrier.

Magnetic resonance–guided interstitial high-intensity focused ultrasound for brain tumor ablation

Science.gov (United States)

MacDonell, Jacquelyn; Patel, Niravkumar; Rubino, Sebastian; Ghoshal, Goutam; Fischer, Gregory; Burdette, E. Clif; Hwang, Roy; Pilitsis, Julie G.

2018-01-01

Currently, treatment of brain tumors is limited to resection, chemotherapy, and radiotherapy. Thermal ablation has been recently explored. High-intensity focused ultrasound (HIFU) is being explored as an alternative. Specifically, the authors propose delivering HIFU internally to the tumor with an MRI-guided robotic assistant (MRgRA). The advantage of the authors’ interstitial device over external MRI-guided HIFU (MRgHIFU) is that it allows for conformal, precise ablation and concurrent tissue sampling. The authors describe their workflow for MRgRA HIFU delivery. PMID:29385926

Trans-abdominal ultrasound evaluation of high-intensity focused ultrasound treatment of uterine leiomyoma

International Nuclear Information System (INIS)

Miao Wei; Huang Jin; Wang Junhua; Wang Yuling

2010-01-01

Objective: To determine the value of dynamic trans-abdominal ultrasound after high-intensity focused ultrasound (HIFU) treatment of uterine leiomyomas. Methods: The trans-abdominal ultrasound images of 63 patients before and after HIFU treatment of uterine leiomyomas were compared. Results: The volume and blood flow of leiomyomas were reduced after the HIFU treatment. Conclusion: Trans-abdominal ultrasound is a valuable method for evaluating the results of HIFU treatment of uterine leiomyomas. (authors)

Transcranial focused ultrasound stimulation of human primary visual cortex

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Lee, Wonhye; Kim, Hyun-Chul; Jung, Yujin; Chung, Yong An; Song, In-Uk; Lee, Jong-Hwan; Yoo, Seung-Schik

2016-09-01

Transcranial focused ultrasound (FUS) is making progress as a new non-invasive mode of regional brain stimulation. Current evidence of FUS-mediated neurostimulation for humans has been limited to the observation of subjective sensory manifestations and electrophysiological responses, thus warranting the identification of stimulated brain regions. Here, we report FUS sonication of the primary visual cortex (V1) in humans, resulting in elicited activation not only from the sonicated brain area, but also from the network of regions involved in visual and higher-order cognitive processes (as revealed by simultaneous acquisition of blood-oxygenation-level-dependent functional magnetic resonance imaging). Accompanying phosphene perception was also reported. The electroencephalo graphic (EEG) responses showed distinct peaks associated with the stimulation. None of the participants showed any adverse effects from the sonication based on neuroimaging and neurological examinations. Retrospective numerical simulation of the acoustic profile showed the presence of individual variability in terms of the location and intensity of the acoustic focus. With exquisite spatial selectivity and capability for depth penetration, FUS may confer a unique utility in providing non-invasive stimulation of region-specific brain circuits for neuroscientific and therapeutic applications.

Laser-Induced Focused Ultrasound for Cavitation Treatment: Toward High-Precision Invisible Sonic Scalpel.

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Lee, Taehwa; Luo, Wei; Li, Qiaochu; Demirci, Hakan; Guo, L Jay

2017-10-01

Beyond the implementation of the photoacoustic effect to photoacoustic imaging and laser ultrasonics, this study demonstrates a novel application of the photoacoustic effect for high-precision cavitation treatment of tissue using laser-induced focused ultrasound. The focused ultrasound is generated by pulsed optical excitation of an efficient photoacoustic film coated on a concave surface, and its amplitude is high enough to produce controllable microcavitation within the focal region (lateral focus <100 µm). Such microcavitation is used to cut or ablate soft tissue in a highly precise manner. This work demonstrates precise cutting of tissue-mimicking gels as well as accurate ablation of gels and animal eye tissues. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function.

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McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2013-11-01

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in

Laser-nucleated acoustic cavitation in focused ultrasound.

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Gerold, Bjoern; Kotopoulis, Spiros; McDougall, Craig; McGloin, David; Postema, Michiel; Prentice, Paul

2011-04-01

Acoustic cavitation can occur in therapeutic applications of high-amplitude focused ultrasound. Studying acoustic cavitation has been challenging, because the onset of nucleation is unpredictable. We hypothesized that acoustic cavitation can be forced to occur at a specific location using a laser to nucleate a microcavity in a pre-established ultrasound field. In this paper we describe a scientific instrument that is dedicated to this outcome, combining a focused ultrasound transducer with a pulsed laser. We present high-speed photographic observations of laser-induced cavitation and laser-nucleated acoustic cavitation, at frame rates of 0.5×10(6) frames per second, from laser pulses of energy above and below the optical breakdown threshold, respectively. Acoustic recordings demonstrated inertial cavitation can be controllably introduced to the ultrasound focus. This technique will contribute to the understanding of cavitation evolution in focused ultrasound including for potential therapeutic applications. © 2011 American Institute of Physics

Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery

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Wu, Shih-Ying; Fix, Samantha M.; Arena, Christopher B.; Chen, Cherry C.; Zheng, Wenlan; Olumolade, Oluyemi O.; Papadopoulou, Virginie; Novell, Anthony; Dayton, Paul A.; Konofagou, Elisa E.

2018-02-01

Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet’s sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using ¼ dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.

Non-Thermal High-Intensity Focused Ultrasound for Breast Cancer Therapy

Science.gov (United States)

2013-07-01

Comet assay reveals DNA strand breaks induced by ultrasonic cavitation in vitro, Ultrasound in medicine & biology 1995; 21: 841-8. 3. Dalecki D...doxorubicin, focused ultrasound , HIFU, prostate cancer I. INTRODUCTION Pulsed high-intensity focused ultrasound (pFUS) is able to create acoustic cavitation ... ultrasound for breast cancer therapy PRINCIPAL INVESTIGATOR: Chang Ming (Charlie) Ma, Ph.D

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

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Payne, Allison H; Hawryluk, Gregory W; Anzai, Yoshimi; Odéen, Henrik; Ostlie, Megan A; Reichert, Ethan C; Stump, Amanda J; Minoshima, Satoshi; Cross, Donna J

2017-12-01

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 (MRgFUS) 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 MRgFUS will aid delivery of therapeutics to the injury. Here, we report our preliminary findings for the ability of MRgFUS 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 MRgFUS blood spinal cord barrier opening. Then, in normal rats, MRgFUS 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.

Optically enhanced blood-brain-barrier crossing of plasmonic-active nanoparticles in preclinical brain tumor animal models

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Yuan, Hsiangkuo; Wilson, Christy M.; Li, Shuqin; Fales, Andrew M.; Liu, Yang; Grant, Gerald; Vo-Dinh, Tuan

2014-02-01

Nanotechnology provides tremendous biomedical opportunities for cancer diagnosis, imaging, and therapy. In contrast to conventional chemotherapeutic agents where their actual target delivery cannot be easily imaged, integrating imaging and therapeutic properties into one platform facilitates the understanding of pharmacokinetic profiles, and enables monitoring of the therapeutic process in each individual. Such a concept dubbed "theranostics" potentiates translational research and improves precision medicine. One particular challenging application of theranostics involves imaging and controlled delivery of nanoplatforms across blood-brain-barrier (BBB) into brain tissues. Typically, the BBB hinders paracellular flux of drug molecules into brain parenchyma. BBB disrupting agents (e.g. mannitol, focused ultrasound), however, suffer from poor spatial confinement. It has been a challenge to design a nanoplatform not only acts as a contrast agent but also improves the BBB permeation. In this study, we demonstrated the feasibility of plasmonic gold nanoparticles as both high-resolution optical contrast agent and focalized tumor BBB permeation-inducing agent. We specifically examined the microscopic distribution of nanoparticles in tumor brain animal models. We observed that most nanoparticles accumulated at the tumor periphery or perivascular spaces. Nanoparticles were present in both endothelial cells and interstitial matrices. This study also demonstrated a novel photothermal-induced BBB permeation. Fine-tuning the irradiating energy induced gentle disruption of the vascular integrity, causing short-term extravasation of nanomaterials but without hemorrhage. We conclude that our gold nanoparticles are a powerful biocompatible contrast agent capable of inducing focal BBB permeation, and therefore envision a strong potential of plasmonic gold nanoparticle in future brain tumor imaging and therapy.

Noninvasive transcranial stimulation of rat abducens nerve by focused ultrasound.

Science.gov (United States)

Kim, Hyungmin; Taghados, Seyed Javid; Fischer, Krisztina; Maeng, Lee-So; Park, Shinsuk; Yoo, Seung-Schik

2012-09-01

Nonpharmacologic and nonsurgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36-msec tone burst duration (TBD), 1.5-kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histologic and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB), as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential for diagnostic and therapeutic applications in diseases of the peripheral nervous system. Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques.

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McDannold, Nathan; Arvanitis, Costas D; Vykhodtseva, Natalia; Livingstone, Margaret S

2012-07-15

The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method.

Albumin extravasation in bicuculline-induced blood-brain barrier dysfunction

International Nuclear Information System (INIS)

Persson, L.I.; Rosengren, L.E.; Johansson, B.B.

1980-01-01

The extravasation of endogeneous rat albumin and exogeneous 125 I-labeled human serum albumin was compared in rats subjected to bicuculline-induced blood-brain barrier dysfunction. The correlation between rocket immunoelectrophoretic assays of endogeneous rat albumin and 125 I-labeled human serum albumin, assayed by gamma scintillation counting, was good irrespective of whether 125 I-labeled albumin was studied in whole brain tissue or in brain homogenates. The ratio of brain to serum albumin was similar with the two assay methods. (author)

Blood-ocular and blood-brain barrier function in streptozocin-induced diabetes in rats

International Nuclear Information System (INIS)

Maeepea, O.; Karlsson, C.; Alm, A.

1984-01-01

Edetic acid labeled with chromium 51 was injected intravenously in normal rats and in rats with streptozocin-induced diabetes. One hour after the injection the animals were killed and the concentrations of edetic acid 51Cr in vitreous body, retina, and brain were determined. No significant difference was observed between the two groups for either tissue. In a second series, a mixture of tritiated 1-glucose and aminohippuric acid tagged with carbon 14 was injected instead of edetic acid. A substantial accumulation of aminohippuric acid 14C compared with tritiated 1-glucose was observed in the vitreous body and the brain of diabetic rats in comparison with the control group. It is concluded that untreated streptozocin-induced diabetes in rats for one to two weeks will not cause a generalized increase in the permeability of the blood-ocular or the blood-brain barriers, but organic acids may accumulate in the vitreous body as well as in the brain as a consequence of reduced outward transport through these barriers

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.

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Downs, Matthew E; Buch, Amanda; Sierra, Carlos; Karakatsani, Maria Eleni; Teichert, Tobias; Chen, Shangshang; Konofagou, Elisa E; Ferrera, Vincent P

2015-01-01

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500 kHz, 200-400 kPa, 4-5 μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4-20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of' visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4-5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.

CT and Ultrasound Guided Stereotactic High Intensity Focused Ultrasound (HIFU)

Science.gov (United States)

Wood, Bradford J.; Yanof, J.; Frenkel, V.; Viswanathan, A.; Dromi, S.; Oh, K.; Kruecker, J.; Bauer, C.; Seip, R.; Kam, A.; Li, K. C. P.

2006-05-01

animals and humans for HIFU-induced ablation and drug delivery. Integrated CT-guided focused ultrasound holds promise for tissue ablation, enhancing local drug delivery, and CT thermometry for monitoring ablation in near real-time.

Hemostatic mechanism underlying microbubble-enhanced non-focused ultrasound in the treatment of a rabbit liver trauma model

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Zhao, Da-wei; Tian, Meng; Yang, Jian-zheng; Du, Peng; Bi, Jie; Zhu, Xinjian

2016-01-01

The aim of our study was to investigate the hemostatic mechanism underlying microbubble-enhanced non-focused ultrasound treatment of liver trauma. Thirty rabbits with liver trauma were randomly divided into three groups—the microbubble-enhanced ultrasound (MEUS; further subdivided based on exposure intensity into MEUS1 [0.11 W/cm2], MEUS2 [0.55 W/cm2], and MEUS3 [1.1 W/cm2]), ultrasound without microbubbles (US), and microbubbles without ultrasound (MB) groups. The pre- and post-treatment bleeding weight and visual bleeding scores were evaluated. The serum liver enzyme concentrations as well as the blood perfusion level represented by mean peak contrast intensity (PI) ratio in the treatment area were analyzed. The hemostatic mechanism was evaluated by histological and transmission electron microscopic examination of liver tissue samples. The MEUS subgroups 1–3 (grade 0–1, grade 0–2, and grade 1–2, respectively) exhibited significantly lower post-treatment visual bleeding scores than the US and MB groups (both, grade 3–4; all, P hepatic cells became edematous and compressed the hepatic sinus and associated blood vessels. However, the serum liver enzyme levels were not significantly altered. Microbubble-enhanced non-focused ultrasound does not significantly affect blood perfusion and liver function and can be used to induce rapid hemostasis in case of liver trauma. PMID:27633577

Ultrasound-mediated drug delivery to the brain: principles, progress and prospects

NARCIS (Netherlands)

Dasgupta, I.; Liu, M.; Ojha, T.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

2016-01-01

The blood–brain barrier (BBB) limits drug delivery to the central nervous system. When combined with microbubbles, ultrasound can transiently permeate blood vessels in the brain. This approach, which can be referred to as sonoporation or sonopermeabilization, holds significant promise for shuttling

MR-guided focused ultrasound: a potentially disruptive technology.

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Bradley, William G

2009-07-01

A disruptive technology is a technological innovation that overturns the existing dominant technologies in a market. Magnetic resonance (MR)-guided focused ultrasound (MRgFUS) is a noninvasive procedure based on the combination of real-time MR anatomic guidance, MR thermometry, and high-intensity focused ultrasound. Several hundred transducer elements become convergent at a point under MR guidance, leading to heating and coagulation necrosis. Outside the focal point, there is no significant heating. There is no need to break the skin for procedures in the body or to perform a craniotomy for procedures in the brain. This lack of invasiveness is what makes MRgFUS so disruptive compared with surgery. At present, MRgFUS has been used for the ablation of uterine fibroids, breast tumors, painful bony metastases, and liver tumors. In the brain, it has been used for the ablation of glioblastomas and for functional neurosurgery. Phantom and animal studies suggest future applications for prostate cancer and acute stroke treatment.

Quantitative analysis of normal fetal brain volume and flow by three-dimensional power Doppler ultrasound

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Ju-Chun Hsu

2013-09-01

Conclusion: 3D ultrasound can be used to assess the fetal brain volume and blood flow development quantitatively. Our study indicates that the fetal brain vascularization and blood flow correlates significantly with the advancement of GA. This information may serve as a reference point for further studies of the fetal brain volume and blood flow in abnormal conditions.

High-intensity focused ultrasound sonothrombolysis: the use of perfluorocarbon droplets to achieve clot lysis at reduced acoustic power.

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Pajek, Daniel; Burgess, Alison; Huang, Yuexi; Hynynen, Kullervo

2014-09-01

The purpose of this study was to evaluate use of intravascular perfluorocarbon droplets to reduce the sonication power required to achieve clot lysis with high-intensity focused ultrasound. High-intensity focused ultrasound with droplets was initially applied to blood clots in an in vitro flow apparatus, and inertial cavitation thresholds were determined. An embolic model for ischemic stroke was used to illustrate the feasibility of this technique in vivo. Recanalization with intravascular droplets was achieved in vivo at 24 ± 5% of the sonication power without droplets. Recanalization occurred in 71% of rabbits that received 1-ms pulsed sonications during continuous intravascular droplet infusion (p = 0.041 vs controls). Preliminary experiments indicated that damage was confined to the ultrasonic focus, suggesting that tolerable treatments would be possible with a more tightly focused hemispheric array that allows the whole focus to be placed inside of the main arteries in the human brain. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

MRI-Guided Focused Ultrasound as a New Method of Drug Delivery

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M. Thanou

2013-01-01

Full Text Available Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS- mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery.

Inferring common cognitive mechanisms from brain blood-flow lateralisation data obtained with functional transcranial Doppler ultrasound.

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Georg eMeyer

2014-06-01

Full Text Available Current neuroimaging techniques with high spatial resolution constrain participant motion so that many natural tasks cannot be carried out. The aim of this paper is to show how a time-locked correlation-analysis of cerebral blood flow velocity (CBFV lateralisation data, obtained with functional TransCranial Doppler (fTCD ultrasound, can be used to infer cerebral activation patterns across tasks. In a first experiment we demonstrate that the proposed analysis method results in data that are comparable with the standard Lateralisation Index (LI for within-task comparisons of CBFV patterns, recorded during cued word generation (CWG at two difficulty levels.In the main experiment we demonstrate that the proposed analysis method shows correlated blood-flow patterns for two different cognitive tasks that are known to draw on common brain areas, CWG and Music Synthesis. We show that CBFV patterns for Music and CWG are correlated only for participants with prior musical training.CBFV patterns for tasks that draw on distinct brain areas, the Tower of London and CWG, are not correlated.The proposed methodology extends conventional fTCD analysis by including temporal information in the analysis of cerebral blood-flow patterns to provide a robust, non-invasive method to infer whether common brain areas are used in different cognitive tasks. It complements conventional high resolution imaging techniques.

Technical characterization of an ultrasound source for noninvasive thermoablation by high-intensity focused ultrasound.

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Köhrmann, K U; Michel, M S; Steidler, A; Marlinghaus, E; Kraut, O; Alken, P

2002-08-01

To develop a generator for high-intensity focused ultrasound (HIFU, a method of delivering ultrasonic energy with resultant heat and tissue destruction to a tight focus at a selected depth within the body), designed for extracorporeal coupling to allow various parenchymal organs to be treated. The ultrasound generated by a cylindrical piezo-ceramic element is focused at a depth of 10 cm using a parabolic reflector with a diameter of 10 cm. A diagnostic B-mode ultrasonographic transducer is integrated into the source to allow the focus to be located in the target area. The field distribution of the sound pressure was measured in degassed water using a needle hydrophone. An ultrasound-force balance was used to determine the acoustic power. These measurements allowed the spatially averaged sound intensity to be calculated. The morphology and extent of tissue necrosis induced by HIFU was examined on an ex-vivo kidney model. The two-dimensional field distribution resulted in an approximately ellipsoidal focus of 32 x 4 mm (- 6 dB). The spatially maximum averaged sound intensity was 8591 W/cm2 at an electrical power of 400 W. The lesion caused to the ex-vivo kidney at this maximum generator power with a pulse duration of 2 s was a clearly delineated ellipsoidal coagulation necrosis up to 8.8 x 2.3 mm (length x width) and with central liquefied necrosis of 7.9 x 1.9 mm. This newly developed ultrasound generator with a focal length of 10 cm can induce clear necrosis in parenchymal tissue. Because of its specific configuration and the available power range of the ultrasound generator, there is potential for therapeutic noninvasive ablation of tissue deep within a patient's body.

Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

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Huppert, Jula; Closhen, Dorothea; Croxford, Andrew; White, Robin; Kulig, Paulina; Pietrowski, Eweline; Bechmann, Ingo; Becher, Burkhard; Luhmann, Heiko J; Waisman, Ari; Kuhlmann, Christoph R W

2010-04-01

Recently T-helper 17 (Th17) cells were demonstrated to disrupt the blood-brain barrier (BBB) by the action of IL-17A. The aim of the present study was to examine the mechanisms that underlie IL-17A-induced BBB breakdown. Barrier integrity was analyzed in the murine brain endothelial cell line bEnd.3 by measuring the electrical resistance values using electrical call impedance sensing technology. Furthermore, in-cell Western blots, fluorescence imaging, and monocyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. IL-17A induced NADPH oxidase- or xanthine oxidase-dependent reactive oxygen species (ROS) production. The resulting oxidative stress activated the endothelial contractile machinery, which was accompanied by a down-regulation of the tight junction molecule occludin. Blocking either ROS formation or myosin light chain phosphorylation or applying IL-17A-neutralizing antibodies prevented IL-17A-induced BBB disruption. Treatment of mice with EAE using ML-7, an inhibitor of the myosin light chain kinase, resulted in less BBB disruption at the spinal cord and less infiltration of lymphocytes via the BBB and subsequently reduced the clinical characteristics of EAE. These observations indicate that IL-17A accounts for a crucial step in the development of EAE by impairing the integrity of the BBB, involving augmented production of ROS.-Huppert, J., Closhen, D., Croxford, A., White, R., Kulig, P., Pietrowski, E., Bechmann, I., Becher, B., Luhmann, H. J., Waisman, A., Kuhlmann, C. R. W. Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

[Blood-brain barrier part III: therapeutic approaches to cross the blood-brain barrier and target the brain].

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Weiss, N; Miller, F; Cazaubon, S; Couraud, P-O

2010-03-01

Over the last few years, the blood-brain barrier has come to be considered as the main limitation for the treatment of neurological diseases caused by inflammatory, tumor or neurodegenerative disorders. In the blood-brain barrier, the close intercellular contact between cerebral endothelial cells due to tight junctions prevents the passive diffusion of hydrophilic components from the bloodstream into the brain. Several specific transport systems (via transporters expressed on cerebral endothelial cells) are implicated in the delivery of nutriments, ions and vitamins to the brain; other transporters expressed on cerebral endothelial cells extrude endogenous substances or xenobiotics, which have crossed the cerebral endothelium, out of the brain and into the bloodstream. Recently, several strategies have been proposed to target the brain, (i) by by-passing the blood-brain barrier by central drug administration, (ii) by increasing permeability of the blood-brain barrier, (iii) by modulating the expression and/or the activity of efflux transporters, (iv) by using the physiological receptor-dependent blood-brain barrier transport, and (v) by creating new viral or chemical vectors to cross the blood-brain barrier. This review focuses on the illustration of these different approaches. Copyright (c) 2009 Elsevier Masson SAS. All rights reserved.

A tissue phantom for visualization and measurement of ultrasound-induced cavitation damage.

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Maxwell, Adam D; Wang, Tzu-Yin; Yuan, Lingqian; Duryea, Alexander P; Xu, Zhen; Cain, Charles A

2010-12-01

Many ultrasound studies involve the use of tissue-mimicking materials to research phenomena in vitro and predict in vivo bioeffects. We have developed a tissue phantom to study cavitation-induced damage to tissue. The phantom consists of red blood cells suspended in an agarose hydrogel. The acoustic and mechanical properties of the gel phantom were found to be similar to soft tissue properties. The phantom's response to cavitation was evaluated using histotripsy. Histotripsy causes breakdown of tissue structures by the generation of controlled cavitation using short, focused, high-intensity ultrasound pulses. Histotripsy lesions were generated in the phantom and kidney tissue using a spherically focused 1-MHz transducer generating 15 cycle pulses, at a pulse repetition frequency of 100 Hz with a peak negative pressure of 14 MPa. Damage appeared clearly as increased optical transparency of the phantom due to rupture of individual red blood cells. The morphology of lesions generated in the phantom was very similar to that generated in kidney tissue at both macroscopic and cellular levels. Additionally, lesions in the phantom could be visualized as hypoechoic regions on a B-mode ultrasound image, similar to histotripsy lesions in tissue. High-speed imaging of the optically transparent phantom was used to show that damage coincides with the presence of cavitation. These results indicate that the phantom can accurately mimic the response of soft tissue to cavitation and provide a useful tool for studying damage induced by acoustic cavitation. Copyright © 2010 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

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Septelia I. Wanandi

2011-02-01

Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

BBB disruption with unfocused ultrasound alone-A paradigm shift

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Kyle, Al

2012-10-01

One paradigm for ultrasound-enabled blood brain barrier disruption uses image guided focused ultrasound and preformed microbubble agents to enable drug delivery to the brain. We propose an alternative approach: unguided, unfocused ultrasound with no adjunctive agent. Compared with the focused approach, the proposed method affects a larger region of the brain, and is aimed at treatment of regional neurological disease including glioblastoma multiforme (GBM). Avoidance of image guidance and focusing reduces cost for equipment and staff training. Avoidance of adjunctive agents also lowers cost and is enabled by a longer exposure time. Since 2004, our group has worked with two animal models, three investigators in four laboratories to safely deliver five compounds, increasing the concentration of large molecule markers in brain tissue two fold or more. Safety and effectiveness data for four studies have been presented at the Ultrasound Industry Association meetings in 2007 and 2010. This paper describes new safety and effectiveness results for a fifth study. We present evidence of delivery of large molecules - including Avastin-to the brains of a large animal model correlated with acoustic pressure, and summarize the advantages and disadvantages of this novel approach.

Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates.

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Fabrice Marquet

Full Text Available The delivery of drugs to specific neural targets faces two fundamental problems: (1 most drugs do not cross the blood-brain barrier, and (2 those that do, spread to the entire brain. To date, there exists only one non-invasive methodology with the potential to solve these problems: selective blood-brain barrier (BBB opening using micro-bubble enhanced focused ultrasound. We have recently developed a single-element 500-kHz spherical transducer ultrasound setup for targeted BBB opening in the non-human primate that does not require simultaneous MRI monitoring. So far, however, the targeting accuracy that can be achieved with this system has not been quantified systematically. In this paper, the accuracy of this system was tested by targeting caudate nucleus and putamen of the basal ganglia in two macaque monkeys. The average lateral targeting error of the system was ∼2.5 mm while the axial targeting error, i.e., along the ultrasound path, was ∼1.5 mm. We have also developed a real-time treatment monitoring technique based on cavitation spectral analysis. This technique also allowed for delineation of a safe and reliable acoustic parameter window for BBB opening. In summary, the targeting accuracy of the system was deemed to be suitable to reliably open the BBB in specific sub-structures of the basal ganglia even in the absence of MRI-based verification of opening volume and position. This establishes the method and the system as a potentially highly useful tool for brain drug delivery.

Focused ultrasound subthalamotomy in patients with asymmetric Parkinson's disease: a pilot study.

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Martínez-Fernández, Raul; Rodríguez-Rojas, Rafael; Del Álamo, Marta; Hernández-Fernández, Frida; Pineda-Pardo, Jose A; Dileone, Michele; Alonso-Frech, Fernando; Foffani, Guglielmo; Obeso, Ignacio; Gasca-Salas, Carmen; de Luis-Pastor, Esther; Vela, Lydia; Obeso, José A

2018-01-01

Ablative neurosurgery has been used to treat Parkinson's disease for many decades. MRI-guided focused ultrasound allows focal lesions to be made in deep brain structures without skull incision. We investigated the safety and preliminary efficacy of unilateral subthalamotomy by focused ultrasound in Parkinson's disease. This prospective, open-label pilot study was done at CINAC (Centro Integral de Neurociencias), University Hospital HM Puerta del Sur in Madrid, Spain. Eligible participants had Parkinson's disease with markedly asymmetric parkinsonism. Patients with severe dyskinesia, history of stereotactic surgery or brain haemorrhage, a diagnosis of an unstable cardiac or psychiatric disease, or a skull density ratio of 0·3 or less were excluded. Enrolled patients underwent focused ultrasound unilateral subthalamotomy. The subthalamic nucleus was targeted by means of brain images acquired with a 3-Tesla MRI apparatus. Several sonications above the definitive ablation temperature of 55°C were delivered and adjusted according to clinical response. The primary outcomes were safety and a change in the motor status of the treated hemibody as assessed with part III of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) in both off-medication and on-medication states at 6 months. Adverse events were monitored up to 48 h after treatment and at scheduled clinic visits at 1, 3, and 6 months after treatment. The study is registered with ClinicalTrials.gov, number NCT02912871. Between April 26 and June 14, 2016, ten patients with markedly asymmetric parkinsonism that was poorly controlled pharmacologically were enrolled for focused ultrasound unilateral subthalamotomy. By 6 months follow-up, 38 incidents of adverse events had been recorded, none of which were serious or severe. Seven adverse events were present at 6 months. Three of these adverse events were directly related to subthalamotomy: off-medication dyskinesia in the treated arm

A computational study for investigating acoustic streaming and tissue heating during high intensity focused ultrasound through blood vessel with an obstacle

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Parvin, Salma; Sultana, Aysha

2017-06-01

The influence of High Intensity Focused Ultrasound (HIFU) on the obstacle through blood vessel is studied numerically. A three-dimensional acoustics-thermal-fluid coupling model is employed to compute the temperature field around the obstacle through blood vessel. The model construction is based on the linear Westervelt and conjugate heat transfer equations for the obstacle through blood vessel. The system of equations is solved using Finite Element Method (FEM). We found from this three-dimensional numerical study that the rate of heat transfer is increasing from the obstacle and both the convective cooling and acoustic streaming can considerably change the temperature field.

Regional brain glucose metabolism and blood flow in streptozocin-induced diabetic rats

International Nuclear Information System (INIS)

Jakobsen, J.; Nedergaard, M.; Aarslew-Jensen, M.; Diemer, N.H.

1990-01-01

Brain regional glucose metabolism and regional blood flow were measured from autoradiographs by the uptake of [ 3 H]-2-deoxy-D-glucose and [ 14 C]iodoantipyrine in streptozocin-induced diabetic (STZ-D) rats. After 2 days of diabetes, glucose metabolism in the neocortex, basal ganglia, and white matter increased by 34, 37, and 8%, respectively, whereas blood flow was unchanged. After 4 mo, glucose metabolism in the same three regions was decreased by 32, 43, and 60%. This reduction was paralleled by a statistically nonsignificant reduction in blood flow in neocortex and basal ganglia. It is suggested that the decrease of brain glucose metabolism in STZ-D reflects increased ketone body oxidation and reduction of electrochemical work

Nano carriers for drug transport across the blood-brain barrier.

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Li, Xinming; Tsibouklis, John; Weng, Tingting; Zhang, Buning; Yin, Guoqiang; Feng, Guangzhu; Cui, Yingde; Savina, Irina N; Mikhalovska, Lyuba I; Sandeman, Susan R; Howel, Carol A; Mikhalovsky, Sergey V

2017-01-01

Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully

Potential mechanism in sonodynamic therapy and focused ultrasound induced apoptosis in sarcoma 180 cells in vitro.

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Tang, Wei; Liu, Quanhong; Wang, Xiaobing; Wang, Pan; Zhang, Jing; Cao, Bing

2009-12-01

Sonodynamic therapy employs a combination of ultrasound and a sonosensitizer to enhance the cytotoxic effect of ultrasound and promote apoptosis. However, the mechanism underlying the synergistic effect of ultrasound and hematoporphyrin is still unclear. In this study, we investigated mechanism of the induction of apoptosis by sonodynamic therapy in Sarcoma 180 cells. The cell suspension was treated by 1.75-MHz focused continuous ultrasound at an acoustic power (I(SATA)) of 1.4+/-0.07 W/cm(2) for 3 min in the absence or presence of 20 microg/ml hematoporphyrin. The proportion of apoptotic cells was determined by flow cytometry. We then analyzed the reactive oxygen species generation and localization by confocal microscopy. Western blotting and reverse transcriptase-polymerase chain reaction were used to analyze the expression of caspase-8, caspase-9, poly(ADP)-ribose polymerase, and nuclear factor-kappaB. The findings of our study indicate that ultrasound treatment induced the activation of nuclear factor-kappaB as an early stress response. When cells were pretreated with hematoporphyrin, the initial response to the therapy was the formation of (1)O(2) in the mitochondria. Our results primarily demonstrate that the mechanisms of induction of apoptosis by ultrasound and hematoporphyrin-sonodynamic therapies are very different. Our findings can provide a basis for explaining the synergistic effect of ultrasound and hematoporphyrin.

Therapeutic Ultrasound Enhancement of Drug Delivery to Soft Tissues

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Lewis, George; Wang, Peng; Lewis, George; Olbricht, William

2009-04-01

Effects of exposure to 1.58 MHz focused ultrasound on transport of Evans Blue Dye (EBD) in soft tissues are investigated when an external pressure gradient is applied to induce convective flow through the tissue. The magnitude of the external pressure gradient is chosen to simulate conditions in brain parenchyma during convection-enhanced drug delivery (CED) to the brain. EBD uptake and transport are measured in equine brain, avian muscle and agarose brain-mimicking phantoms. Results show that ultrasound enhances EBD uptake and transport, and the greatest enhancement occurs when the external pressure gradient is applied. The results suggest that exposure of the brain parenchyma to ultrasound could enhance penetration of material infused into the brain during CED therapy.

On a computational study for investigating acoustic streaming and heating during focused ultrasound ablation of liver tumor

International Nuclear Information System (INIS)

Solovchuk, Maxim A.; Sheu, Tony W.H.; Thiriet, Marc; Lin, Win-Li

2013-01-01

The influences of blood vessels and focused location on temperature distribution during high-intensity focused ultrasound (HIFU) ablation of liver tumors are studied numerically. A three-dimensional acoustics-thermal-fluid coupling model is employed to compute the temperature field in the hepatic cancerous region. The model construction is based on the linear Westervelt and bioheat equations as well as the nonlinear Navier–Stokes equations for the liver parenchyma and blood vessels. The effect of acoustic streaming is also taken into account in the present HIFU simulation study. Different blood vessel diameters and focal point locations were investigated. We found from this three-dimensional numerical study that in large blood vessels both the convective cooling and acoustic streaming can considerably change the temperature field and the thermal lesion near blood vessels. If the blood vessel is located within the beam width, both acoustic streaming and blood flow cooling effects should be addressed. The temperature rise on the blood vessel wall generated by a 1.0 MHz focused ultrasound transducer with the focal intensity 327 W/cm 2 was 54% lower when acoustic streaming effect was taken into account. Subject to the applied acoustic power the streaming velocity in a 3 mm blood vessel is 12 cm/s. Thirty percent of the necrosed volume can be reduced, when taking into account the acoustic streaming effect. -- Highlights: • 3D three-field coupling physical model for focused ultrasound tumor ablation is presented. • Acoustic streaming and blood flow cooling effects on ultrasound heating are investigated. • Acoustic streaming can considerably affect the temperature distribution. • The lesion can be reduced by 30% due to the acoustic streaming effect. • Temperature on the blood vessel wall is reduced by 54% due to the acoustic streaming effect

Restraint stress-induced morphological changes at the blood-brain barrier in adult rats

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Petra eSántha

2016-01-01

Full Text Available Stress is well known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognised in the development of neurodegenerative disorders, such as Alzheimer’s disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3 and 21 days were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occludin and glucose transporter-1 and astroglia (GFAP. Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, one-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5 and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes

Computational exploration of wave propagation and heating from transcranial focused ultrasound for neuromodulation

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Mueller, Jerel K.; Ai, Leo; Bansal, Priya; Legon, Wynn

2016-10-01

Objective. While ultrasound is largely established for use in diagnostic imaging, its application for neuromodulation is relatively new and crudely understood. The objective of the present study was to investigate the effects of tissue properties and geometry on the wave propagation and heating in the context of transcranial neuromodulation. Approach. A computational model of transcranial-focused ultrasound was constructed and validated against empirical data. The models were then incrementally extended to investigate a number of issues related to the use of ultrasound for neuromodulation, including the effect on wave propagation of variations in geometry of skull and gyral anatomy as well as the effect of multiple tissue and media layers, including scalp, skull, CSF, and gray/white matter. In addition, a sensitivity analysis was run to characterize the influence of acoustic properties of intracranial tissues. Finally, the heating associated with ultrasonic stimulation waveforms designed for neuromodulation was modeled. Main results. The wave propagation of a transcranially focused ultrasound beam is significantly influenced by the cranial domain. The half maximum acoustic beam intensity profiles are insensitive overall to small changes in material properties, though the inclusion of sulci in models results in greater peak intensity values compared to a model without sulci (1%-30% greater). Finally, heating using currently employed stimulation parameters in humans is highest in bone (0.16 °C) and is negligible in brain (4.27 × 10-3 °C) for a 0.5 s exposure. Significance. Ultrasound for noninvasive neuromodulation holds great promise and appeal for its non-invasiveness, high spatial resolution and deep focal lengths. Here we show gross brain anatomy and biological material properties to have limited effect on ultrasound wave propagation and to result in safe heating levels in the skull and brain.

Externally Delivered Focused Ultrasound for Renal Denervation.

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Neuzil, Petr; Ormiston, John; Brinton, Todd J; Starek, Zdenek; Esler, Murray; Dawood, Omar; Anderson, Thomas L; Gertner, Michael; Whitbourne, Rob; Schmieder, Roland E

2016-06-27

The aim of this study was to assess clinical safety and efficacy outcomes of renal denervation executed by an externally delivered, completely noninvasive focused therapeutic ultrasound device. Renal denervation has emerged as a potential treatment approach for resistant hypertension. Sixty-nine subjects received renal denervation with externally delivered focused ultrasound via the Kona Medical Surround Sound System. This approach was investigated across 3 consecutive studies to optimize targeting, tracking, and dosing. In the third study, treatments were performed in a completely noninvasive way using duplex ultrasound image guidance to target the therapy. Short- and long-term safety and efficacy were evaluated through use of clinical assessments, magnetic resonance imaging scans prior to and 3 and 24 weeks after renal denervation, and, in cases in which a targeting catheter was used to facilitate targeting, fluoroscopic angiography with contrast. All patients tolerated renal denervation using externally delivered focused ultrasound. Office blood pressure (BP) decreased by 24.6 ± 27.6/9.0 ± 15.0 mm Hg (from baseline BP of 180.0 ± 18.5/97.7 ± 13.7 mm Hg) in 69 patients after 6 months and 23.8 ± 24.1/10.3 ± 13.1 mm Hg in 64 patients with complete 1-year follow-up. The response rate (BP decrease >10 mm Hg) was 75% after 6 months and 77% after 1 year. The most common adverse event was post-treatment back pain, which was reported in 32 of 69 patients and resolved within 72 h in most cases. No intervention-related adverse events involving motor or sensory deficits were reported. Renal function was not altered, and vascular safety was established by magnetic resonance imaging (all patients), fluoroscopic angiography (n = 48), and optical coherence tomography (n = 5). Using externally delivered focused ultrasound and noninvasive duplex ultrasound, image-guided targeting was associated with substantial BP reduction without any major safety signals. Further

Impact of cavitation on lesion formation induced by high intensity focused ultrasound

International Nuclear Information System (INIS)

Fan Pengfei; Jie Yu; Yang Xin; Tu Juan; Guo Xiasheng; Zhang Dong; Huang Pintong

2017-01-01

High intensity focused ultrasound (HIFU) has shown a great promise in noninvasive cancer therapy. The impact of acoustic cavitation on the lesion formation induced by HIFU is investigated both experimentally and theoretically in transparent protein-containing gel and ex vivo liver tissue samples. A numerical model that accounts for nonlinear acoustic propagation and heat transfer is used to simulate the lesion formation induced by the thermal effect. The results showed that lesions could be induced in the samples exposed to HIFU with various acoustic pressures and pulse lengths. The measured areas of lesions formed in the lateral direction were comparable to the simulated results, while much larger discrepancy was observed between the experimental and simulated data for the areas of longitudinal lesion cross-section. Meanwhile, a series of stripe-wiped-off B-mode pictures were obtained by using a special imaging processing method so that HIFU-induced cavitation bubble activities could be monitored in real-time and quantitatively analyzed as the functions of acoustic pressure and pulse length. The results indicated that, unlike the lateral area of HIFU-induced lesion that was less affected by the cavitation activity, the longitudinal cross-section of HIFU-induced lesion was significantly influenced by the generation of cavitation bubbles through the temperature elevation resulting from HIFU exposures. Therefore, considering the clinical safety in HIFU treatments, more attention should be paid on the lesion formation in the longitudinal direction to avoid uncontrollable variation resulting from HIFU-induced cavitation activity. (paper)

Prediction of thermal coagulation from the instantaneous strain distribution induced by high-intensity focused ultrasound

Science.gov (United States)

Iwasaki, Ryosuke; Takagi, Ryo; Tomiyasu, Kentaro; Yoshizawa, Shin; Umemura, Shin-ichiro

2017-07-01

The targeting of the ultrasound beam and the prediction of thermal lesion formation in advance are the requirements for monitoring high-intensity focused ultrasound (HIFU) treatment with safety and reproducibility. To visualize the HIFU focal zone, we utilized an acoustic radiation force impulse (ARFI) imaging-based method. After inducing displacements inside tissues with pulsed HIFU called the push pulse exposure, the distribution of axial displacements started expanding and moving. To acquire RF data immediately after and during the HIFU push pulse exposure to improve prediction accuracy, we attempted methods using extrapolation estimation and applying HIFU noise elimination. The distributions going back in the time domain from the end of push pulse exposure are in good agreement with tissue coagulation at the center. The results suggest that the proposed focal zone visualization employing pulsed HIFU entailing the high-speed ARFI imaging method is useful for the prediction of thermal coagulation in advance.

An electro-optic spatial light modulator for thermoelastic generation of programmably focused ultrasound

Science.gov (United States)

1984-12-01

The concept proposed is an electro-optic technique that would make it possible to spatially modulate a high power pulsed laser beam to thermoelastically induce focused ultrasound in a test material. Being a purely electro-optic device, the modulator, and therefore the depth at which the acoustic focus occurs, can be programmed electronically at electronic speeds. If successful, it would become possible to scan ultrasound continuously in three dimensions within the component or structure under test.

Reversible and irreversible vascular bioeffects induced by ultrasound and microbubbles in chorioallantoic membrane model

Science.gov (United States)

Tarapacki, Christine; Kuebler, Wolfgang M.; Tabuchi, Arata; Karshafian, Raffi

2017-03-01

Background: The application of ultrasound and microbubbles at therapeutic conditions has been shown to improve delivery of molecules, cause vasoconstriction, modulate blood flow and induce a vascular shut down in in vivo cancerous tissues. The underlying mechanism has been associated with the interaction of ultrasonically-induced microbubble oscillation and cavitation with the blood vessel wall. In this study, the effect of ultrasound and microbubbles on blood flow and vascular architecture was studied using a fertilized chicken egg CAM (chorioallantoic membrane) model. Methods: CAM at day 12 of incubation (Hamburger-Hamilton stage 38-40) were exposed to ultrasound at varying acoustic pressures (160, 240 and 320 kPa peak negative pressure) in the presence of Definity microbubbles and 70 kDa FITC dextran fluorescent molecules. A volume of 50 µL Definity microbubbles were injected into a large anterior vein of the CAM prior to ultrasound exposure. The ultrasound treatment sequence consisted of 5 s exposure at 500 kHz frequency, 8 cycles and 1 kHz pulse repetition frequency with 5 s off for a total exposure of 2 minutes. Fluorescent videos and images of the CAM vasculature were acquired using intravital microscopy prior, during and following the ultrasound exposure. Perfusion was quantified by measuring the length of capillaries in a region of interest using Adobe Illustrator. Results and Discussion: The vascular bioeffects induced by USMB increased with acoustic peak negative pressure. At 160 kPa, no visible differences were observed compared to the control. At 240 kPa, a transient decrease in perfusion with subsequent recovery within 15 minutes was observed, whereas at 320 kPa, the fluorescent images showed an irreversible vascular damage. The study indicates that a potential mechanism for the transient decrease in perfusion may be related to blood coagulation. The results suggest that ultrasound and microbubbles can induce reversible and irreversible vascular

Synthetic focusing in ultrasound modulated tomography

KAUST Repository

Kuchment, Peter; Kunyansky, Leonid

2010-01-01

Several hybrid tomographic methods utilizing ultrasound modulation have been introduced lately. Success of these methods hinges on the feasibility of focusing ultrasound waves at an arbitrary point of interest. Such focusing, however, is difficult to achieve in practice. We thus propose a way to avoid the use of focused waves through what we call synthetic focusing, i.e. by reconstructing the would-be response to the focused modulation from the measurements corresponding to realistic unfocused waves. Examples of reconstructions from simulated data are provided. This non-technical paper describes only the general concept, while technical details will appear elsewhere. © 2010 American Institute of Mathematical Sciences.

Synthetic focusing in ultrasound modulated tomography

KAUST Repository

Kuchment, Peter

2010-09-01

Several hybrid tomographic methods utilizing ultrasound modulation have been introduced lately. Success of these methods hinges on the feasibility of focusing ultrasound waves at an arbitrary point of interest. Such focusing, however, is difficult to achieve in practice. We thus propose a way to avoid the use of focused waves through what we call synthetic focusing, i.e. by reconstructing the would-be response to the focused modulation from the measurements corresponding to realistic unfocused waves. Examples of reconstructions from simulated data are provided. This non-technical paper describes only the general concept, while technical details will appear elsewhere. © 2010 American Institute of Mathematical Sciences.

Focused ultrasound as a tool to input sensory information to humans (Review)

Science.gov (United States)

Gavrilov, L. R.; Tsirulnikov, E. M.

2012-01-01

This review is devoted to the analysis of studies and implementations related to the use of focused ultrasound for functional effects on neuroreceptor structures. Special attention was paid to the stimulation of neuroreceptor structures in order to input sensory information to humans. This branch of medical and physiological acoustics appeared in Russia in the early 1970s and was being efficiently developed up to the late 1980s. Then, due to lack of financial support, only individual researchers remained at this field and, as a result, we have no full- fledged theoretical research and practical implementations in this area yet. Many promising possibilities of using functional effects of focused ultrasound in medicine and physiology have remained unimplemented for a long time. However, new interesting ideas and approaches have appeared in recent years. Very recently, very questionable projects have been reported related to the use of ultrasound for targeted functional effects on the human brain performed in some laboratories. In this review, the stages of the development of scientific research devoted to the functional effects of focused ultrasound are described. By activating the neuroreceptor structures of the skin by means pulses of focused ultrasound, one can cause all the sensations perceived by human beings through the skin in everyday life, such as tactile sensations, thermal (heat and cold), tickling, itching, and various types of pain. Stimulation of the ear labyrinth of humans with normal hearing using amplitude-modulated ultrasound causes auditory sensations corresponding to an audio modulating signal (pure tones, music, speech, etc.). Activation of neuroreceptor structures by means of focused ultrasound is used for the diagnosis of various neurological and skin diseases, as well as hearing disorders. It has been shown that the activation is related to the mechanical action of ultrasound, for example, by the radiation force, as well as to the direct

Relationship between thrombolysis efficiency induced by pulsed focused ultrasound and cavitation bubble size

International Nuclear Information System (INIS)

Xu, S; Liu, X; Wang, S; Wan, M

2015-01-01

In this study, the relationship between the efficiency of pulsed focused ultrasound (FUS)-induced thrombolysis and the size distribution of cavitation bubbles has been studied. Firstly, the thrombolysis efficiency, evaluated by degree of mechanical fragmentation was investigated with varying duty cycle. Secondly, the size distribution of cavitation bubbles after the 1st, 10 3 th and 10 5 th pulse during experiments for various duty cycles was studied. It was revealed that the thrombolysis efficiency was highest when the cavitation bubble size distribution was centred around linear resonance radius of the emission frequency of the FUS transducer. Therefore, in cavitation enhanced therapeutic applications, the essential of using a pulsed FUS may be controlling the size distribution of cavitation nuclei within an active size range so as to increase the treatment efficiency. (paper)

Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia

DEFF Research Database (Denmark)

Andrade, Chittaranjan; Bolwig, Tom G

2014-01-01

Preclinical and clinical evidence show that electroconvulsive therapy (ECT)-induced intraictal surge in blood pressure may result in a small, transient breach in the blood-brain barrier, leading to mild cerebral edema and a possible leach of noxious substances from blood into brain tissues...... convincing evidence of benefits. It is concluded that there is insufficient support, at present, for the hypothesis that the hypertensive surge during ECT and the resultant blood-brain barrier breach contribute meaningfully to ECT-induced cognitive deficits. Future research should address the subset....... These changes may impair neuronal functioning and contribute to the mechanisms underlying ECT-induced cognitive deficits. Some but not all clinical data on the subject suggest that blood pressure changes during ECT correlate with indices of cognitive impairment. In animal models, pharmacological manipulations...

Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models.

Directory of Open Access Journals (Sweden)

Scott B Raymond

Full Text Available Alzheimer's disease is a neurodegenerative disorder typified by the accumulation of a small protein, beta-amyloid, which aggregates and is the primary component of amyloid plaques. Many new therapeutic and diagnostic agents for reducing amyloid plaques have limited efficacy in vivo because of poor transport across the blood-brain barrier. Here we demonstrate that low-intensity focused ultrasound with a microbubble contrast agent may be used to transiently disrupt the blood-brain barrier, allowing non-invasive, localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid plaques. We administered intravenous Trypan blue, an amyloid staining red fluorophore, and anti-amyloid antibodies, concurrently with focused ultrasound therapy in plaque-bearing, transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance permitted selective treatment and monitoring of plaque-heavy anatomical regions, such as the hippocampus. Treated brain regions exhibited 16.5+/-5.4-fold increase in Trypan blue fluorescence and 2.7+/-1.2-fold increase in anti-amyloid antibodies that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced in two different transgenic strains (APPswe:PSEN1dE9, PDAPP, across a large age range (9-26 months, with and without MR guidance, and with little or no tissue damage. Ultrasound-mediated, transient blood-brain barrier disruption allows the delivery of both therapeutic and molecular imaging agents in Alzheimer's mouse models, which should aid pre-clinical drug screening and imaging probe development. Furthermore, this technique may be used to deliver a wide variety of small and large molecules to the brain for imaging and therapy in other neurodegenerative diseases.

MRI-controlled interstitial ultrasound brain therapy: An initial in-vivo study

Science.gov (United States)

N'Djin, W. Apoutou; Burtnyk, Mathieu; Lipsman, Nir; Bronskill, Michael; Schwartz, Michael; Kucharczyk, Walter; Chopra, Rajiv

2012-11-01

The recent emergence at the clinical level of minimally-invasive focal therapy such as laser-induced thermal therapy (LITT) has demonstrated promise in the management of brain metastasis [1], although control over the spatial pattern of heating is limited. Delivery of HIFU from minimally-invasive applicators enables high spatial control of the heat deposition in biological tissues, large treatment volumes and high treatment rate in well chosen conditions [2,3]. In this study, the feasibility of MRI-guided interstitial ultrasound therapy in brain was studies in-vivo in a porcine model. A prototype system originally developed for transurethral ultrasound therapy [4,5,6] was used in this study. Two burr holes of 12 mm in diameter were created in the animal's skull to allow the insertion of the therapeutic ultrasound applicator (probe) into the brain at two locations (right and left frontal lobe). A 4-element linear ultrasound transducer (f = 8 MHz) was mounted at the tip of a 25-cm linear probe (6 mm in diameter). The target boundary was traced to cover in 2D a surface compatible with the treatment of a 2 cm brain tumor. Acoustic power of each element and rotation rate of the device were adjusted in real-time based on MR-thermometry feedback control to optimize heat deposition at the target boundary [2,4,5]. Two MRT-controlled ultrasound brain treatments per animal have been performed using a maximal surface acoustic power of 10W.cm-2. In all cases, it was possible to increase accurately the temperature of the brain tissues in the targeted region over the 55°C threshold necessary for the creation of irreversible thermal lesion. Tissue changes were visible on T1w contrast-enhanced images immediately after treatment. These changes were also evident on T2w FSE images taken 2 hours after the 1st treatment and correlated well with the temperature image. On average, the targeted volume was 4.7 ± 2.3 cm3 and the 55°C treated volume was 6.7 ± 4.4 cm3. The volumetric

Optimizing MR imaging-guided navigation for focused ultrasound interventions in the brain

Science.gov (United States)

Werner, B.; Martin, E.; Bauer, R.; O'Gorman, R.

2017-03-01

MR imaging during transcranial MR imaging-guided Focused Ultrasound surgery (tcMRIgFUS) is challenging due to the complex ultrasound transducer setup and the water bolus used for acoustic coupling. Achievable image quality in the tcMRIgFUS setup using the standard body coil is significantly inferior to current neuroradiologic standards. As a consequence, MR image guidance for precise navigation in functional neurosurgical interventions using tcMRIgFUS is basically limited to the acquisition of MR coordinates of salient landmarks such as the anterior and posterior commissure for aligning a stereotactic atlas. Here, we show how improved MR image quality provided by a custom built MR coil and optimized MR imaging sequences can support imaging-guided navigation for functional tcMRIgFUS neurosurgery by visualizing anatomical landmarks that can be integrated into the navigation process to accommodate for patient specific anatomy.

Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects.

Science.gov (United States)

Krasovitski, Boris; Frenkel, Victor; Shoham, Shy; Kimmel, Eitan

2011-02-22

The purpose of this study was to develop a unified model capable of explaining the mechanisms of interaction of ultrasound and biological tissue at both the diagnostic nonthermal, noncavitational (cavitational (>100 mW · cm(-2)) spatial peak temporal average intensity levels. The cellular-level model (termed "bilayer sonophore") combines the physics of bubble dynamics with cell biomechanics to determine the dynamic behavior of the two lipid bilayer membrane leaflets. The existence of such a unified model could potentially pave the way to a number of controlled ultrasound-assisted applications, including CNS modulation and blood-brain barrier permeabilization. The model predicts that the cellular membrane is intrinsically capable of absorbing mechanical energy from the ultrasound field and transforming it into expansions and contractions of the intramembrane space. It further predicts that the maximum area strain is proportional to the acoustic pressure amplitude and inversely proportional to the square root of the frequency (ε A,max ∝ P(A)(0.8f - 0.5) and is intensified by proximity to free surfaces, the presence of nearby microbubbles in free medium, and the flexibility of the surrounding tissue. Model predictions were experimentally supported using transmission electron microscopy (TEM) of multilayered live-cell goldfish epidermis exposed in vivo to continuous wave (CW) ultrasound at cavitational (1 MHz) and noncavitational (3 MHz) conditions. Our results support the hypothesis that ultrasonically induced bilayer membrane motion, which does not require preexistence of air voids in the tissue, may account for a variety of bioeffects and could elucidate mechanisms of ultrasound interaction with biological tissue that are currently not fully understood.

In vitro models of the blood-brain barrier

DEFF Research Database (Denmark)

Helms, Hans Christian Cederberg; Abbott, N Joan; Burek, Malgorzata

2016-01-01

The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic...... components of plasma and xenobiotics. This "blood-brain barrier" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug...... transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established blood-brain barrier characteristics. As an ideal cell culture...

Multiple high-intensity focused ultrasound probes for kidney-tissue ablation.

Science.gov (United States)

Häcker, Axel; Chauhan, Sunita; Peters, Kristina; Hildenbrand, Ralf; Marlinghaus, Ernst; Alken, Peter; Michel, Maurice Stephan

2005-10-01

To investigate kidney-tissue ablation by high-intensity focused ultrasound (HIFU) using multiple and single probes. Ultrasound beams (1.75 MHz) produced by a piezoceramic element (focal distance 80 mm) were focused at the center of renal parenchyma. One of the three probes (mounted on a jig) could also be used for comparison with a single probe at comparable power ratings. Lesion dimensions were examined in perfused and unperfused ex vivo porcine kidneys at different power levels (40, 60, and 80 W) and treatment times (4, 6, and 8 seconds). At identical power levels, the lesions induced by multiple probes were larger than those induced by a single probe. Lesion size increased with increasing pulse duration and generator power. The sizes and shapes of the lesions were predictably repeatable in all samples. Lesions in perfused kidneys were smaller than those in unperfused kidneys. Ex vivo, kidney-tissue ablation by means of multiple HIFU probes offers significant advantages over single HIFU probes in respect of lesion size and formation. These advantages need to be confirmed by tests in vivo at higher energy levels.

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer

OpenAIRE

Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood–brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers non...

Cerebral autoregulation control of blood flow in the brain

CERN Document Server

Payne, Stephen

2016-01-01

This Brief provides a comprehensive introduction to the control of blood flow in the brain. Beginning with the basic physiology of autoregulation, the author goes on to discuss measurement techniques, mathematical models, methods of analysis, and relevant clinical conditions, all within this single volume. The author draws together this disparate field, and lays the groundwork for future research directions. The text gives an up-to-date review of the state of the art in cerebral autoregulation, which is particularly relevant as cerebral autoregulation moves from the laboratory to the bedside. Cerebral Autoregulation will be useful to researchers in the physical sciences such as mathematical biology, medical physics, and biomedical engineering whose work is concerned with the brain. Researchers in the medical sciences and clinicians dealing with the brain and blood flow, as well as industry professionals developing techniques such as ultrasound, MRI, and CT will also find this Brief of interest.

Molecular targets in radiation-induced blood-brain barrier disruption

International Nuclear Information System (INIS)

Nordal, Robert A.; Wong, C. Shun

2005-01-01

Disruption of the blood-brain barrier (BBB) is a key feature of radiation injury to the central nervous system. Studies suggest that endothelial cell apoptosis, gene expression changes, and alteration of the microenvironment are important in initiation and progression of injury. Although substantial effort has been directed at understanding the impact of radiation on endothelial cells and oligodendrocytes, growing evidence suggests that other cell types, including astrocytes, are important in responses that include induced gene expression and microenvironmental changes. Endothelial apoptosis is important in early BBB disruption. Hypoxia and oxidative stress in the later period that precedes tissue damage might lead to astrocytic responses that impact cell survival and cell interactions. Cell death, gene expression changes, and a toxic microenvironment can be viewed as interacting elements in a model of radiation-induced disruption of the BBB. These processes implicate particular genes and proteins as targets in potential strategies for neuroprotection

[The effect of focused ultrasound on the physicochemical properties of Sarcoma 180 cell membrane].

Science.gov (United States)

Li, Tao; Hao, Qiao; Wang, Xiaobing; Liu, Quanhong

2009-10-01

This study was amied to detect the changes in the cell membrane of Sarcoma 180 (S180) cells induced by focused ultrasound and to probe the underlying mechanism. The viability of tumor cells was examined at various intensities and different treatment times by ultrasound at the frequency of 2.2MHz. Flow cytometry and fluorescence microscopy were used to detect the loading of fluorescein isothiocyanate dextran (FD500) which signifies the change of membrane permeability. The results showed that after the cells were treated by ultrasound, especially when irradiated for 60s, the number of fluorescent cell, which represented the transient change of membrane permeabilization with cell survival, increased significantly. Then the damage of cell membrane was evaluated by the measurement of lactate dehydrogenase (LDH) release which became more severe as the radiation time was increasing. The generation of lipid peroxidation was estimated using the Thibabituric Acid (TBA) method after irradiation. The results reveal that the instant cell damage effects induced by ultrasound may be related to the improved membrane lipid peroxidation levels post-treatment. The physicochemical properties of S180 cell membrane were changed by focused ultrasound. The findings also imply an exposure time-dependent pattern and suggest that the lipid peroxidation produced by acoustic cavitation may play important roles in these actions.

Open-source, small-animal magnetic resonance-guided focused ultrasound system.

Science.gov (United States)

Poorman, Megan E; Chaplin, Vandiver L; Wilkens, Ken; Dockery, Mary D; Giorgio, Todd D; Grissom, William A; Caskey, Charles F

2016-01-01

MR-guided focused ultrasound or high-intensity focused ultrasound (MRgFUS/MRgHIFU) is a non-invasive therapeutic modality with many potential applications in areas such as cancer therapy, drug delivery, and blood-brain barrier opening. However, the large financial costs involved in developing preclinical MRgFUS systems represent a barrier to research groups interested in developing new techniques and applications. We aim to mitigate these challenges by detailing a validated, open-source preclinical MRgFUS system capable of delivering thermal and mechanical FUS in a quantifiable and repeatable manner under real-time MRI guidance. A hardware and software package was developed that includes closed-loop feedback controlled thermometry code and CAD drawings for a therapy table designed for a preclinical MRI scanner. For thermal treatments, the modular software uses a proportional integral derivative controller to maintain a precise focal temperature rise in the target given input from MR phase images obtained concurrently. The software computes the required voltage output and transmits it to a FUS transducer that is embedded in the delivery table within the magnet bore. The delivery table holds the FUS transducer, a small animal and its monitoring equipment, and a transmit/receive RF coil. The transducer is coupled to the animal via a water bath and is translatable in two dimensions from outside the magnet. The transducer is driven by a waveform generator and amplifier controlled by real-time software in Matlab. MR acoustic radiation force imaging is also implemented to confirm the position of the focus for mechanical and thermal treatments. The system was validated in tissue-mimicking phantoms and in vivo during murine tumor hyperthermia treatments. Sonications were successfully controlled over a range of temperatures and thermal doses for up to 20 min with minimal temperature overshoot. MR thermometry was validated with an optical temperature probe, and focus

TU-B-210-00: MR-Guided Focused Ultrasound Therapy in Oncology

Energy Technology Data Exchange (ETDEWEB)

NONE

2015-06-15

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advanced techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips.

Non-invasive high-intensity focused ultrasound for UV-induced hyperpigmentation in Fitzpatrick skin types III and IV: a prospective, randomized, controlled, evaluator-blinded trial.

Science.gov (United States)

Vachiramon, Vasanop; Jurairattanaporn, Natthachat; Harnchoowong, Sarawin; Chayavichitsilp, Pamela

2018-02-01

Skin hyperpigmentation is a frequently encountered problem, particularly in darker skin types. Unfortunately, standard treatments for this condition have shown disappointing results. High-intensity focused ultrasound (HIFU) is commonly indicated for skin laxity, but recently was used to treat UV-induced hyperpigmentation in animal models. This study is aimed to evaluate the efficacy and safety of high-intensity focused ultrasound for UVB-induced hyperpigmentation in human subjects. A randomized, evaluator-blinded pilot study was conducted on 20 subjects. Each subject was induced three hyperpigmentary spots by local broadband UVB. After 2 weeks, each spot was randomly allocated to control, low-energy, and high-energy HIFU. Subjects were instructed to follow up weekly for a duration of 1 month. Lightness index measurements, mean improvement scores, subjects' satisfaction, pain scores, and side effects were evaluated. All 20 subjects completed the study. Fourteen subjects had Fitzpatrick (FPT) skin type III and six subjects had FPT skin type IV. Twelve subjects showed greater improvement at control sites while eight subjects showed greater improvement at HIFU-treated sites. In FPT skin type III, HIFU appeared to be inferior to control in both lightness index and mean improvement scores, but in FPT skin type IV, HIFU had greater lightness index improvement and higher improvement scores than control. Side effects were more frequent in high-energy-treated areas. Focused ultrasound may be offered in some patients with hyperpigmentary conditions. More research is needed to determine proper energy settings for optimal outcome.

Elucidation of the role of biological factors and device design in cerebral NIRS using an in vivo hematoma model based on high-intensity focused ultrasound

Science.gov (United States)

Wang, Jianting; Huang, Stanley; Myers, Matthew; Chen, Yu; Welle, Cristin; Pfefer, Joshua

2016-03-01

Near-Infrared Spectroscopy (NIRS) is an emerging medical countermeasure for rapid, field detection of hematomas caused by traumatic brain injury (TBI). Bench and animal tests to determine NIRS sensitivity and specificity are needed. However, current animal models involving non-invasively induced, localized neural damage are limited. We investigated an in vivo murine hematoma model in which cerebral hemorrhage was induced noninvasively by high-intensity focused ultrasound (HIFU) with calibrated positioning and parameters. To characterize the morphology of induced hematomas, we used skull-intact histological evaluation. A multi-wavelength fiber-optic NIRS system with three source-detector separation distances was used to detect hematoma A 1.1 MHz transducer produced consistent small-to-medium hematoma localized to a single hemisphere, along with bruising of the scalp, with a low mortality rate. A 220 kHz transducer produced larger, more diffuse hematomas, with higher variability in size and a correspondingly higher mortality rate. No skin bruising or blood accumulation between the skin and skull was observed following injury application with the 220 kHz transducer. Histological analysis showed higher sensitivity for larger hematomas (>4x4 mm2). NIRS optical density change after HIFU was able to detect all hematomas, with sensitivity dependent on wavelength and separation distance. While improvements in methods for validating cerebral blood distribution are needed, the HIFU hematoma model provided useful insights that will inform development of biologically relevant, performance test methods for cerebral NIRS systems.

Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.

Directory of Open Access Journals (Sweden)

Andreas Üllen

Full Text Available Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl formed via the myeloperoxidase (MPO-H2O2-Cl(- system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl(- system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl(- system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuroinflammatory conditions.

Evaluation of ultrasound techniques for brain injury detection

Science.gov (United States)

Mobley, Joel; Kasili, Paul M.; Norton, Stephen J.; Vo-Dinh, Tuan

1998-05-01

In this work, we examine the physics underlying wave propagation in the head to evaluate various ultrasonic transducers for use in a brian injury detection device. The results of measurements of the attenuation coefficient and phase velocity for ultrasonic propagation in samples of brain tissue and skull bone from sheep are presented. The material properties are then used to investigate the propagation of ultrasonic pressure fields in the head. The ultrasound fields for three different transducers are calculated for propagation in a simulated brain/skull model. The model is constructed using speed-of-sound and mass density values of the two tissue types. The impact of the attenuation on the ultrasound fields is then examined. Finally, the relevant points drawn from these discussions are summarized. We hope to minimize the confounding effects of the skull by using sub-MHz ultrasound while maintaining the necessary temporal and spatial resolution to successfully detect injury in the brain.

In vivo photoacoustics and high frequency ultrasound imaging of mechanical high intensity focused ultrasound (HIFU) ablation.

Science.gov (United States)

Daoudi, Khalid; Hoogenboom, Martijn; den Brok, Martijn; Eikelenboom, Dylan; Adema, Gosse J; Fütterer, Jürgen J; de Korte, Chris L

2017-04-01

The thermal effect of high intensity focused ultrasound (HIFU) has been clinically exploited over a decade, while the mechanical HIFU is still largely confined to laboratory investigations. This is in part due to the lack of adequate imaging techniques to better understand the in-vivo pathological and immunological effects caused by the mechanical treatment. In this work, we explore the use of high frequency ultrasound (US) and photoacoustics (PA) as a potential tool to evaluate the effect of mechanical ablation in-vivo , e.g. boiling histotripsy. Two mice bearing a neuroblastoma tumor in the right leg were ablated using an MRI-HIFU system conceived for small animals and monitored using MRI thermometry. High frequency US and PA imaging were performed before and after the HIFU treatment. Afterwards, the tumor was resected for further assessment and evaluation of the ablated region using histopathology. High frequency US imaging revealed the presence of liquefied regions in the treated area together with fragmentized tissue which appeared with different reflecting proprieties compared to the surrounding tissue. Photoacoustic imaging on the other hand revealed the presence of deoxygenated blood within the tumor after the ablation due to the destruction of blood vessel network while color Doppler imaging confirmed the blood vessel network destruction within the tumor. The treated area and the presence of red blood cells detected by photoacoustics were further confirmed by the histopathology. This feasibility study demonstrates the potential of high frequency US and PA approach for assessing in-vivo the effect of mechanical HIFU tumor ablation.

A simulation model for predicting the temperature during the application of MR-guided focused ultrasound for stroke treatment using pulsed ultrasound

Science.gov (United States)

Hadjisavvas, V.; Damianou, C.

2011-09-01

In this paper a simulation model for predicting the temperature during the application of MR-guided focused ultrasound for stroke treatment using pulsed ultrasound is presented. A single element spherically focused transducer of 5 cm diameter, focusing at 10 cm and operating at either 0.5 MHz or 1 MHz was considered. The power field was estimated using the KZK model. The temperature was estimated using the bioheat equation. The goal was to extract the acoustic parameters (power, pulse duration, duty factor and pulse repetition frequency) that maintain a temperature increase of less than 1 °C during the application of a pulse ultrasound protocol. It was found that the temperature change increases linearly with duty factor. The higher the power, the lower the duty factor needed to keep the temperature change to the safe limit of 1 °C. The higher the frequency the lower the duty factor needed to keep the temperature change to the safe limit of 1 °C. Finally, the deeper the target, the higher the duty factor needed to keep the temperature change to the safe limit of 1 °C. The simulation model was tested in brain tissue during the application of pulse ultrasound and the measured temperature was in close agreement with the simulated temperature. This simulation model is considered to be very useful tool for providing acoustic parameters (frequency, power, duty factor, pulse repetition frequency) during the application of pulsed ultrasound at various depths in tissue so that a safe temperature is maintained during the treatment. This model could be tested soon during stroke clinical trials.

Transport and metabolism at blood-brain interfaces and in neural cells: relevance to bilirubin-induced encephalopathy

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Silvia eGazzin

2012-05-01

Full Text Available Bilirubin, the end-product of heme catabolism, circulates in non pathological plasma mostly as a protein-bound species. When bilirubin concentration builds up, the free fraction of the molecule increases. Unbound bilirubin then diffuses across blood-brain interfaces into the brain, where it accumulates and exerts neurotoxic effects. In this classical view of bilirubin neurotoxicity, blood-brain interfaces act merely as structural barriers impeding the penetration of the pigment-bound carrier protein, and neural cells are considered as passive targets of its toxicity. Yet, the role of blood-brain interfaces in the occurrence of bilirubin encephalopathy appears more complex than being simple barriers to the diffusion of bilirubin, and neural cells such as astrocytes and neurons can play an active role in controlling the balance between the neuroprotective and neurotoxic effects of bilirubin. This article reviews the emerging in vivo and in vitro data showing that transport and metabolic detoxification mechanisms at the blood-brain and blood-CSF barriers may modulate bilirubin flux across both cellular interfaces, and that these protective functions can be affected in chronic hyperbilirubinemia. Then the in vivo and in vitro arguments in favor of the physiological antioxidant function of intracerebral bilirubin are presented, as well as with the potential role of transporters such as ABCC-1 and metabolizing enzymes such as cytochromes P-450 in setting the cerebral cell- and structure-specific toxicity of bilirubin following hyperbilirubinemia. The relevance of these data to the pathophysiology of bilirubin-induced neurological diseases is discussed.

The protective influence of the locus ceruleus on the blood-brain barrier

International Nuclear Information System (INIS)

Harik, S.I.; McGunigal, T. Jr.

1984-01-01

The functions of the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus remain ambiguous. Although most evidence indicates that such innervation does not have a major role in the control of cerebral blood flow, there are increasing indications that it modulates transport and permeability functions of the blood-brain barrier. In this study we investigated the effect of unilateral chemical lesioning of the locus ceruleus on the leakage of radioiodinated human serum albumin across the blood-brain barrier. Experiments were performed in awake and restrained rats under steady-state conditions and during drug-induced systemic arterial hypertension, and in anesthetized and paralyzed rats during bicuculline-induced seizures. Both hypertension and seizures are known to be associated with increased leakage of macromolecules across the blood-brain barrier. Albumin leakage into norepinephrine-depleted forebrain structures ipsilateral to the locus ceruleus lesion was compared with that of the contralateral side. There were no side-to-side differences in blood-brain barrier permeability to albumin under steady-state conditions, the stress of restraint, or angiotensin-induced hypertension, or after isoproterenol administration. Norepinephrine-induced hypertension and seizures, however, caused significant increases in albumin leakage into forebrain structures ipsilateral to the lesion. These results suggest that noradrenergic innervation of cerebral microvessels from the locus ceruleus helps preserve the integrity of the blood-brain barrier during pathophysiological states associated with hypertension and increased circulating catecholamines

The bubble-dependent mechanism of FUS-induced blood-brain barrier opening in mice and in monkeys in vivo

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Tung, Yao-Sheng; Marquet, Fabrice; Vlachos, Fotios; Feshitan, Jameel A.; Borden, Mark A.; Konofagou, Elisa E.

2012-10-01

The blood-brain barrier (BBB) prevents most neurological drugs from traversing from the cerebral microvasculature into the brain parenchyma. Previous studies have shown that the presence of bubbles in an acoustic field temporarily opens the BBB. The BBB opening pressure threshold was previously identified to lie between 0.30 and 0.46 MPa in the case of the smaller bubbles and between 0.15 and 0.30 MPa in the larger bubble case. However, the physical effects responsible for BBB opening remain unknown. In addition, the noninvasive in vivo cavitation detection with mono-dispersed microbubbles has not been studied as of yet. The purpose of this study is to unveil the physical mechanism of the FUS-induced BBB opening with monodispersed microbubbles. Lipid-shelled microbubbles with three different diameters (1-2, 4-5 and 6-8 μm) were manufactured in-house and size-isolated using differential centrifugation. Sixty-seven (n=67) mice were each injected intravenously with bubbles of either 1-2, 4-5 or 6-8 μm in diameter and the concentration of 107 numbers/mL. The right hippocampus of each mouse was then sonicated using focused ultrasound (1.5 MHz frequency; 100 cycles (67 μs) pulse length; 10 Hz pulse repetition frequency; 1 minute sonication duration) while the left hippocampus served as the control. A 10-MHz transducer was used as a passive cavitation detector (PCD) to determine the threshold of inertial cavitation (IC). Each mouse was sonicated at a specific acoustic peak-rarefactional pressure at 0.15, 0.30, 0.45 or 0.60 MPa in order to identify the threshold of BBB opening and IC. T1-weighted MRI was used to verify the BBB opening and spectrograms were generated in order to detect the IC onset and duration. Our results suggest that the BBB opens as a result of nonlinear (harmonic) bubble oscillation when the bubble diameter is similar to the capillary diameter and with inertial cavitation when it is not. The bubble may thus have to be in contact with the capillary

Ultrasound effects on brain-targeting mannosylated liposomes: in vitro and blood–brain barrier transport investigations

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Zidan AS

2015-07-01

Full Text Available Ahmed S Zidan,1,2 Hibah Aldawsari1 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt Abstract: Delivering drugs to intracerebral regions can be accomplished by improving the capacity of transport through blood–brain barrier. Using sertraline as model drug for brain targeting, the current study aimed at modifying its liposomal vesicles with mannopyranoside. Box-Behnken design was employed to statistically optimize the ultrasound parameters, namely ultrasound amplitude, time, and temperature, for maximum mannosylation capacity, sertraline entrapment, and surface charge while minimizing vesicular size. Moreover, in vitro blood–brain barrier transport model was established to assess the transendothelial capacity of the optimized mannosylated vesicles. Results showed a dependence of vesicular size, mannosylation capacity, and sertraline entrapment on cavitation and bubble implosion events that were related to ultrasound power amplitude, temperature. However, short ultrasound duration was required to achieve >90% mannosylation with nanosized vesicles (<200 nm of narrow size distribution. Optimized ultrasound parameters of 65°C, 27%, and 59 seconds for ultrasound temperature, amplitude, and time were elucidated to produce 81.1%, 46.6 nm, and 77.6% sertraline entrapment, vesicular size, and mannosylation capacity, respectively. Moreover, the transendothelial ability was significantly increased by 2.5-fold by mannosylation through binding with glucose transporters. Hence, mannosylated liposomes processed by ultrasound could be a promising approach for manufacturing and scale-up of brain-targeting liposomes. Keywords: CNS delivery, sizing, lipid based formulations, quality by design, sertraline hydrochloride

Brain magnetic resonance imaging with contrast dependent on blood oxygenation

International Nuclear Information System (INIS)

Ogawa, S.; Lee, T.M.; Kay, A.R.; Tank, D.W.

1990-01-01

Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high yields, the authors demonstrate in vivo images of brain microvasculature with image contrast reflecting the blood oxygen level. This blood oxygenation level-dependent (BOLD) contrast follows blood oxygen changes induced by anesthetics, by insulin-induced hypoglycemia, and by inhaled gas mixtures that alter metabolic demand or blood flow. The results suggest that BOLD contrast can be used to provide in vivo real-time maps of blood oxygenation in the brain under normal physiological conditions. BOLD contrast adds an additional feature to magnetic resonance imaging and complement other techniques that are attempting to provide position emission tomography-like measurements related to regional neural activity

Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules.

Science.gov (United States)

He, Bo; Jabouille, Arnaud; Steri, Veronica; Johansson-Percival, Anna; Michael, Iacovos P; Kotamraju, Venkata Ramana; Junckerstorff, Reimar; Nowak, Anna K; Hamzah, Juliana; Lee, Gabriel; Bergers, Gabriele; Ganss, Ruth

2018-06-01

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Stimulation of the sphenopalatine ganglion induces reperfusion and blood-brain barrier protection in the photothrombotic stroke model.

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Haviv Levi

Full Text Available The treatment of stroke remains a challenge. Animal studies showing that electrical stimulation of the sphenopalatine ganglion (SPG exerts beneficial effects in the treatment of stroke have led to the initiation of clinical studies. However, the detailed effects of SPG stimulation on the injured brain are not known.The effect of acute SPG stimulation was studied by direct vascular imaging, fluorescent angiography and laser Doppler flowmetry in the sensory motor cortex of the anaesthetized rat. Focal cerebral ischemia was induced by the rose bengal (RB photothrombosis method. In chronic experiments, SPG stimulation, starting 15 min or 24 h after photothrombosis, was given for 3 h per day on four consecutive days. Structural damage was assessed using histological and immunohistochemical methods. Cortical functions were assessed by quantitative analysis of epidural electro-corticographic (ECoG activity continuously recorded in behaving animals.Stimulation induced intensity- and duration-dependent vasodilation and increased cerebral blood flow in both healthy and photothrombotic brains. In SPG-stimulated rats both blood brain-barrier (BBB opening, pathological brain activity and lesion volume were attenuated compared to untreated stroke animals, with no apparent difference in the glial response surrounding the necrotic lesion.SPG-stimulation in rats induces vasodilation of cortical arterioles, partial reperfusion of the ischemic lesion, and normalization of brain functions with reduced BBB dysfunction and stroke volume. These findings support the potential therapeutic effect of SPG stimulation in focal cerebral ischemia even when applied 24 h after stroke onset and thus may extend the therapeutic window of currently administered stroke medications.

MRI monitoring of focused ultrasound sonications near metallic hardware.

Science.gov (United States)

Weber, Hans; Ghanouni, Pejman; Pascal-Tenorio, Aurea; Pauly, Kim Butts; Hargreaves, Brian A

2018-07-01

To explore the temperature-induced signal change in two-dimensional multi-spectral imaging (2DMSI) for fast thermometry near metallic hardware to enable MR-guided focused ultrasound surgery (MRgFUS) in patients with implanted metallic hardware. 2DMSI was optimized for temperature sensitivity and applied to monitor focus ultrasound surgery (FUS) sonications near metallic hardware in phantoms and ex vivo porcine muscle tissue. Further, we evaluated its temperature sensitivity for in vivo muscle in patients without metallic hardware. In addition, we performed a comparison of temperature sensitivity between 2DMSI and conventional proton-resonance-frequency-shift (PRFS) thermometry at different distances from metal devices and different signal-to-noise ratios (SNR). 2DMSI thermometry enabled visualization of short ultrasound sonications near metallic hardware. Calibration using in vivo muscle yielded a constant temperature sensitivity for temperatures below 43 °C. For an off-resonance coverage of ± 6 kHz, we achieved a temperature sensitivity of 1.45%/K, resulting in a minimum detectable temperature change of ∼2.5 K for an SNR of 100 with a temporal resolution of 6 s per frame. The proposed 2DMSI thermometry has the potential to allow MR-guided FUS treatments of patients with metallic hardware and therefore expand its reach to a larger patient population. Magn Reson Med 80:259-271, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Assessment of local changes of cerebral perfusion and blood concentration by ultrasound harmonic B-mode contrast measurement in piglet.

NARCIS (Netherlands)

Wijk, M.C. van; Klaessens, J.H.G.M.; Hopman, J.C.W.; Liem, K.D.; Thijssen, J.M.

2003-01-01

This study tested the hypothesis that changes in the blood concentration, and possibly in the perfusion, of different areas in the brain can be assessed by the use of ultrasound contrast agent (CA) and (linear) echo densitometry. The experiments were performed with piglets (n=3) under general

Barrier mechanisms in the Drosophila blood-brain barrier

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Samantha Jane Hindle

2014-12-01

Full Text Available The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many blood-brain barrier mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the blood-brain barrier can govern whole animal physiologies. This includes novel functions of blood-brain barrier gap junctions in orchestrating synchronized neuroblast proliferation, and of blood-brain barrier secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate blood-brain barrier anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study.

Ultrasound-induced radical polymerization

NARCIS (Netherlands)

Kuijpers, M.W.A.; Kemmere, M.F.; Keurentjes, J.T.F.

2004-01-01

Sonochemistry comprises all chemical effects that are induced by ultrasound. Most of these effects are caused by cavitations, ie, the collapse of microscopic bubbles in a liquid. The chemical effects of ultrasound include the formation of radicals and the enhancement of reaction rates at ambient

Image-guided Navigation of Single-element Focused Ultrasound Transducer

Science.gov (United States)

Kim, Hyungmin; Chiu, Alan; Park, Shinsuk; Yoo, Seung-Schik

2014-01-01

The spatial specificity and controllability of focused ultrasound (FUS), in addition to its ability to modify the excitability of neural tissue, allows for the selective and reversible neuromodulation of the brain function, with great potential in neurotherapeutics. Intra-operative magnetic resonance imaging (MRI) guidance (in short, MRg) has limitations due to its complicated examination logistics, such as fixation through skull screws to mount the stereotactic frame, simultaneous sonication in the MRI environment, and restrictions in choosing MR-compatible materials. In order to overcome these limitations, an image-guidance system based on optical tracking and pre-operative imaging data is developed, separating the imaging acquisition for guidance and sonication procedure for treatment. Techniques to define the local coordinates of the focal point of sonication are presented. First, mechanical calibration detects the concentric rotational motion of a rigid-body optical tracker, attached to a straight rod mimicking the sonication path, pivoted at the virtual FUS focus. The spatial error presented in the mechanical calibration was compensated further by MRI-based calibration, which estimates the spatial offset between the navigated focal point and the ground-truth location of the sonication focus obtained from a temperature-sensitive MR sequence. MRI-based calibration offered a significant decrease in spatial errors (1.9±0.8 mm; 57% reduction) compared to the mechanical calibration method alone (4.4±0.9 mm). Using the presented method, pulse-mode FUS was applied to the motor area of the rat brain, and successfully stimulated the motor cortex. The presented techniques can be readily adapted for the transcranial application of FUS to intact human brain. PMID:25232203

A long arm for ultrasound: a combined robotic focused ultrasound setup for magnetic resonance-guided focused ultrasound surgery.

Science.gov (United States)

Krafft, Axel J; Jenne, Jürgen W; Maier, Florian; Stafford, R Jason; Huber, Peter E; Semmler, Wolfhard; Bock, Michael

2010-05-01

Focused ultrasound surgery (FUS) is a highly precise noninvasive procedure to ablate pathogenic tissue. FUS therapy is often combined with magnetic resonance (MR) imaging as MR imaging offers excellent target identification and allows for continuous monitoring of FUS induced temperature changes. As the dimensions of the ultrasound (US) focus are typically much smaller than the targeted volume, multiple sonications and focus repositioning are interleaved to scan the focus over the target volume. Focal scanning can be achieved electronically by using phased-array US transducers or mechanically by using dedicated mechanical actuators. In this study, the authors propose and evaluate the precision of a combined robotic FUS setup to overcome some of the limitations of the existing MRgFUS systems. Such systems are typically integrated into the patient table of the MR scanner and thus only provide an application of the US wave within a limited spatial range from below the patient. The fully MR-compatible robotic assistance system InnoMotion (InnoMedic GmbH, Herxheim, Germany) was originally designed for MR-guided interventions with needles. It offers five pneumatically driven degrees of freedom and can be moved over a wide range within the bore of the magnet. In this work, the robotic system was combined with a fixed-focus US transducer (frequency: 1.7 MHz; focal length: 68 mm, and numerical aperture: 0.44) that was integrated into a dedicated, in-house developed treatment unit for FUS application. A series of MR-guided focal scanning procedures was performed in a polyacrylamide-egg white gel phantom to assess the positioning accuracy of the combined FUS setup. In animal experiments with a 3-month-old domestic pig, the system's potential and suitability for MRgFUS was tested. In phantom experiments, a total targeting precision of about 3 mm was found, which is comparable to that of the existing MRgFUS systems. Focus positioning could be performed within a few seconds

Apoptosis induced by low-intensity ultrasound in vitro: Alteration of protein profile and potential molecular mechanism

Science.gov (United States)

Feng, Yi; Wan, Mingxi

2017-03-01

To analyze the potential mechanism related to the apoptosis induced by low intensity focused ultrasound, comparative proteomic method was introduced in the study. After ultrasound irradiation (3.0 W/cm2, 1 minute, 6 hours incubation post-irradiation), the human SMMC-7721 hepatocarcinoma cells were stained by trypan blue to detect the morphologic changes, and then the percentage of early apoptosis were tested by the flow cytometry with double staining of FITC-labelled Annexin V/Propidium iodide. Two-dimensional SDS polyacrylamide gel electrophoresis was used to get the protein profile and some proteins differently expressed after ultrasound irradiation were identified by MALDI-TOF mass spectrometry. It's proved early apoptosis of cells were induced by low intentisy focused ultrasound. After ultrasound irradiation, the expressing characteristics of several proteins changed, in which protein p53 and heat shock proteins are associated with apoptosis initiation. It is suggested that the low-intensity ultrasound-induced apoptotic cancer therapy has the potential application via understanding its relevant molecular signaling and key proteins. Moreover, the comparative proteomic method is proved to be useful to supply information about the protein expression to analyze the metabolic processes related to bio-effects of biomedical ultrasound.

MO-AB-210-00: Diagnostic Ultrasound Imaging Quality Control and High Intensity Focused Ultrasound Therapy Hands-On Workshop

International Nuclear Information System (INIS)

2015-01-01

The goal of this ultrasound hands-on workshop is to demonstrate advancements in high intensity focused ultrasound (HIFU) and to demonstrate quality control (QC) testing in diagnostic ultrasound. HIFU is a therapeutic modality that uses ultrasound waves as carriers of energy. HIFU is used to focus a beam of ultrasound energy into a small volume at specific target locations within the body. The focused beam causes localized high temperatures and produces a well-defined regions of necrosis. This completely non-invasive technology has great potential for tumor ablation and targeted drug delivery. At the workshop, attendees will see configurations, applications, and hands-on demonstrations with on-site instructors at separate stations. The involvement of medical physicists in diagnostic ultrasound imaging service is increasing due to QC and accreditation requirements. At the workshop, an array of ultrasound testing phantoms and ultrasound scanners will be provided for attendees to learn diagnostic ultrasound QC in a hands-on environment with live demonstrations of the techniques. Target audience: Medical physicists and other medical professionals in diagnostic imaging and radiation oncology with interest in high-intensity focused ultrasound and in diagnostic ultrasound QC. Learning Objectives: Learn ultrasound physics and safety for HIFU applications through live demonstrations Get an overview of the state-of-the art in HIFU technologies and equipment Gain familiarity with common elements of a quality control program for diagnostic ultrasound imaging Identify QC tools available for testing diagnostic ultrasound systems and learn how to use these tools List of supporting vendors for HIFU and diagnostic ultrasound QC hands-on workshop: Philips Healthcare Alpinion Medical Systems Verasonics, Inc Zonare Medical Systems, Inc Computerized Imaging Reference Systems (CIRS), Inc. GAMMEX, Inc., Cablon Medical BV Steffen Sammet: NIH/NCI grant 5R25CA132822, NIH/NINDS grant 5R25NS

MO-AB-210-00: Diagnostic Ultrasound Imaging Quality Control and High Intensity Focused Ultrasound Therapy Hands-On Workshop

Energy Technology Data Exchange (ETDEWEB)

NONE

2015-06-15

The goal of this ultrasound hands-on workshop is to demonstrate advancements in high intensity focused ultrasound (HIFU) and to demonstrate quality control (QC) testing in diagnostic ultrasound. HIFU is a therapeutic modality that uses ultrasound waves as carriers of energy. HIFU is used to focus a beam of ultrasound energy into a small volume at specific target locations within the body. The focused beam causes localized high temperatures and produces a well-defined regions of necrosis. This completely non-invasive technology has great potential for tumor ablation and targeted drug delivery. At the workshop, attendees will see configurations, applications, and hands-on demonstrations with on-site instructors at separate stations. The involvement of medical physicists in diagnostic ultrasound imaging service is increasing due to QC and accreditation requirements. At the workshop, an array of ultrasound testing phantoms and ultrasound scanners will be provided for attendees to learn diagnostic ultrasound QC in a hands-on environment with live demonstrations of the techniques. Target audience: Medical physicists and other medical professionals in diagnostic imaging and radiation oncology with interest in high-intensity focused ultrasound and in diagnostic ultrasound QC. Learning Objectives: Learn ultrasound physics and safety for HIFU applications through live demonstrations Get an overview of the state-of-the art in HIFU technologies and equipment Gain familiarity with common elements of a quality control program for diagnostic ultrasound imaging Identify QC tools available for testing diagnostic ultrasound systems and learn how to use these tools List of supporting vendors for HIFU and diagnostic ultrasound QC hands-on workshop: Philips Healthcare Alpinion Medical Systems Verasonics, Inc Zonare Medical Systems, Inc Computerized Imaging Reference Systems (CIRS), Inc. GAMMEX, Inc., Cablon Medical BV Steffen Sammet: NIH/NCI grant 5R25CA132822, NIH/NINDS grant 5R25NS

Can ultrasound be used to stimulate nerve tissue?

Directory of Open Access Journals (Sweden)

Norton Stephen J

2003-03-01

Full Text Available Abstract Background The stimulation of nerve or cortical tissue by magnetic induction is a relatively new tool for the non-invasive study of the brain and nervous system. Transcranial magnetic stimulation (TMS, for example, has been used for the functional mapping of the motor cortex and may have potential for treating a variety of brain disorders. Methods and Results A new method of stimulating active tissue is proposed by propagating ultrasound in the presence of a magnetic field. Since tissue is conductive, particle motion created by an ultrasonic wave will induce an electric current density generated by Lorentz forces. An analytical derivation is given for the electric field distribution induced by a collimated ultrasonic beam. An example shows that peak electric fields of up to 8 V/m appear to be achievable at the upper range of diagnostic intensities. This field strength is about an order of magnitude lower than fields typically associated with TMS; however, the electric field gradients induced by ultrasound can be quite high (about 60 kV/m2 at 4 MHz, which theoretically play a more important role in activation than the field magnitude. The latter value is comparable to TMS-induced gradients. Conclusion The proposed method could be used to locally stimulate active tissue by inducing an electric field in regions where the ultrasound is focused. Potential advantages of this method compared to TMS is that stimulation of cortical tissue could be highly localized as well as achieved at greater depths in the brain than is currently possible with TMS.

Non-human primate skull effects on the cavitation detection threshold of FUS-induced blood-brain barrier opening

Science.gov (United States)

Wu, Shih-Ying; Tung, Yao-Sheng; Marquet, Fabrice; Chen, Cherry C.; Konofagou, Elisa E.

2012-11-01

Microbubble (MB)-assisted focused ultrasound is a promising technique for delivering drugs to the brain by noninvasively and transiently opening the blood-brain barrier (BBB), and monitoring BBB opening using passive cavitation detection (PCD) is critical in detecting its occurrence, extent as well as assessing its mechanism. One of the main obstacles in achieving those objectives in large animals is the transcranial attenuation. To study the effects, the cavitation response through the in-vitro non-human primate (NHP) skull was investigated. In-house manufactured lipid-shelled MB (medium diameter: 4-5 um) were injected into a 4-mm channel of a phantom below a degassed monkey skull. A hydrophone confocally aligned with the FUS transducer served as PCD during sonication (frequency: 0.50 MHz, peak rarefactional pressures: 0.05-0.60 MPa, pulse length: 100 cycles, PRF: 10 Hz, duration: 2 s) for four cases: water without skull, water with skull, MB without skull and MB with skull. A 5.1-MHz linear-array transducer was also used to monitor the MB disruption. The frequency spectra, spectrograms, stable cavitation dose (SCD) and inertial cavitation dose (ICD) were quantified. Results showed that the onset of stable cavitation and inertial cavitation in the experiments occurred at 50 kPa, and was detectable throught the NHP skull since the both the detection thresholds for stable cavitation and inertial cavitation remained unchanged compared to the non-skull case, and the SCD and ICD acquired transcranially may not adequately represent the true extent of stable and inertial cavitation due to the skull attenuation.

Transport characteristics of guanidino compounds at the blood-brain barrier and blood-cerebrospinal fluid barrier: relevance to neural disorders

Directory of Open Access Journals (Sweden)

Tachikawa Masanori

2011-02-01

Full Text Available Abstract Guanidino compounds (GCs, such as creatine, phosphocreatine, guanidinoacetic acid, creatinine, methylguanidine, guanidinosuccinic acid, γ-guanidinobutyric acid, β-guanidinopropionic acid, guanidinoethane sulfonic acid and α-guanidinoglutaric acid, are present in the mammalian brain. Although creatine and phosphocreatine play important roles in energy homeostasis in the brain, accumulation of GCs may induce epileptic discharges and convulsions. This review focuses on how physiologically important and/or neurotoxic GCs are distributed in the brain under physiological and pathological conditions. Transporters for GCs at the blood-brain barrier (BBB and the blood-cerebrospinal fluid (CSF barrier (BCSFB have emerged as substantial contributors to GCs distribution in the brain. Creatine transporter (CRT/solute carrier (SLC 6A8 expressed at the BBB regulates creatine concentration in the brain, and represents a major pathway for supply of creatine from the circulating blood to the brain. CRT may be a key factor facilitating blood-to-brain guanidinoacetate transport in patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase, the creatine biosynthetic enzyme, resulting in cerebral accumulation of guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6 and organic cation transporter (OCT3/SLC22A3 expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB efflux transport of GCs, including guanidinoacetate and creatinine, is negligible, though the BBB has a variety of efflux transport systems for synthetic precursors of GCs, such as amino acids and neurotransmitters. Instead, the BCSFB functions as a major cerebral clearance system for GCs. In conclusion, transport of GCs at the BBB and BCSFB appears to be the key determinant of the cerebral levels of GCs, and changes in the transport characteristics may cause the abnormal distribution of GCs in the brain seen

Iron supplement prevents lead-induced disruption of the blood-brain barrier during rat development

International Nuclear Information System (INIS)

Wang Qiang; Luo Wenjing; Zheng Wei; Liu Yiping; Xu Hui; Zheng Gang; Dai Zhongming; Zhang Wenbin; Chen Yaoming; Chen Jingyuan

2007-01-01

Children are known to be venerable to lead (Pb) toxicity. The blood-brain barrier (BBB) in immature brain is particularly vulnerable to Pb insults. This study was designed to test the hypothesis that Pb exposure damaged the integrity of the BBB in young animals and iron (Fe) supplement may prevent against Pb-induced BBB disruption. Male weanling Sprague-Dawley rats were divided into four groups. Three groups of rats were exposed to Pb in drinking water containing 342 μg Pb/mL as Pb acetate, among which two groups were concurrently administered by oral gavage once every other day with 7 mg Fe/kg and 14 mg Fe/kg as FeSO 4 solution as the low and high Fe treatment group, respectively, for 6 weeks. The control group received sodium acetate in drinking water. Pb exposure significantly increased Pb concentrations in blood by 6.6-folds (p < 0.05) and brain tissues by 1.5-2.0-folds (p < 0.05) as compared to controls. Under the electron microscope, Pb exposure in young animals caused an extensive extravascular staining of lanthanum nitrate in brain parenchyma, suggesting a leakage of cerebral vasculature. Western blot showed that Pb treatment led to 29-68% reduction (p < 0.05) in the expression of occludin as compared to the controls. Fe supplement among Pb-exposed rats maintained the normal ultra-structure of the BBB and restored the expression of occludin to normal levels. Moreover, the low dose Fe supplement significantly reduced Pb levels in blood and brain tissues. These data suggest that Pb exposure disrupts the structure of the BBB in young animals. The increased BBB permeability may facilitate the accumulation of Pb. Fe supplement appears to protect the integrity of the BBB against Pb insults, a beneficial effect that may have significant clinical implications

De-coupling of blood flow and metabolism in the rat brain induced by glutamate

International Nuclear Information System (INIS)

Hirose, Shinichiro; Momosaki, Sotaro; Sasaki, Kazunari; Hosoi, Rie; Abe, Kohji; Inoue, Osamu; Gee, A.

2009-01-01

Glutamate plays an essential role in neuronal cell death in many neurological disorders. In this study, we examined both glucose metabolism and cerebral blood flow in the same rat following infusion of glutamate or ibotenic acid using the dual-tracer technique. The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-kainate receptor antagonist, on the changes in the glucose metabolism and cerebral blood flow induced by glutamate were also examined. The rats were microinjected with glutamate (1 μmol/μl, 2 μl) or ibotenic acid (10 μg/μl, 1 μl) into the right striatum, and dual-tracer autoradiograms of [ 18 F]fluorodeoxyglucose (FDG) and [ 14 C]iofetamine (IMP) were obtained. MK-801 and NBQX were injected intravenously about 45 and 30 min, respectively, after the infusion of glutamate. De-coupling of blood flow and metabolism was noted in the glutamate-infused hemisphere (as assessed by no alteration of [ 18 F]FDG uptake and significant decrease of [ 14 C]IMP uptake). Pretreatments with MK-801, NBQX, or combined use of MK-801 and NBQX did not affect the de-coupling of the blood flow and metabolism induced by glutamate. A histochemical study revealed that about 20% neuronal cell death had occurred in the striatum at 105 min after the infusion of glutamate. In addition, a significant increase of the [ 18 F]FDG uptake and decrease of [ 14 C]IMP uptake were also seen in the rat brain infused with ibotenic acid. These results indicate that glutamate and ibotenic acid caused a significant de-coupling of blood flow and glucose metabolism in the intact rat brain during the early phase of neurodegeneration. It is necessary to evaluate the relation between metabotropic glutamate receptors and de-coupling of blood flow and metabolism. (author)

WE-G-12A-01: High Intensity Focused Ultrasound Surgery and Therapy

Energy Technology Data Exchange (ETDEWEB)

Farahani, K [National Cancer Institute, Rockville, MD (United States); O' Neill, B [The Methodist Hospital Research Institute, Houston, TX (United States)

2014-06-15

More and more emphasis is being made on alternatives to invasive surgery and the use of ionizing radiation to treat various diseases including cancer. Novel screening, diagnosis, treatment and monitoring of response to treatment are also hot areas of research and new clinical technologies. Ultrasound(US) has gained traction in all of the aforementioned areas of focus. Especially with recent advances in the use of ultrasound to noninvasively treat various diseases/organ systems. This session will focus on covering MR-guided focused ultrasound and the state of the art clinical applications, and the second speaker will survey the more cutting edge technologies e.g. Focused Ultrasound (FUS) mediated drug delivery, principles of cavitation and US guided FUS. Learning Objectives: Fundamental physics and physical limitations of US interaction with tissue and nanoparticles The alteration of tissue transport using focused ultrasound US control of nanoparticle drug carriers for targeted release The basic principles of MRI-guided focused ultrasound (MRgFUS) surgery and therapy the current state of the art clinical applications of MRgFUS requirements for quality assurance and treatment planning.

Kainic acid-induced albumin leak across the blood-brain barrier facilitates epileptiform hyperexcitability in limbic regions.

Science.gov (United States)

Noé, Francesco M; Bellistri, Elisa; Colciaghi, Francesca; Cipelletti, Barbara; Battaglia, Giorgio; de Curtis, Marco; Librizzi, Laura

2016-06-01

Systemic administration of kainic acid (KA) is a widely used procedure utilized to develop a model of temporal lobe epilepsy (TLE). Despite its ability to induce status epilepticus (SE) in vivo, KA applied to in vitro preparations induces only interictal-like activity and/or isolated ictal discharges. The possibility that extravasation of the serum protein albumin from the vascular compartment enhances KA-induced brain excitability is investigated here. Epileptiform activity was induced by arterial perfusion of 6 μm KA in the in vitro isolated guinea pig brain preparation. Simultaneous field potential recordings were carried out bilaterally from limbic (CA1, dentate gyrus [DG], and entorhinal cortex) and extralimbic regions (piriform cortex and neocortex). Blood-brain barrier (BBB) breakdown associated with KA-induced epileptiform activity was assessed by parenchymal leakage of intravascular fluorescein-isothiocyanate albumin. Seizure-induced brain inflammation was evaluated by western blot analysis of interleukin (IL)-1β expression in brain tissue. KA infusion caused synchronized activity at 15-30 Hz in limbic (but not extralimbic) cortical areas, associated with a brief, single seizure-like event. A second bolus of KA, 60 min after the induction of the first ictal event, did not further enhance excitability. Perfusion of serum albumin between the two administrations of KA enhanced epileptiform discharges and allowed a recurrent ictal event during the second KA infusion. Our data show that arterial KA administration selectively alters the synchronization of limbic networks. However, KA is not sufficient to generate recurrent seizures unless serum albumin is co-perfused during KA administration. These findings suggest a role of serum albumin in facilitating acute seizure generation. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Numerical simulations of clinical focused ultrasound functional neurosurgery

Science.gov (United States)

Pulkkinen, Aki; Werner, Beat; Martin, Ernst; Hynynen, Kullervo

2014-04-01

A computational model utilizing grid and finite difference methods were developed to simulate focused ultrasound functional neurosurgery interventions. The model couples the propagation of ultrasound in fluids (soft tissues) and solids (skull) with acoustic and visco-elastic wave equations. The computational model was applied to simulate clinical focused ultrasound functional neurosurgery treatments performed in patients suffering from therapy resistant chronic neuropathic pain. Datasets of five patients were used to derive the treatment geometry. Eight sonications performed in the treatments were then simulated with the developed model. Computations were performed by driving the simulated phased array ultrasound transducer with the acoustic parameters used in the treatments. Resulting focal temperatures and size of the thermal foci were compared quantitatively, in addition to qualitative inspection of the simulated pressure and temperature fields. This study found that the computational model and the simulation parameters predicted an average of 24 ± 13% lower focal temperature elevations than observed in the treatments. The size of the simulated thermal focus was found to be 40 ± 13% smaller in the anterior-posterior direction and 22 ± 14% smaller in the inferior-superior direction than in the treatments. The location of the simulated thermal focus was off from the prescribed target by 0.3 ± 0.1 mm, while the peak focal temperature elevation observed in the measurements was off by 1.6 ± 0.6 mm. Although the results of the simulations suggest that there could be some inaccuracies in either the tissue parameters used, or in the simulation methods, the simulations were able to predict the focal spot locations and temperature elevations adequately for initial treatment planning performed to assess, for example, the feasibility of sonication. The accuracy of the simulations could be improved if more precise ultrasound tissue properties (especially of the

Focused ultrasound-modulated glomerular ultrafiltration assessed by functional changes in renal arteries.

Directory of Open Access Journals (Sweden)

Feng-Yi Yang

Full Text Available This study demonstrates the feasibility of using focused ultrasound (FUS to modulate glomerular ultrafiltration by renal artery sonication and determine if protein-creatinine ratios are estimated through vascular parameters. All animal experiments were approved by our Animal Care and Use Committee. The renal arteries of Sprague-Dawley rats were surgically exposed and sonicated at various acoustic power levels using a FUS transducer with a resonant frequency of 1 MHz. The mean peak systolic velocity (PSV of the blood flow was measured by Doppler ultrasound imaging. Urinary protein-creatinine ratios were calculated during the experiments. Histological examination of renal arteries and whole kidneys was performed. The PSV, pulsatility index, and resistance index of blood flow significantly increased in the arteries after FUS sonication without microbubbles (p<0.05. The change in normalized protein-creatinine ratios significantly increased with increasing acoustic power, but such was not observed when microbubbles were administered. Furthermore, no histological changes were observed in the hematoxylin- and eosin-stained sections. Glomerular ultrafiltration is regulated temporarily by renal artery sonication without microbubbles. Monitoring vascular parameters are useful in estimating the normalized change in protein-creatinine ratios.

MO-AB-210-03: Workshop [Advancements in high intensity focused ultrasound

Energy Technology Data Exchange (ETDEWEB)

Lu, Z. [University of Chicago (United States)

2015-06-15

The goal of this ultrasound hands-on workshop is to demonstrate advancements in high intensity focused ultrasound (HIFU) and to demonstrate quality control (QC) testing in diagnostic ultrasound. HIFU is a therapeutic modality that uses ultrasound waves as carriers of energy. HIFU is used to focus a beam of ultrasound energy into a small volume at specific target locations within the body. The focused beam causes localized high temperatures and produces a well-defined regions of necrosis. This completely non-invasive technology has great potential for tumor ablation and targeted drug delivery. At the workshop, attendees will see configurations, applications, and hands-on demonstrations with on-site instructors at separate stations. The involvement of medical physicists in diagnostic ultrasound imaging service is increasing due to QC and accreditation requirements. At the workshop, an array of ultrasound testing phantoms and ultrasound scanners will be provided for attendees to learn diagnostic ultrasound QC in a hands-on environment with live demonstrations of the techniques. Target audience: Medical physicists and other medical professionals in diagnostic imaging and radiation oncology with interest in high-intensity focused ultrasound and in diagnostic ultrasound QC. Learning Objectives: Learn ultrasound physics and safety for HIFU applications through live demonstrations Get an overview of the state-of-the art in HIFU technologies and equipment Gain familiarity with common elements of a quality control program for diagnostic ultrasound imaging Identify QC tools available for testing diagnostic ultrasound systems and learn how to use these tools List of supporting vendors for HIFU and diagnostic ultrasound QC hands-on workshop: Philips Healthcare Alpinion Medical Systems Verasonics, Inc Zonare Medical Systems, Inc Computerized Imaging Reference Systems (CIRS), Inc. GAMMEX, Inc., Cablon Medical BV Steffen Sammet: NIH/NCI grant 5R25CA132822, NIH/NINDS grant 5R25NS

Complex blood flow quantification using real-time in vivo vector flow ultrasound

DEFF Research Database (Denmark)

Pedersen, Mads Møller; Pihl, Michael Johannes; Per, Haugaard

A new method to define and quantify complex blood flow is presented. The standard deviations of real-time in vivo vector flow angle estimates are used. Using vector flow ultrasound imaging both carotid bifurcations of two healthy volunteers were scanned. Scanning was performed with a 7.6 MHz linear...... transducer (8670, B-K Medical, Denmark) and a commercial vector flow ultrasound scanner (ProFocus 2202, B-K Medical). Eight video sequences of one cardiac cycle were obtained. In every frame boxes were placed to define the common carotid artery(box1) and the carotid bulb(box2). The standard deviation...... for the vector angle estimates was calculated for each box in every frame. For comparison three ultrasound experts evaluated the presence of complex flow in every box. The trial was blinded. For every sequence the mean standard deviation of the vector angle estimates were calculated for box1 {39...

Bacterial lipopolysaccharide-induced systemic inflammation alters perfusion of white matter-rich regions without altering flow in brain-irrigating arteries: Relationship to blood-brain barrier breakdown?

Science.gov (United States)

Dhaya, Ibtihel; Griton, Marion; Raffard, Gérard; Amri, Mohamed; Hiba, Bassem; Konsman, Jan Pieter

2018-01-15

To better understand brain dysfunction during sepsis, cerebral arterial blood flow was assessed with Phase Contrast Magnetic Resonance Imaging, perfusion with Arterial Spin Labeling and structure with diffusion-weighted Magnetic Resonance Imaging in rats after intraperitoneal administration of bacterial lipopolysaccharides. Although cerebral arterial flow was not altered, perfusion of the corpus callosum region and diffusion parallel to its fibers were higher after lipopolysaccharide administration as compared to saline injection. In parallel, lipopolysaccharide induced perivascular immunoglobulin-immunoreactivity in white matter. These findings indicate that systemic inflammation can result in increased perfusion, blood-brain barrier breakdown and altered water diffusion in white matter. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel PET imaging protocol identifies seizure-induced regional overactivity of P-glycoprotein at the blood-brain barrier

Science.gov (United States)

Bankstahl, Jens P.; Bankstahl, Marion; Kuntner, Claudia; Stanek, Johann; Wanek, Thomas; Meier, Martin; Ding, Xiao-Qi; Müller, Markus; Langer, Oliver; Löscher, Wolfgang

2013-01-01

About one third of epilepsy patients are pharmacoresistant. Overexpression of P-glycoprotein and other multidrug transporters at the blood-brain barrier is thought to play an important role in drug-refractory epilepsy. Thus, quantification of regionally different P-glycoprotein activity in the brain in vivo is essential to identify P-glycoprotein overactivity as the relevant mechanism for drug-resistance in an individual patient. Using the radiolabeled P-glycoprotein substrate (R)-[11C]verapamil and different doses of co-administered tariquidar, which is an inhibitor of P-glycoprotein, we evaluated whether small-animal positron emission tomography (PET) can quantify regional changes in transporter function in the rat brain at baseline and 48 h after a pilocarpine-induced status epilepticus. P-glycoprotein expression was additionally quantified by immunohistochemistry. To reveal putative seizure-induced changes in blood-brain barrier integrity, we performed gadolinium-enhanced magnetic resonance scans on a 7.0 Tesla small-animal scanner. Before P-glycoprotein modulation, brain uptake of (R)-[11C]verapamil was low in all regions investigated in control and post-status epilepticus rats. After administration of 3 mg/kg tariquidar, which inhibits P-glycoprotein only partially, we observed increased regional differentiation in brain activity uptake in post-status epilepticus versus control rats, which diminished after maximal P-glycoprotein inhibition. Regional increases in the efflux rate constant k2, but not in distribution volume VT or influx rate constant K1, correlated significantly with increases in P-glycoprotein expression measured by immunohistochemistry. This imaging protocol proves to be suitable to detect seizure-induced regional changes in P-glycoprotein activity and is readily applicable to humans, with the aim to detect relevant mechanisms of pharmacoresistance in epilepsy in vivo. PMID:21677164

Fluid and solid mechanics in a poroelastic network induced by ultrasound.

Science.gov (United States)

Wang, Peng; Olbricht, William L

2011-01-04

We made a theoretical analysis on the fluid and solid mechanics in a poroelastic medium induced by low-power ultrasound. Using a perturbative approach, we were able to linearize the governing equations and obtain analytical solutions. We found that ultrasound could propagate in the medium as a mechanical wave, but would dissipate due to frictional forces between the fluid and the solid phase. The amplitude of the wave depends on the ultrasonic power input. We applied this model to the problem of drug delivery to soft biological tissues by low-power ultrasound and proposed a mechanism for enhanced drug penetration. We have also found the coexistence of two acoustic waves under certain circumstances and pointed out the importance of very accurate experimental determination of the high-frequency properties of brain tissue. Copyright © 2010 Elsevier Ltd. All rights reserved.

Hydrogen Sulfide Ameliorates Homocysteine-Induced Alzheimer's Disease-Like Pathology, Blood-Brain Barrier Disruption, and Synaptic Disorder.

Science.gov (United States)

Kamat, Pradip K; Kyles, Philip; Kalani, Anuradha; Tyagi, Neetu

2016-05-01

Elevated plasma total homocysteine (Hcy) level is associated with an increased risk of Alzheimer's disease (AD). During transsulfuration pathways, Hcy is metabolized into hydrogen sulfide (H2S), which is a synaptic modulator, as well as a neuro-protective agent. However, the role of hydrogen sulfide, as well as N-methyl-D-aspartate receptor (NMDAR) activation, in hyperhomocysteinemia (HHcy) induced blood-brain barrier (BBB) disruption and synaptic dysfunction, leading to AD pathology is not clear. Therefore, we hypothesized that the inhibition of neuronal NMDA-R by H2S and MK801 mitigate the Hcy-induced BBB disruption and synapse dysfunction, in part by decreasing neuronal matrix degradation. Hcy intracerebral (IC) treatment significantly impaired cerebral blood flow (CBF), and cerebral circulation and memory function. Hcy treatment also decreases the expression of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) in the brain along with increased expression of NMDA-R (NR1) and synaptosomal Ca(2+) indicating excitotoxicity. Additionally, we found that Hcy treatment increased protein and mRNA expression of intracellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP)-2, and MMP-9 and also increased MMP-2 and MMP-9 activity in the brain. The increased expression of ICAM-1, glial fibrillary acidic protein (GFAP), and the decreased expression of vascular endothelial (VE)-cadherin and claudin-5 indicates BBB disruption and vascular inflammation. Moreover, we also found decreased expression of microtubule-associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), synapse-associated protein 97 (SAP-97), synaptosomal-associated protein 25 (SNAP-25), synaptophysin, and brain-derived neurotrophic factor (BDNF) showing synapse dysfunction in the hippocampus. Furthermore, NaHS and MK801 treatment ameliorates BBB disruption, CBF, and synapse functions in the mice brain. These results demonstrate a neuro-protective effect of H2S over Hcy-induced

High-intensity focused ultrasound for potential treatment of polycystic ovary syndrome: toward a noninvasive surgery.

Science.gov (United States)

Shehata, Islam A; Ballard, John R; Casper, Andrew J; Hennings, Leah J; Cressman, Erik; Ebbini, Emad S

2014-02-01

To investigate the feasibility of using high-intensity focused ultrasound (HIFU), under dual-mode ultrasound arrays (DMUAs) guidance, to induce localized thermal damage inside ovaries without damage to the ovarian surface. Laboratory feasibility study. University-based laboratory. Ex vivo canine and bovine ovaries. DMUA-guided HIFU. Detection of ovarian damage by ultrasound imaging, gross pathology, and histology. It is feasible to induce localized thermal damage inside ovaries without damage to the ovarian surface. DMUA provided sensitive imaging feedback regarding the anatomy of the treated ovaries and the ablation process. Different ablation protocols were tested, and thermal damage within the treated ovaries was histologically characterized. The absence of damage to the ovarian surface may eliminate many of the complications linked to current laparoscopic ovarian drilling (LOD) techniques. HIFU may be used as a less traumatic tool to perform LOD. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Medical ultrasound imaging

DEFF Research Database (Denmark)

Jensen, Jørgen Arendt

2007-01-01

The paper gives an introduction to current medical ultrasound imaging systems. The basics of anatomic and blood flow imaging are described. The properties of medical ultrasound and its focusing are described, and the various methods for two- and three-dimensional imaging of the human anatomy...

Microwave hyperthermia-induced blood-brain barrier alterations

International Nuclear Information System (INIS)

Lin, J.C.; Lin, M.F.

1982-01-01

We have studied the interaction of microwaves with the blood-brain barrier in Wistar rats. Indwelling catheters were placed in the femoral vein. Evans blue in isotonic saline was used as a visual indicator of barrier permeation. Irradiation with pulsed 2450-MHz microwaves for 20 min at average power densities of 0.5 to 2600 mW/cm 2 , which resulted in average specific absorption rages (SARs) of 0.04 to 200 mW/g in the brain, did not produce staining, except in regions that normally are highly permeable. When the incident power density was increased to 3000 mW/cm 2 (SAR of 240 mW/g), extravasation of Evans blue could be seen in the cortex, hippocampus, and midbrain. The rectal temperature, as monitored by a copper-constantan thermocouple, showed a maximum increase of less than 1.0/sup o/C. the brain temperature recorded in a similar group of animals using a non-field-perturbing thermistor exceeded 43/sup o/C. At the higher power density the extravasation depended on the irradition and euthanization times. In one series of experiments, rats were irradiated at 3000 mW/cm 2 for 5, 10, 15, and 20 min. Immediately after irradiation all except the 5-min animals exhibited increased permeability in some regions of the brain. Brains of rats euthanized 30 min after irradiation were free of Evans blue, while those euthanized 10 and 20 min postirradiation showed significant dye staining but with less intensity than those euthanized immediately after irradiation

Ultrasound evaluation of cortical brain development in fetuses with intrauterine growth restriction.

Science.gov (United States)

Businelli, Caterina; de Wit, Charlotte; Visser, Gerard H A; Pistorius, Lourens R

2014-09-10

Abstract Objective: We evaluated the ultrasound appearance of brain volume and cortical development in fetuses with early growth restriction and placental insufficiency. Methods: We examined a cohort of 20 fetuses with severe intrauterine growth restriction (IUGR) and evidence of placental insufficiency by three-dimensional (3D) ultrasound between 24 and 34 weeks. We graded cortical development and measured the supratentorial intracranial volume. The cortical grading and volume were compared to data obtained from a reference population of 28 adequate for gestational age (AGA) fetuses. Results: Ultrasound examinations were performed in 20 fetuses with IUGR. The biometry and brain volume were significantly reduced in IUGR fetuses. There was evidence of accelerated cortical development in IUGR fetuses. Conclusion: This study confirms that the smaller brain volume in IUGR fetuses, with normal or accelerated cortical maturation as previously depicted with postnatal MRI examination, can be demonstrated by prenatal 3D ultrasound.

Design and validation of an MR-conditional robot for transcranial focused ultrasound surgery in infants

Energy Technology Data Exchange (ETDEWEB)

Price, Karl D., E-mail: karl.price@sickkids.ca [Centre for Image Guided Innovation and Therapeutic Intervention, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 (Canada); The Department of Mechanical Engineering, The University of Toronto, Toronto, Ontario M5S 3G8 (Canada); Sin, Vivian W. [Centre for Image Guided Innovation and Therapeutic Intervention, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 (Canada); Mougenot, Charles [Philips Healthcare Canada, Markham, Ontario L6C 2S3 (Canada); Pichardo, Samuel [Electrical Engineering, Lakehead University, Thunder Bay, Ontario P7B 5E1 (Canada); Looi, Thomas [Centre for Image Guided Innovation and Therapeutic Intervention, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 (Canada); The Institute of Biomaterials and Biomedical Engineering, The University of Toronto, Toronto, Ontario M5G 3G9 (Canada); Waspe, Adam C. [Centre for Image Guided Innovation and Therapeutic Intervention, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 (Canada); Department of Medical Imaging, The University of Toronto, Toronto, Ontario M5T 1W7 (Canada); Drake, James M. [Centre for Image Guided Innovation and Therapeutic Intervention, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 (Canada); Department of Neurosurgery, The University of Toronto, Toronto, Ontario M5S 1A1 (Canada); The Institute of Biomaterials and Biomedical Engineering, The University of Toronto, Toronto, Ontario M5G 3G9 (Canada)

2016-09-15

Purpose: Current treatment of intraventricular hemorrhage (IVH) involves cerebral shunt placement or an invasive brain surgery. Magnetic resonance-guided focused ultrasound (MRgFUS) applied to the brains of pediatric patients presents an opportunity to treat IVH in a noninvasive manner, termed “incision-less surgery.” Current clinical and research focused ultrasound systems lack the capability to perform neonatal transcranial surgeries due to either range of motion or dexterity requirements. A novel robotic system is proposed to position a focused ultrasound transducer accurately above the head of a neonatal patient inside an MRI machine to deliver the therapy. Methods: A clinical Philips Sonalleve MRgFUS system was expanded to perform transcranial treatment. A five degree-of-freedom MR-conditional robot was designed and manufactured using MR compatible materials. The robot electronics and control were integrated into existing Philips electronics and software interfaces. The user commands the position of the robot with a graphical user interface, and is presented with real-time MR imaging of the patient throughout the surgery. The robot is validated through a series of experiments that characterize accuracy, signal-to-noise ratio degeneration of an MR image as a result of the robot, MR imaging artifacts generated by the robot, and the robot’s ability to operate in a representative surgical environment inside an MR machine. Results: Experimental results show the robot responds reliably within an MR environment, has achieved 0.59 ± 0.25 mm accuracy, does not produce severe MR-imaging artifacts, has a workspace providing sufficient coverage of a neonatal brain, and can manipulate a 5 kg payload. A full system demonstration shows these characteristics apply in an application environment. Conclusions: This paper presents a comprehensive look at the process of designing and validating a new robot from concept to implementation for use in an MR environment. An MR

Design and validation of an MR-conditional robot for transcranial focused ultrasound surgery in infants

International Nuclear Information System (INIS)

Price, Karl D.; Sin, Vivian W.; Mougenot, Charles; Pichardo, Samuel; Looi, Thomas; Waspe, Adam C.; Drake, James M.

2016-01-01

Purpose: Current treatment of intraventricular hemorrhage (IVH) involves cerebral shunt placement or an invasive brain surgery. Magnetic resonance-guided focused ultrasound (MRgFUS) applied to the brains of pediatric patients presents an opportunity to treat IVH in a noninvasive manner, termed “incision-less surgery.” Current clinical and research focused ultrasound systems lack the capability to perform neonatal transcranial surgeries due to either range of motion or dexterity requirements. A novel robotic system is proposed to position a focused ultrasound transducer accurately above the head of a neonatal patient inside an MRI machine to deliver the therapy. Methods: A clinical Philips Sonalleve MRgFUS system was expanded to perform transcranial treatment. A five degree-of-freedom MR-conditional robot was designed and manufactured using MR compatible materials. The robot electronics and control were integrated into existing Philips electronics and software interfaces. The user commands the position of the robot with a graphical user interface, and is presented with real-time MR imaging of the patient throughout the surgery. The robot is validated through a series of experiments that characterize accuracy, signal-to-noise ratio degeneration of an MR image as a result of the robot, MR imaging artifacts generated by the robot, and the robot’s ability to operate in a representative surgical environment inside an MR machine. Results: Experimental results show the robot responds reliably within an MR environment, has achieved 0.59 ± 0.25 mm accuracy, does not produce severe MR-imaging artifacts, has a workspace providing sufficient coverage of a neonatal brain, and can manipulate a 5 kg payload. A full system demonstration shows these characteristics apply in an application environment. Conclusions: This paper presents a comprehensive look at the process of designing and validating a new robot from concept to implementation for use in an MR environment. An MR

A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption.

Science.gov (United States)

Sharabi, Shirley; Kos, Bor; Last, David; Guez, David; Daniels, Dianne; Harnof, Sagi; Mardor, Yael; Miklavcic, Damijan

2016-03-01

Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning. Cell death and BBB disruption models were developed based on the Peleg-Fermi model in combination with numerical models of the electric field. The model calculates the electric field thresholds for cell kill and BBB disruption and describes the dependence on the number of treatment pulses. The model was validated using in vivo experimental data consisting of rats brains MRIs post electroporation treatments. Linear regression analysis confirmed that the model described the IRE and BBB disruption volumes as a function of treatment pulses number (r(2) = 0.79; p disruption, the ratio increased with the number of pulses. BBB disruption radii were on average 67% ± 11% larger than IRE volumes. The statistical model can be used to describe the dependence of treatment-effects on the number of pulses independent of the experimental setup.

Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

Science.gov (United States)

Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

2013-07-10

Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

In vitro characterization of perfluorocarbon droplets for focused ultrasound therapy

Energy Technology Data Exchange (ETDEWEB)

Schad, Kelly C; Hynynen, Kullervo, E-mail: khynynen@sri.utoronto.c [Imaging Research, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario M4N 3M5 (Canada); Department of Medical Biophysics, University of Toronto (Canada)

2010-09-07

Focused ultrasound therapy can be enhanced with microbubbles by thermal and cavitation effects. However, localization of treatment is difficult as bioeffects can occur outside of the target region. Spatial control of bubbles can be achieved by ultrasound-induced conversion of liquid perfluorocarbon droplets to gas bubbles. This study was undertaken to determine the acoustic parameters for bubble production by droplet conversion and how it depends on the acoustic conditions and droplet physical parameters. Lipid-encapsulated droplets containing dodecafluoropentane were manufactured with sizes ranging from 1.9 to 7.2 {mu}m in diameter and diluted to a concentration of 8 x 10{sup 6} droplets mL{sup -1}. The droplets were sonicated in vitro with a focused ultrasound transducer and varying frequency and exposure under flow conditions through an acoustically transparent vessel. The sonications were 10 ms in duration at frequencies of 0.578, 1.736 and 2.855 MHz. The pressure threshold for droplet conversion was measured with an active transducer operating in pulse-echo mode and simultaneous measurements of broadband acoustic emissions were performed with passive acoustic detection. The results show that droplets cannot be converted at low frequency without broadband emissions occurring. However, the pressure threshold for droplet conversion decreased with increasing frequency, exposure and droplet size. The pressure threshold for broadband emissions was independent of the droplet size and was 2.9, 4.4 and 5.3 MPa for 0.578, 1736 and 2.855 MHz, respectively. In summary, we have demonstrated that droplet conversion is feasible for clinically relevant sized droplets and acoustic exposures.

In vitro characterization of perfluorocarbon droplets for focused ultrasound therapy

International Nuclear Information System (INIS)

Schad, Kelly C; Hynynen, Kullervo

2010-01-01

Focused ultrasound therapy can be enhanced with microbubbles by thermal and cavitation effects. However, localization of treatment is difficult as bioeffects can occur outside of the target region. Spatial control of bubbles can be achieved by ultrasound-induced conversion of liquid perfluorocarbon droplets to gas bubbles. This study was undertaken to determine the acoustic parameters for bubble production by droplet conversion and how it depends on the acoustic conditions and droplet physical parameters. Lipid-encapsulated droplets containing dodecafluoropentane were manufactured with sizes ranging from 1.9 to 7.2 μm in diameter and diluted to a concentration of 8 x 10 6 droplets mL -1 . The droplets were sonicated in vitro with a focused ultrasound transducer and varying frequency and exposure under flow conditions through an acoustically transparent vessel. The sonications were 10 ms in duration at frequencies of 0.578, 1.736 and 2.855 MHz. The pressure threshold for droplet conversion was measured with an active transducer operating in pulse-echo mode and simultaneous measurements of broadband acoustic emissions were performed with passive acoustic detection. The results show that droplets cannot be converted at low frequency without broadband emissions occurring. However, the pressure threshold for droplet conversion decreased with increasing frequency, exposure and droplet size. The pressure threshold for broadband emissions was independent of the droplet size and was 2.9, 4.4 and 5.3 MPa for 0.578, 1736 and 2.855 MHz, respectively. In summary, we have demonstrated that droplet conversion is feasible for clinically relevant sized droplets and acoustic exposures.

In vitro characterization of perfluorocarbon droplets for focused ultrasound therapy

Science.gov (United States)

Schad, Kelly C.; Hynynen, Kullervo

2010-09-01

Focused ultrasound therapy can be enhanced with microbubbles by thermal and cavitation effects. However, localization of treatment is difficult as bioeffects can occur outside of the target region. Spatial control of bubbles can be achieved by ultrasound-induced conversion of liquid perfluorocarbon droplets to gas bubbles. This study was undertaken to determine the acoustic parameters for bubble production by droplet conversion and how it depends on the acoustic conditions and droplet physical parameters. Lipid-encapsulated droplets containing dodecafluoropentane were manufactured with sizes ranging from 1.9 to 7.2 µm in diameter and diluted to a concentration of 8 × 106 droplets mL-1. The droplets were sonicated in vitro with a focused ultrasound transducer and varying frequency and exposure under flow conditions through an acoustically transparent vessel. The sonications were 10 ms in duration at frequencies of 0.578, 1.736 and 2.855 MHz. The pressure threshold for droplet conversion was measured with an active transducer operating in pulse-echo mode and simultaneous measurements of broadband acoustic emissions were performed with passive acoustic detection. The results show that droplets cannot be converted at low frequency without broadband emissions occurring. However, the pressure threshold for droplet conversion decreased with increasing frequency, exposure and droplet size. The pressure threshold for broadband emissions was independent of the droplet size and was 2.9, 4.4 and 5.3 MPa for 0.578, 1736 and 2.855 MHz, respectively. In summary, we have demonstrated that droplet conversion is feasible for clinically relevant sized droplets and acoustic exposures.

WE-B-210-02: The Advent of Ultrafast Imaging in Biomedical Ultrasound

International Nuclear Information System (INIS)

Tanter, M.

2015-01-01

In the last fifteen years, the introduction of plane or diverging wave transmissions rather than line by line scanning focused beams has broken the conventional barriers of ultrasound imaging. By using such large field of view transmissions, the frame rate reaches the theoretical limit of physics dictated by the ultrasound speed and an ultrasonic map can be provided typically in tens of micro-seconds (several thousands of frames per second). Interestingly, this leap in frame rate is not only a technological breakthrough but it permits the advent of completely new ultrasound imaging modes, including shear wave elastography, electromechanical wave imaging, ultrafast doppler, ultrafast contrast imaging, and even functional ultrasound imaging of brain activity (fUltrasound) introducing Ultrasound as an emerging full-fledged neuroimaging modality. At ultrafast frame rates, it becomes possible to track in real time the transient vibrations – known as shear waves – propagating through organs. Such “human body seismology” provides quantitative maps of local tissue stiffness whose added value for diagnosis has been recently demonstrated in many fields of radiology (breast, prostate and liver cancer, cardiovascular imaging, …). Today, Supersonic Imagine company is commercializing the first clinical ultrafast ultrasound scanner, Aixplorer with real time Shear Wave Elastography. This is the first example of an ultrafast Ultrasound approach surpassing the research phase and now widely spread in the clinical medical ultrasound community with an installed base of more than 1000 Aixplorer systems in 54 countries worldwide. For blood flow imaging, ultrafast Doppler permits high-precision characterization of complex vascular and cardiac flows. It also gives ultrasound the ability to detect very subtle blood flow in very small vessels. In the brain, such ultrasensitive Doppler paves the way for fUltrasound (functional ultrasound imaging) of brain activity with unprecedented

WE-B-210-02: The Advent of Ultrafast Imaging in Biomedical Ultrasound

Energy Technology Data Exchange (ETDEWEB)

Tanter, M. [Laboratoire Ondes et Acoustique (France)

2015-06-15

In the last fifteen years, the introduction of plane or diverging wave transmissions rather than line by line scanning focused beams has broken the conventional barriers of ultrasound imaging. By using such large field of view transmissions, the frame rate reaches the theoretical limit of physics dictated by the ultrasound speed and an ultrasonic map can be provided typically in tens of micro-seconds (several thousands of frames per second). Interestingly, this leap in frame rate is not only a technological breakthrough but it permits the advent of completely new ultrasound imaging modes, including shear wave elastography, electromechanical wave imaging, ultrafast doppler, ultrafast contrast imaging, and even functional ultrasound imaging of brain activity (fUltrasound) introducing Ultrasound as an emerging full-fledged neuroimaging modality. At ultrafast frame rates, it becomes possible to track in real time the transient vibrations – known as shear waves – propagating through organs. Such “human body seismology” provides quantitative maps of local tissue stiffness whose added value for diagnosis has been recently demonstrated in many fields of radiology (breast, prostate and liver cancer, cardiovascular imaging, …). Today, Supersonic Imagine company is commercializing the first clinical ultrafast ultrasound scanner, Aixplorer with real time Shear Wave Elastography. This is the first example of an ultrafast Ultrasound approach surpassing the research phase and now widely spread in the clinical medical ultrasound community with an installed base of more than 1000 Aixplorer systems in 54 countries worldwide. For blood flow imaging, ultrafast Doppler permits high-precision characterization of complex vascular and cardiac flows. It also gives ultrasound the ability to detect very subtle blood flow in very small vessels. In the brain, such ultrasensitive Doppler paves the way for fUltrasound (functional ultrasound imaging) of brain activity with unprecedented

Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

DEFF Research Database (Denmark)

Schellenberg, Angela E; Buist, Richard; Del Bigio, Marc R

2012-01-01

infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx). METHODS: This study uses contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood-brain barrier (BBB) disruption in this model pre- and post-PTx administration compared to wild type mice....... Contrast-enhanced MR images were obtained before and 1, 3, and 5 days after PTx injection in each animal. After the final imaging session fluorescent dextran tracers were administered intravenously to each mouse and brains were examined histologically for cellular infiltrates, BBB leakage and tight...... junction protein. RESULTS: BBB breakdown, defined as a disruption of both the endothelium and glia limitans, was found only in CCL2 transgenic mice following PTx administration seen on MR images as focal areas of contrast enhancement and histologically as dextrans leaking from blood vessels. No evidence...

Minocycline Attenuates Iron-Induced Brain Injury.

Science.gov (United States)

Zhao, Fan; Xi, Guohua; Liu, Wenqaun; Keep, Richard F; Hua, Ya

2016-01-01

Iron plays an important role in brain injury after intracerebral hemorrhage (ICH). Our previous study found minocycline reduces iron overload after ICH. The present study examined the effects of minocycline on the subacute brain injury induced by iron. Rats had an intracaudate injection of 50 μl of saline, iron, or iron + minocycline. All the animals were euthanized at day 3. Rat brains were used for immunohistochemistry (n = 5-6 per each group) and Western blotting assay (n = 4). Brain swelling, blood-brain barrier (BBB) disruption, and iron-handling proteins were measured. We found that intracerebral injection of iron resulted in brain swelling, BBB disruption, and brain iron-handling protein upregulation (p minocycline with iron significantly reduced iron-induced brain swelling (n = 5, p Minocycline significantly decreased albumin protein levels in the ipsilateral basal ganglia (p minocycline co-injected animals. In conclusion, the present study suggests that minocycline attenuates brain swelling and BBB disruption via an iron-chelation mechanism.

Ultrasound-controlled neuronavigator-guided brain surgery.

Science.gov (United States)

Koivukangas, J; Louhisalmi, Y; Alakuijala, J; Oikarinen, J

1993-07-01

The development of a unique neurosurgical navigator is described and a preliminary series of seven cases of intracerebral lesions approached with the assistance of this neuronavigation system under ultrasound control is presented. The clinical series included five low-grade astrocytomas, one chronic intracerebral hematoma, and one porencephalic cyst. Management procedures included biopsy in all cases, drainage of the hematoma, and endoscopy and fenestration for the cyst. The features of the neuronavigation system are interactive reconstructions of preoperative computerized tomography and magnetic resonance imaging data, corresponding intraoperative ultrasound images, versatility of the interchangeable end-effector instruments, graphic presentation of instruments on the reconstructed images, and voice control of the system. The principle of a common axis in the reconstructed images served to align the navigational pointer, biopsy guide, endoscope guide, ultrasound transducer, and surgical microscope to the brain anatomy. Intraoperative ultrasound imaging helped to verify the accuracy of the neuronavigator and check the results of the procedures. The arm of the neuronavigation system served as a holder for instruments, such as the biopsy guide, endoscope guide, and ultrasound transducer, in addition to functioning as a navigational pointer. Also, the surgical microscope was aligned with the neuronavigator for inspection and biopsy of the hematoma capsule to rule out tumor etiology. Voice control freed the neurosurgeon from manual exercises during start-up and calibration of the system.

[Control parameters for high-intensity focused ultrasound (HIFU) for tissue ablation in the ex-vivo kidney].

Science.gov (United States)

Köhrmann, K U; Michel, M S; Steidler, A; Marlinghaus, E H; Kraut, O; Alken, P

2002-01-01

Therapeutic application of contactless thermoablation by high-intensity focused ultrasound (HIFU) demands precise physical definition of focal size and determination of control parameters. Our objective was to define the focal expansion of a new ultrasound generator and to evaluate the extent of tissue ablation under variable generator parameters in an ex vivo model. Axial and transversal distribution of ultrasound intensity in the area of the focal point was calculated by needle hydrophone. The extent of tissue necrosis after focused ultrasound was assessed in an ex vivo porcine kidney model applying generator power up to 400 Watt and pulse duration up to 8 s. The measurement of field distribution revealed a physical focal size of 32 x 4 mm. Sharp demarcation between coagulation necrosis and intact tissue was observed in our tissue model. Lesion size was kept under control by variation of both generator power and impulse duration. At a constant impulse duration of 2 s, generator power of 100 W remained below the threshold doses for induction of a reproducible lesion. An increase in power up to 200 W and 400 W, respectively, induced lesions with diameters up to 11.2 x 3 mm. Constant total energy (generator power x impulse duration) led to a larger lesion size under higher generator power. It is possible to induce sharply demarcated, reproducible thermonecrosis, which can be regulated by generator power and impulse duration, by means of a cylindrical piezo element with a paraboloid reflector at a focal distance of 10 cm. The variation of generator power was an especially suitable control parameter for the inducement of a defined lesion size.

The blood-brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates--evidence from in vivo neuroimaging studies

DEFF Research Database (Denmark)

Astradsson, Arnar; Jenkins, Bruce G; Choi, Ji-Kyung

2009-01-01

It has been suggested, based on rodent studies, that levodopa (L-dopa) induced dyskinesia is associated with a disrupted blood-brain barrier (BBB). We have investigated BBB integrity with in vivo neuroimaging techniques in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned primates...

Streaming flow from ultrasound contrast agents by acoustic waves in a blood vessel model.

Science.gov (United States)

Cho, Eunjin; Chung, Sang Kug; Rhee, Kyehan

2015-09-01

To elucidate the effects of streaming flow on ultrasound contrast agent (UCA)-assisted drug delivery, streaming velocity fields from sonicated UCA microbubbles were measured using particle image velocimetry (PIV) in a blood vessel model. At the beginning of ultrasound sonication, the UCA bubbles formed clusters and translated in the direction of the ultrasound field. Bubble cluster formation and translation were faster with 2.25MHz sonication, a frequency close to the resonance frequency of the UCA. Translation of bubble clusters induced streaming jet flow that impinged on the vessel wall, forming symmetric vortices. The maximum streaming velocity was about 60mm/s at 2.25MHz and decreased to 15mm/s at 1.0MHz for the same acoustic pressure amplitude. The effect of the ultrasound frequency on wall shear stress was more noticeable. Maximum wall shear stress decreased from 0.84 to 0.1Pa as the ultrasound frequency decreased from 2.25 to 1.0MHz. The maximum spatial gradient of the wall shear stress also decreased from 1.0 to 0.1Pa/mm. This study showed that streaming flow was induced by bubble cluster formation and translation and was stronger upon sonication by an acoustic wave with a frequency near the UCA resonance frequency. Therefore, the secondary radiant force, which is much stronger at the resonance frequency, should play an important role in UCA-assisted drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

A new brain stimulation method: Noninvasive transcranial magneto–acoustical stimulation

International Nuclear Information System (INIS)

Yuan Yi; Chen Yu-Dong; Li Xiao-Li

2016-01-01

We investigate transcranial magneto–acoustical stimulation (TMAS) for noninvasive brain neuromodulation in vivo. TMAS as a novel technique uses an ultrasound wave to induce an electric current in the brain tissue in the static magnetic field. It has the advantage of high spatial resolution and penetration depth. The mechanism of TMAS onto a neuron is analyzed by combining the TMAS principle and Hodgkin–Huxley neuron model. The anesthetized rats are stimulated by TMAS, resulting in the local field potentials which are recorded and analyzed. The simulation results show that TMAS can induce neuronal action potential. The experimental results indicate that TMAS can not only increase the amplitude of local field potentials but also enhance the effect of focused ultrasound stimulation on the neuromodulation. In summary, TMAS can accomplish brain neuromodulation, suggesting a potentially powerful noninvasive stimulation method to interfere with brain rhythms for diagnostic and therapeutic purposes. (paper)

Manipulation of Microbubble Clusters Using Focused Ultrasound

Science.gov (United States)

Matsuzaki, Hironobu; Osaki, Taichi; Kawaguchi, Kei; Unga, Johan; Ichiyanagi, Mitsuhisa; Azuma, Takashi; Suzuki, Ryo; Maruyama, Kazuo; Takagi, Shu

2017-11-01

In recent years, microbubbles (MBs) are expected to be utilized for the ultrasound drug delivery system (DDS). For the MB-DDS, it is important to establish a method of controlling bubbles and bubble clusters using ultrasound field. The objective of this study is to clarify behaviors of bubble clusters with various physical conditions. MBs in the ultrasound field are subjected to the primary Bjerknes force. The force traps MBs at the focal region of the focused ultrasound field. The trapped MBs form a bubble cluster at the region. A bubble cluster continues growing with absorbing surrounding bubbles until it reaches a maximum size beyond which it disappears from the focal region. In the present study, two kinds of MBs are used for the experiment. One is Sonazoid with average diameter of 2.6 um and resonant frequency of 5 MHz. The other is developed by Teikyo Univ., with average diameter of 1.5 um and presumed resonant frequency of 4 MHz. The bubble cluster's behaviors are analyzed using the high-speed camera. Sonazoid clusters have larger critical size than the other in every frequency, and its cluster size is inversely proportional to the ultrasound frequency, while Teikyo-bubble clusters have different tendency. These results are discussed in the presentation.

Intracranial inertial cavitation threshold and thermal ablation lesion creation using MRI-guided 220-kHz focused ultrasound surgery: preclinical investigation.

Science.gov (United States)

Xu, Zhiyuan; Carlson, Carissa; Snell, John; Eames, Matt; Hananel, Arik; Lopes, M Beatriz; Raghavan, Prashant; Lee, Cheng-Chia; Yen, Chun-Po; Schlesinger, David; Kassell, Neal F; Aubry, Jean-Francois; Sheehan, Jason

2015-01-01

In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology. Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions. Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as

Improved heating efficiency with High-Intensity Focused Ultrasound using a new ultrasound source excitation.

Science.gov (United States)

Bigelow, Timothy A

2009-01-01

High-Intensity Focused Ultrasound (HIFU) is quickly becoming one of the best methods to thermally ablate tissue noninvasively. Unlike RF or Laser ablation, the tissue can be destroyed without inserting any probes into the body minimizing the risk of secondary complications such as infections. In this study, the heating efficiency of HIFU sources is improved by altering the excitation of the ultrasound source to take advantage of nonlinear propagation. For ultrasound, the phase velocity of the ultrasound wave depends on the amplitude of the wave resulting in the generation of higher harmonics. These higher harmonics are more efficiently converted into heat in the body due to the frequency dependence of the ultrasound absorption in tissue. In our study, the generation of the higher harmonics by nonlinear propagation is enhanced by transmitting an ultrasound wave with both the fundamental and a higher harmonic component included. Computer simulations demonstrated up to a 300% increase in temperature increase compared to transmitting at only the fundamental for the same acoustic power transmitted by the source.

Mechanism of the protective effects of long chain n-alkyl glucopyranosides against ultrasound-induced cytolysis of HL-60 cells

OpenAIRE

Cheng, Jason Y.; Riesz, Peter

2007-01-01

Recently it has been shown that long chain (C5 to C8) n-alkyl glucopyranosides completely inhibit ultrasound-induced cytolysis [1]. This protective effect has possible applications in HIFU (high intensity focused ultrasound) for tumor treatment, and in ultrasound assisted drug delivery and gene therapy. n-Alkyl glucopyranosides with hexyl (5mM), heptyl (3mM), octyl (2mM) n-alkyl chains protected 100% of HL-60 cells in-vitro from 1.057 MHz ultrasound induced cytolysis under a range of conditio...

MR-guided focused ultrasound. Current and future applications; MR-gesteuerter fokussierter Ultraschall. Aktuelle und potenzielle Indikationen

Energy Technology Data Exchange (ETDEWEB)

Trumm, C.G.; Peller, M.; Clevert, D.A.; Stahl, R.; Reiser, M. [Klinikum der Ludwig-Maximilians-Universitaet Muenchen-Grosshadern, Institut fuer Klinische Radiologie, Muenchen (Germany); Napoli, A. [Sapienza Universitaet Rom, Abteilung fuer Radiologie (Department of Radiological Sciences), MRgFUS and Cardiovascular Imaging Unit, Rom (Italy); Matzko, M. [Klinikum Dachau, Abteilung fuer diagnostische und interventionelle Radiologie, Dachau (Germany)

2013-03-15

High-intensity focused ultrasound (synonyms FUS and HIFU) under magnetic resonance imaging (MRI) guidance (synonyms MRgFUS and MR-HIFU) is a completely non-invasive technology for accurate thermal ablation of a target tissue while neighboring tissues and organs are preserved. The combination of FUS with MRI for planning, (near) real-time monitoring and outcome assessment of treatment markedly enhances the safety of the procedure. The MRgFUS procedure is clinically established in particular for the treatment of symptomatic uterine fibroids, followed by palliative ablation of painful bone metastases. Furthermore, promising results have been shown for the treatment of adenomyosis, malignant tumors of the prostate, breast and liver and for various intracranial applications, such as thermal ablation of brain tumors, functional neurosurgery and transient disruption of the blood-brain barrier. (orig.) [German] MRT-gesteuerter hochintensiver fokussierter Ultraschall (MRgFUS bzw. MR-HIFU) ist ein nichtinvasives Verfahren zur praezisen Thermoablation eines Zielgewebes. Bei dieser Methode werden benachbarte Gewebe und Organe geschont. Die Kombination des fokussierten Ultraschalls (FUS) mit der MRT zwecks Planung und Monitoring (nahezu) in Echtzeit sowie zur Erfolgskontrolle von Behandlungen traegt wesentlich zur Sicherheit dieser Methode bei. MRgFUS ist klinisch v. a. zur Behandlung von symptomatischen Uterusmyomen etabliert, gefolgt von der palliativen Ablation von Knochenmetastasen. Weitere vielversprechende Anwendungsgebiete des MRgFUS sind die Adenomyose des Uterus, die Behandlung von Prostata-, Mamma- und Lebertumoren sowie der intrakranielle Einsatz. (orig.)

Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

Directory of Open Access Journals (Sweden)

Murrin L Charles

2011-03-01

Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

Fast Blood Vector Velocity Imaging using ultrasound: In-vivo examples of complex blood flow in the vascular system

DEFF Research Database (Denmark)

Hansen, Kristoffer Lindskov; Udesen, Jesper; Gran, Fredrik

2008-01-01

Conventional ultrasound methods for acquiring color flow images of the blood motion are restricted by a relatively low frame rate and angle dependent velocity estimates. The Plane Wave Excitation (PWE) method has been proposed to solve these limitations. The frame rate can be increased, and the 2-D...... vector velocity of the blood motion can be estimated. The transmitted pulse is not focused, and a full speckle image of the blood can be acquired for each emission. A 13 bit Barker code is transmitted simultaneously from each transducer element. The 2-D vector velocity of the blood is found using 2-D...... speckle tracking between segments in consecutive speckle images. The flow patterns of six bifurcations and two veins were investigated in-vivo. It was shown: 1) that a stable vortex in the carotid bulb was present opposed to other examined bifurcations, 2) that retrograde flow was present...

Integrated ultrasound and magnetic resonance imaging for simultaneous temperature and cavitation monitoring during focused ultrasound therapies.

Science.gov (United States)

Arvanitis, Costas D; McDannold, Nathan

2013-11-01

Ultrasound can be used to noninvasively produce different bioeffects via viscous heating, acoustic cavitation, or their combination, and these effects can be exploited to develop a wide range of therapies for cancer and other disorders. In order to accurately localize and control these different effects, imaging methods are desired that can map both temperature changes and cavitation activity. To address these needs, the authors integrated an ultrasound imaging array into an MRI-guided focused ultrasound (MRgFUS) system to simultaneously visualize thermal and mechanical effects via passive acoustic mapping (PAM) and MR temperature imaging (MRTI), respectively. The system was tested with an MRgFUS system developed for transcranial sonication for brain tumor ablation in experiments with a tissue mimicking phantom and a phantom-filled ex vivo macaque skull. In experiments on cavitation-enhanced heating, 10 s continuous wave sonications were applied at increasing power levels (30-110 W) until broadband acoustic emissions (a signature for inertial cavitation) were evident. The presence or lack of signal in the PAM, as well as its magnitude and location, were compared to the focal heating in the MRTI. Additional experiments compared PAM with standard B-mode ultrasound imaging and tested the feasibility of the system to map cavitation activity produced during low-power (5 W) burst sonications in a channel filled with a microbubble ultrasound contrast agent. When inertial cavitation was evident, localized activity was present in PAM and a marked increase in heating was observed in MRTI. The location of the cavitation activity and heating agreed on average after registration of the two imaging modalities; the distance between the maximum cavitation activity and focal heating was -3.4 ± 2.1 mm and -0.1 ± 3.3 mm in the axial and transverse ultrasound array directions, respectively. Distortions and other MRI issues introduced small uncertainties in the PAM�

Non-invasive treatment efficacy evaluation for high-intensity focused ultrasound therapy using magnetically induced magnetoacoustic measurement

Science.gov (United States)

Guo, Gepu; Wang, Jiawei; Ma, Qingyu; Tu, Juan; Zhang, Dong

2018-04-01

Although the application of high intensity focused ultrasound (HIFU) has been demonstrated to be a non-invasive treatment technology for tumor therapy, the real-time temperature monitoring is still a key issue in the practical application. Based on the temperature-impedance relation, a fixed-point magnetically induced magnetoacoustic measurement technology of treatment efficacy evaluation for tissue thermocoagulation during HIFU therapy is developed with a sensitive indicator of critical temperature monitoring in this study. With the acoustic excitation of a focused transducer in the magnetoacoustic tomography with the magnetic induction system, the distributions of acoustic pressure, temperature, electrical conductivity, and acoustic source strength in the focal region are simulated, and the treatment time dependences of the peak amplitude and the corresponding amplitude derivative under various acoustic powers are also achieved. It is proved that the strength peak of acoustic sources is generated by tissue thermocoagulation with a sharp conductivity variation. The peak amplitude of the transducer collected magnetoacoustic signal increases accordingly along with the increase in the treatment time under a fixed acoustic power. When the temperature in the range with the radial and axial widths of about ±0.46 mm and ±2.2 mm reaches 69 °C, an obvious peak of the amplitude derivative can be achieved and used as a sensitive indicator of the critical status of treatment efficacy. The favorable results prove the feasibility of real-time non-invasive temperature monitoring and treatment efficacy evaluation for HIFU ablation using the magnetically induced magnetoacoustic measurement, and might provide a new strategy for accurate dose control during HIFU therapy.

Ultrasound image based visual servoing for moving target ablation by high intensity focused ultrasound.

Science.gov (United States)

Seo, Joonho; Koizumi, Norihiro; Mitsuishi, Mamoru; Sugita, Naohiko

2017-12-01

Although high intensity focused ultrasound (HIFU) is a promising technology for tumor treatment, a moving abdominal target is still a challenge in current HIFU systems. In particular, respiratory-induced organ motion can reduce the treatment efficiency and negatively influence the treatment result. In this research, we present: (1) a methodology for integration of ultrasound (US) image based visual servoing in a HIFU system; and (2) the experimental results obtained using the developed system. In the visual servoing system, target motion is monitored by biplane US imaging and tracked in real time (40 Hz) by registration with a preoperative 3D model. The distance between the target and the current HIFU focal position is calculated in every US frame and a three-axis robot physically compensates for differences. Because simultaneous HIFU irradiation disturbs US target imaging, a sophisticated interlacing strategy was constructed. In the experiments, respiratory-induced organ motion was simulated in a water tank with a linear actuator and kidney-shaped phantom model. Motion compensation with HIFU irradiation was applied to the moving phantom model. Based on the experimental results, visual servoing exhibited a motion compensation accuracy of 1.7 mm (RMS) on average. Moreover, the integrated system could make a spherical HIFU-ablated lesion in the desired position of the respiratory-moving phantom model. We have demonstrated the feasibility of our US image based visual servoing technique in a HIFU system for moving target treatment. © 2016 The Authors The International Journal of Medical Robotics and Computer Assisted Surgery Published by John Wiley & Sons Ltd.

Enhancement of Toxic Substances Clearance from Blood Equvalent Solution and Human Whole Blood through High Flux Dialyzer by 1 MHz Ultrasound

Directory of Open Access Journals (Sweden)

Shiran M. B.

2017-06-01

Full Text Available Background: Hemodialysis is a process of removing waste and excess fluid from blood when kidneys cannot function efficiently. It often involves diverting blood to the filter of the dialysis machin to be cleared of toxic substances. Fouling of pores in dialysis membrane caused by adhesion of plasma protein and other toxins will reduce the efficacy of the filtre. Objective: In This study, the influence of pulsed ultrasound waves on diffusion and the prevention of fouling in the filter membrane were investigated. Material and Methods: Pulsed ultrasound waves with frequency of 1 MHz at an intensity of 1 W/cm2 was applied to the high flux (PES 130 filter. Blood and blood equivalent solutions were passed through the filter in separate experimental setups. The amount of Creatinine, Urea and Inulin cleared from both blood equvalent solution and human whole blood passed through High Flux (PES 130 filter were measured in the presence and absence of ultrasound irradiation. Samples were taken from the outlet of the dialyzer every five minutes and the clearance of each constituent was calculated. Results: Statistical analysis of the blood equvalent solution and whole blood indicated the clearance of Urea and Inulin in the presence of ultrasound increased (p<0.05, while no significant effects were observed for Creatinine. Conclusion: It may be concluded that ultrasound, as a mechanical force, can increase the rate of clearance of some toxins (such as middle and large molecules in the hemodialysis process.

Enhancement of Toxic Substances Clearance from Blood Equvalent Solution and Human Whole Blood through High Flux Dialyzer by 1 MHz Ultrasound

Science.gov (United States)

Shiran, M.B.; Barzegar Marvasti, M.; Shakeri-Zadeh, A.; Shahidi, M.; Tabkhi, N.; Farkhondeh, F.; Kalantar, E.; Asadinejad, A.

2017-01-01

Background: Hemodialysis is a process of removing waste and excess fluid from blood when kidneys cannot function efficiently. It often involves diverting blood to the filter of the dialysis machin to be cleared of toxic substances. Fouling of pores in dialysis membrane caused by adhesion of plasma protein and other toxins will reduce the efficacy of the filtre. Objective: In This study, the influence of pulsed ultrasound waves on diffusion and the prevention of fouling in the filter membrane were investigated. Material and Methods: Pulsed ultrasound waves with frequency of 1 MHz at an intensity of 1 W/cm2 was applied to the high flux (PES 130) filter. Blood and blood equivalent solutions were passed through the filter in separate experimental setups. The amount of Creatinine, Urea and Inulin cleared from both blood equvalent solution and human whole blood passed through High Flux (PES 130) filter were measured in the presence and absence of ultrasound irradiation. Samples were taken from the outlet of the dialyzer every five minutes and the clearance of each constituent was calculated. Results: Statistical analysis of the blood equvalent solution and whole blood indicated the clearance of Urea and Inulin in the presence of ultrasound increased (p<0.05), while no significant effects were observed for Creatinine. Conclusion: It may be concluded that ultrasound, as a mechanical force, can increase the rate of clearance of some toxins (such as middle and large molecules) in the hemodialysis process. PMID:28580332

Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit.

Science.gov (United States)

Banks, William A; Gray, Alicia M; Erickson, Michelle A; Salameh, Therese S; Damodarasamy, Mamatha; Sheibani, Nader; Meabon, James S; Wing, Emily E; Morofuji, Yoichi; Cook, David G; Reed, May J

2015-11-25

Disruption of the blood-brain barrier (BBB) occurs in many diseases and is often mediated by inflammatory and neuroimmune mechanisms. Inflammation is well established as a cause of BBB disruption, but many mechanistic questions remain. We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in mice. BBB disruption was measured using (14)C-sucrose and radioactively labeled albumin. Brain cytokine responses were measured using multiplex technology and dependence on cyclooxygenase (COX) and oxidative stress determined by treatments with indomethacin and N-acetylcysteine. Astrocyte and microglia/macrophage responses were measured using brain immunohistochemistry. In vitro studies used Transwell cultures of primary brain endothelial cells co- or tri-cultured with astrocytes and pericytes to measure effects of LPS on transendothelial electrical resistance (TEER), cellular distribution of tight junction proteins, and permeability to (14)C-sucrose and radioactive albumin. In comparison to LPS-induced weight loss, the BBB was relatively resistant to LPS-induced disruption. Disruption occurred only with the highest dose of LPS and was most evident in the frontal cortex, thalamus, pons-medulla, and cerebellum with no disruption in the hypothalamus. The in vitro and in vivo patterns of LPS-induced disruption as measured with (14)C-sucrose, radioactive albumin, and TEER suggested involvement of both paracellular and transcytotic pathways. Disruption as measured with albumin and (14)C-sucrose, but not TEER, was blocked by indomethacin. N-acetylcysteine did not affect disruption. In vivo, the measures of neuroinflammation induced by LPS were mainly not reversed by indomethacin. In vitro, the effects on LPS and indomethacin were not altered when brain endothelial cells (BECs) were cultured with astrocytes or pericytes. The BBB is relatively resistant to LPS-induced disruption with some brain regions more vulnerable than others. LPS-induced disruption appears is

General Ultrasound Imaging

Medline Plus

Full Text Available ... that allows the physician to see and evaluate blood flow through arteries and veins in the abdomen, arms, legs, neck and/or brain (in infants and children) or within various body organs such as the liver or kidneys. There are three types of Doppler ultrasound: Color Doppler uses a computer ...

Review of magnetic resonance-guided focused ultrasound in the treatment of uterine fibroids

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Pedro Felipe Magalhães Peregrino

Full Text Available Uterine leiomyoma is the most frequently occurring solid pelvic tumor in women during the reproductive period. Magnetic resonance-guided high-intensity focused ultrasound is a promising technique for decreasing menorrhagia and dysmenorrhea in symptomatic women. The aim of this study is to review the role of Magnetic resonance-guided high-intensity focused ultrasound in the treatment of uterine fibroids in symptomatic patients. We performed a review of the MEDLINE and Cochrane databases up to April 2016. The analysis and data collection were performed using the following keywords: Leiomyoma, High-Intensity Focused Ultrasound Ablation, Ultrasonography, Magnetic Resonance Imaging, Menorrhagia. Two reviewers independently performed a quality assessment; when there was a disagreement, a third reviewer was consulted. Nineteen studies of Magnetic resonance-guided high-intensity focused ultrasound-treated fibroid patients were selected. The data indicated that tumor size was reduced and that symptoms were improved after treatment. There were few adverse effects, and they were not severe. Some studies have reported that in some cases, additional sessions of Magnetic resonance-guided high-intensity focused ultrasound or other interventions, such as myomectomy, uterine artery embolization or even hysterectomy, were necessary. This review suggests that Magnetic resonance-guided high-intensity focused ultrasound is a safe and effective technique. However, additional evidence from future studies will be required before the technique can be recommended as an alternative treatment for fibroids.

Simultaneous acoustic stimulation of human primary and secondary somatosensory cortices using transcranial focused ultrasound.

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Lee, Wonhye; Chung, Yong An; Jung, Yujin; Song, In-Uk; Yoo, Seung-Schik

2016-10-26

Transcranial focused ultrasound (FUS) is gaining momentum as a novel non-invasive brain stimulation method, with promising potential for superior spatial resolution and depth penetration compared to transcranial magnetic stimulation or transcranial direct current stimulation. We examined the presence of tactile sensations elicited by FUS stimulation of two separate brain regions in humans-the primary (SI) and secondary (SII) somatosensory areas of the hand, as guided by individual-specific functional magnetic resonance imaging data. Under image-guidance, acoustic stimulations were delivered to the SI and SII areas either separately or simultaneously. The SII areas were divided into sub-regions that are activated by four types of external tactile sensations to the palmar side of the right hand-vibrotactile, pressure, warmth, and coolness. Across the stimulation conditions (SI only, SII only, SI and SII simultaneously), participants reported various types of tactile sensations that arose from the hand contralateral to the stimulation, such as the palm/back of the hand or as single/neighboring fingers. The type of tactile sensations did not match the sensations that are associated with specific sub-regions in the SII. The neuro-stimulatory effects of FUS were transient and reversible, and the procedure did not cause any adverse changes or discomforts in the subject's mental/physical status. The use of multiple FUS transducers allowed for simultaneous stimulation of the SI/SII in the same hemisphere and elicited various tactile sensations in the absence of any external sensory stimuli. Stimulation of the SII area alone could also induce perception of tactile sensations. The ability to stimulate multiple brain areas in a spatially restricted fashion can be used to study causal relationships between regional brain activities and their cognitive/behavioral outcomes.

Effect of Exercise Intensity on Neurotrophic Factors and Blood-Brain Barrier Permeability Induced by Oxidative-Nitrosative Stress in Male College Students.

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Roh, Hee-Tae; Cho, Su-Youn; Yoon, Hyung-Gi; So, Wi-Young

2017-06-01

We investigated the effects of aerobic exercise intensity on oxidative-nitrosative stress, neurotrophic factor expression, and blood-brain barrier (BBB) permeability. Fifteen healthy men performed treadmill running under low-intensity (LI), moderate-intensity (MI), and high-intensity (HI) conditions. Blood samples were collected immediately before exercise (IBE), immediately after exercise (IAE), and 60 min after exercise (60MAE) to examine oxidative-nitrosative stress (reactive oxygen species [ROS]; nitric oxide [NO]), neurotrophic factors (brain-derived neurotrophic factor [BDNF]; nerve growth factor [NGF]), and blood-brain barrier (BBB) permeability (S-100β; neuron-specific enolase). ROS concentration significantly increased IAE and following HI (4.9 ± 1.7 mM) compared with that after LI (2.8 ± 1.4 mM) exercise (p exercise (p exercise (p exercise (p exercise (p .05). Moderate- and/or high-intensity exercise may induce higher oxidative-nitrosative stress than may low-intensity exercise, which can increase peripheral neurotrophic factor levels by increasing BBB permeability.

Ionizing radiation alters beta-endorphin-like immunoreactivity in brain but not blood

International Nuclear Information System (INIS)

Mickley, G.A.; Stevens, K.E.; Moore, G.H.; Deere, W.; White, G.A.; Gibbs, G.L.; Mueller, G.P.

1983-01-01

Previous behavioral and pharmacological studies have implicated endorphins in radiation-induced locomotor hyperactivity of the C57BL/6J mouse. However, the endogenous opiate(s) responsible for this behavioral change have not been identified. The present study measured beta-endorphin-like immunoreactivity (beta-END-LI) in brain, blood, and combined brain and pituitary samples from irradiated and sham-irradiated C57BL/6J mice. After radiation exposure, levels of beta-END-LI decreased significantly in the brain. A similar, but not statistically significant, decline was measured in combined brain and pituitary samples. Concentrations of blood beta-END-LI were not changed by irradiation. These radiogenic changes in beta-END-LI are in some ways similar to those observed after other stresses. However, radiation-induced locomotor hyperactivity may be mediated more by alterations of beta-END-LI in the brain than in the periphery. Other endogenous opiate systems may also contribute to this behavioral change in the C57BL/6J mouse

Ionizing radiation alters beta-endorphin-like immunoreactivity in brain but not blood

Energy Technology Data Exchange (ETDEWEB)

Mickley, G.A.; Stevens, K.E.; Moore, G.H.; Deere, W.; White, G.A.; Gibbs, G.L.; Mueller, G.P.

1983-12-01

Previous behavioral and pharmacological studies have implicated endorphins in radiation-induced locomotor hyperactivity of the C57BL/6J mouse. However, the endogenous opiate(s) responsible for this behavioral change have not been identified. The present study measured beta-endorphin-like immunoreactivity (beta-END-LI) in brain, blood, and combined brain and pituitary samples from irradiated and sham-irradiated C57BL/6J mice. After radiation exposure, levels of beta-END-LI decreased significantly in the brain. A similar, but not statistically significant, decline was measured in combined brain and pituitary samples. Concentrations of blood beta-END-LI were not changed by irradiation. These radiogenic changes in beta-END-LI are in some ways similar to those observed after other stresses. However, radiation-induced locomotor hyperactivity may be mediated more by alterations of beta-END-LI in the brain than in the periphery. Other endogenous opiate systems may also contribute to this behavioral change in the C57BL/6J mouse.

Vascular Structure Identification in Intraoperative 3D Contrast-Enhanced Ultrasound Data

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Elisee Ilunga-Mbuyamba

2016-04-01

Full Text Available In this paper, a method of vascular structure identification in intraoperative 3D Contrast-Enhanced Ultrasound (CEUS data is presented. Ultrasound imaging is commonly used in brain tumor surgery to investigate in real time the current status of cerebral structures. The use of an ultrasound contrast agent enables to highlight tumor tissue, but also surrounding blood vessels. However, these structures can be used as landmarks to estimate and correct the brain shift. This work proposes an alternative method for extracting small vascular segments close to the tumor as landmark. The patient image dataset involved in brain tumor operations includes preoperative contrast T1MR (cT1MR data and 3D intraoperative contrast enhanced ultrasound data acquired before (3D-iCEUS s t a r t and after (3D-iCEUS e n d tumor resection. Based on rigid registration techniques, a preselected vascular segment in cT1MR is searched in 3D-iCEUS s t a r t and 3D-iCEUS e n d data. The method was validated by using three similarity measures (Normalized Gradient Field, Normalized Mutual Information and Normalized Cross Correlation. Tests were performed on data obtained from ten patients overcoming a brain tumor operation and it succeeded in nine cases. Despite the small size of the vascular structures, the artifacts in the ultrasound images and the brain tissue deformations, blood vessels were successfully identified.

The Blood-Brain Barrier: Connecting the Gut and the Brain

OpenAIRE

Banks, William A.

2008-01-01

The BBB prevents the unrestricted exchange of substances between the central nervous system (CNS) and the blood. The blood-brain barrier (BBB) also conveys information between the CNS and the gastrointestinal (GI) tract through several mechanisms. Here, we review three of those mechanisms. First, the BBB selectively transports some peptides and regulatory proteins in the blood-to-brain or the brain-to-blood direction. The ability of GI hormones to affect functions of the BBB, as illustrated b...

Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response.

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Liu, Hao-Li; Hsieh, Han-Yi; Lu, Li-An; Kang, Chiao-Wen; Wu, Ming-Fang; Lin, Chun-Yen

2012-11-11

High-intensity focused-ultrasound (HIFU) has been successfully employed for thermal ablation of tumors in clinical settings. Continuous- or pulsed-mode HIFU may also induce a host antitumor immune response, mainly through expansion of antigen-presenting cells in response to increased cellular debris and through increased macrophage activation/infiltration. Here we demonstrated that another form of focused ultrasound delivery, using low-pressure, pulsed-mode exposure in the presence of microbubbles (MBs), may also trigger an antitumor immunological response and inhibit tumor growth. A total of 280 tumor-bearing animals were subjected to sonographically-guided FUS. Implanted tumors were exposed to low-pressure FUS (0.6 to 1.4 MPa) with MBs to increase the permeability of tumor microvasculature. Tumor progression was suppressed by both 0.6 and 1.4-MPa MB-enhanced FUS exposures. We observed a transient increase in infiltration of non-T regulatory (non-Treg) tumor infiltrating lymphocytes (TILs) and continual infiltration of CD8+ cytotoxic T-lymphocytes (CTL). The ratio of CD8+/Treg increased significantly and tumor growth was inhibited. Our findings suggest that low-pressure FUS exposure with MBs may constitute a useful tool for triggering an anticancer immune response, for potential cancer immunotherapy.

High-resolution ultrasound imaging and noninvasive optoacoustic monitoring of blood variables in peripheral blood vessels

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Petrov, Irene Y.; Petrov, Yuriy; Prough, Donald S.; Esenaliev, Rinat O.

2011-03-01

Ultrasound imaging is being widely used in clinics to obtain diagnostic information non-invasively and in real time. A high-resolution ultrasound imaging platform, Vevo (VisualSonics, Inc.) provides in vivo, real-time images with exceptional resolution (up to 30 microns) using high-frequency transducers (up to 80 MHz). Recently, we built optoacoustic systems for probing radial artery and peripheral veins that can be used for noninvasive monitoring of total hemoglobin concentration, oxyhemoglobin saturation, and concentration of important endogenous and exogenous chromophores (such as ICG). In this work we used the high-resolution ultrasound imaging system Vevo 770 for visualization of the radial artery and peripheral veins and acquired corresponding optoacoustic signals from them using the optoacoustic systems. Analysis of the optoacoustic data with a specially developed algorithm allowed for measurement of blood oxygenation in the blood vessels as well as for continuous, real-time monitoring of arterial and venous blood oxygenation. Our results indicate that: 1) the optoacoustic technique (unlike pure optical approaches and other noninvasive techniques) is capable of accurate peripheral venous oxygenation measurement; and 2) peripheral venous oxygenation is dependent on skin temperature and local hemodynamics. Moreover, we performed for the first time (to the best of our knowledge) a comparative study of optoacoustic arterial oximetry and a standard pulse oximeter in humans and demonstrated superior performance of the optoacoustic arterial oximeter, in particular at low blood flow.

Lifelong consumption of sodium selenite: gender differences on blood-brain barrier permeability in convulsive, hypoglycemic rats.

Science.gov (United States)

Seker, F Burcu; Akgul, Sibel; Oztas, Baria

2008-07-01

The aim of this study was to compare the effects of hypoglycemia and induced convulsions on the blood-brain barrier permeability in rats with or without lifelong administration of sodium selenite. There is a significant decrease of the blood-brain barrier permeability in three brain regions of convulsive, hypoglycemic male rats treated with sodium selenite when compared to sex-matched untreated rats (p0.05). The blood-brain barrier permeability of the left and right hemispheres of untreated, moderately hypoglycemic convulsive rats of both genders was better than their untreated counterparts (peffect against blood-brain barrier permeability during convulsions and that the effects of sodium selenite are gender-dependent.

Evans blue dye-enhanced imaging of the brain microvessels using spectral focusing coherent anti-Stokes Raman scattering microscopy.

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Bo-Ram Lee

Full Text Available We performed dye-enhanced imaging of mouse brain microvessels using spectral focusing coherent anti-Stokes Raman scattering (SF-CARS microscopy. The resonant signals from C-H stretching in forward CARS usually show high background intensity in tissues, which makes CARS imaging of microvessels difficult. In this study, epi-detection of back-scattered SF-CARS signals showed a negligible background, but the overall intensity of resonant CARS signals was too low to observe the network of brain microvessels. Therefore, Evans blue (EB dye was used as contrasting agent to enhance the back-scattered SF-CARS signals. Breakdown of brain microvessels by inducing hemorrhage in a mouse was clearly visualized using backward SF-CARS signals, following intravenous injection of EB. The improved visualization of brain microvessels with EB enhanced the sensitivity of SF-CARS, detecting not only the blood vessels themselves but their integrity as well in the brain vasculature.

Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.

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Carnevale, Daniela; Mascio, Giada; D'Andrea, Ivana; Fardella, Valentina; Bell, Robert D; Branchi, Igor; Pallante, Fabio; Zlokovic, Berislav; Yan, Shirley Shidu; Lembo, Giuseppe

2012-07-01

Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer disease, such as amyloid plaques, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer disease of hypertensive mice. We focused on receptor for advanced glycation end products (RAGE) that critically regulates Aβ transport at the blood-brain barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE upregulation in brain vessels of the cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease.

Nanoparticle transport across the blood brain barrier.

Science.gov (United States)

Grabrucker, Andreas M; Ruozi, Barbara; Belletti, Daniela; Pederzoli, Francesca; Forni, Flavio; Vandelli, Maria Angela; Tosi, Giovanni

2016-01-01

While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.

Science.gov (United States)

Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam; Castro, Kamilah; Zhang, Jingya; Asp, Linnea; Loo, Hannah; Laitman, Benjamin M; Mariani, John N; Straus Farber, Rebecca; Zaslavsky, Elena; Nudelman, German; Raine, Cedric S; John, Gareth R

2015-06-01

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an

Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

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Redzic Zoran

2011-01-01

Full Text Available Abstract Efficient processing of information by the central nervous system (CNS represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB, which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF barrier (BCSFB, which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC transport proteins at those two barriers and underlines

Novel Cranial Implants of Yttria-Stabilized Zirconia as Acoustic Windows for Ultrasonic Brain Therapy.

Science.gov (United States)

Gutierrez, Mario I; Penilla, Elias H; Leija, Lorenzo; Vera, Arturo; Garay, Javier E; Aguilar, Guillermo

2017-11-01

Therapeutic ultrasound can induce changes in tissues by means of thermal and nonthermal effects. It is proposed for treatment of some brain pathologies such as Alzheimer's, Parkinson's, Huntington's diseases, and cancer. However, cranium highly absorbs ultrasound reducing transmission efficiency. There are clinical applications of transcranial focused ultrasound and implantable ultrasound transducers proposed to address this problem. In this paper, biocompatible materials are proposed for replacing part of the cranium (cranial implants) based on low porosity polycrystalline 8 mol% yttria-stabilized-zirconia (8YSZ) ceramics as acoustic windows for brain therapy. In order to assess the viability of 8YSZ implants to effectively transmit ultrasound, various 8YSZ ceramics with different porosity are tested; their acoustic properties are measured; and the results are validated using finite element models simulating wave propagation to brain tissue through 8YSZ windows. The ultrasound attenuation is found to be linearly dependent on ceramics' porosity. Results for the nearly pore-free case indicate that 8YSZ is highly effective in transmitting ultrasound, with overall maximum transmission efficiency of ≈81%, compared to near total absorption of cranial bone. These results suggest that 8YSZ polycrystals could be suitable acoustic windows for ultrasound brain therapy at 1 MHz. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Methamphetamine Effects on Blood-Brain Barrier Structure and Function

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Nicole Alia Northrop

2015-03-01

Full Text Available Methamphetamine (Meth is a widely abuse psychostimulant. Traditionally, studies have focused on the neurotoxic effects of Meth on monoaminergic neurotransmitter terminals. Recently, both in vitro and in vivo studies have investigated the effects of Meth on the BBB and found that Meth produces a decrease in BBB structural proteins and an increase in BBB permeability to various molecules. Moreover, preclinical studies are validated by clinical studies in which human Meth users have increased concentrations of toxins in the brain. Therefore, this review will focus on the structural and functional disruption of the BBB caused by Meth and the mechanisms that contribute to Meth-induced BBB disruption. The review will reveal that the mechanisms by which Meth damages dopamine and serotonin terminals are similar to the mechanisms by which the blood-brain barrier (BBB is damaged. Furthermore, this review will cover the factors that are known to potentiate the effects of Meth on the BBB, such as stress and HIV, both of which are co-morbid conditions associated with Meth abuse. Overall, the goal of this review is to demonstrate that the scope of damage produced by Meth goes beyond damage to monoaminergic neurotransmitter systems to include BBB disruption as well as provide a rationale for investigating therapeutics to treat Meth-induced BBB disruption. Since a breach of the BBB can have a multitude of consequences, therapies directed towards the treatment of BBB disruption may help to ameliorate the long-term neurodegeneration and cognitive deficits produced by Meth and possibly even Meth addiction.

Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders

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Qingying Meng

2017-02-01

Full Text Available The complexity of the traumatic brain injury (TBI pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing, and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.

Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances.

Science.gov (United States)

Doolittle, Nancy D; Muldoon, Leslie L; Culp, Aliana Y; Neuwelt, Edward A

2014-01-01

The blood-brain barrier (BBB) limits drug delivery to brain tumors. We utilize intraarterial infusion of hyperosmotic mannitol to reversibly open the BBB by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain. Our preclinical studies have optimized the BBB disruption (BBBD) technique and clinical studies have shown its safety and efficacy. The delivery of methotrexate-based chemotherapy in conjunction with BBBD provides excellent outcomes in primary central nervous system lymphoma (PCNSL) including stable or improved cognitive function in survivors a median of 12 years (range 2-26 years) after diagnosis. The addition of rituximab to chemotherapy with BBBD for PCNSL can be safely accomplished with excellent overall survival. Our translational studies of thiol agents to protect against platinum-induced toxicities led to the development of a two-compartment model in brain tumor patients. We showed that delayed high-dose sodium thiosulfate protects against carboplatin-induced hearing loss, providing the framework for large cooperative group trials of hearing chemoprotection. Neuroimaging studies have identified that ferumoxytol, an iron oxide nanoparticle blood pool agent, appears to be a superior contrast agent to accurately assess therapy-induced changes in brain tumor vasculature, in brain tumor response to therapy, and in differentiating central nervous system lesions with inflammatory components. This chapter reviews the breakthroughs, challenges, and future directions for BBBD. © 2014 Elsevier Inc. All rights reserved.

Intensity dependence of focused ultrasound lesion position

Science.gov (United States)

Meaney, Paul M.; Cahill, Mark D.; ter Haar, Gail R.

1998-04-01

Knowledge of the spatial distribution of intensity loss from an ultrasonic beam is critical to predicting lesion formation in focused ultrasound surgery. To date most models have used linear propagation models to predict the intensity profiles needed to compute the temporally varying temperature distributions. These can be used to compute thermal dose contours that can in turn be used to predict the extent of thermal damage. However, these simulations fail to adequately describe the abnormal lesion formation behavior observed for in vitro experiments in cases where the transducer drive levels are varied over a wide range. For these experiments, the extent of thermal damage has been observed to move significantly closer to the transducer with increasing transducer drive levels than would be predicted using linear propagation models. The simulations described herein, utilize the KZK (Khokhlov-Zabolotskaya-Kuznetsov) nonlinear propagation model with the parabolic approximation for highly focused ultrasound waves, to demonstrate that the positions of the peak intensity and the lesion do indeed move closer to the transducer. This illustrates that for accurate modeling of heating during FUS, nonlinear effects must be considered.

Enhancement of High-Intensity Focused Ultrasound Heating by Short-Pulse Generated Cavitation

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Shin Yoshizawa

2017-03-01

Full Text Available A target tissue can be thermally coagulated in high-intensity focused ultrasound (HIFU treatment noninvasively. HIFU thermal treatments have been clinically applied to various solid tumors. One of the problems in HIFU treatments is a long treatment time. Acoustically driven microbubbles can accelerate the ultrasonic heating, resulting in the significant reduction of the treatment time. In this paper, a method named “trigger HIFU exposure” which employs cavitation microbubbles is introduced and its results are reviewed. A trigger HIFU sequence consists of high-intensity short pulses followed by moderate-intensity long bursts. Cavitation bubbles induced in a multiple focal regions by rapidly scanning the focus of high-intensity pulses enhanced the temperature increase significantly and produced a large coagulation region with high efficiency.

Lead poisoning and the blood-brain barrier

International Nuclear Information System (INIS)

Hertz, M.H.; Bolwig, T.G.; Grandjean, P.; Westergaard, E.

1981-01-01

Lead exposure may produce varying degrees of neuropsychiatric manifestations from discrete phenomena, quite often seen in children and as an occupational disease, to the rare fulminant lead encephalopathy. It was determined whether or not damage of the blood-brain barrier permeability in adult rats, as has been demonstr rated in neonatal animals exposed to lead, could also play a role. Massive lead exposure did not induce any change in the transfer (facilitated diffusion) of phenylalanine and tyrosine measured by means of the indicator dilution technique. Ultrastructural examination, after application of horseradish peroxidase, did not reveal any pahtological changes in the permeability to the tracer. It is concluded that in adult rats, in contrast to neonatal anmials, the observed pathological signs clearly seen in the chronically exposed animals must be ascribed to a noxious influence of lead on the extravascular side of the blood-brain barrier. (author)

Focused ultrasound for treatment of uterine myoma: From experimental model to clinical practice

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Terzić Milan

2008-01-01

Full Text Available It is well known that focused ultrasound has a biologic effect on tissue. High intensity focused ultrasound (HIFU on a small target area raises the temperature of the tissue enough to denaturate proteins and cause irreversible cell damage. The tight focus of the ultrasound energy allows delivery of the intended dose to a very precise location. The resulting coagulation necrosis is relatively painless. The application of this method in the human clinical setting has required pilot studies on an animal model. Although the treatment had a high success rate, there was a significant percentage of complications, mainly attributed to the technical drawbacks of the procedure. Therefore, this method has been modified for use in humans, and the HIFU is now guided, monitored and controlled by magnetic resonance imaging (MRI. In October 2004, Food and Drug Adiministration (FDA approved MRI guided focused ultrasound treatment of uterine fibroids in humans. Since then, successful treatment of uterine myomas by HIFU has been performed in thousands of women.

Glutamate Transporters in the Blood-Brain Barrier

DEFF Research Database (Denmark)

Helms, Hans Christian Cederberg; Nielsen, Carsten Uhd; Waagepetersen, Helle S

2017-01-01

concentration of L-glutamate causes excitotoxicity. A tight control of the brain interstitial fluid L-glutamate levels is therefore imperative, in order to maintain optimal neurotransmission and to avoid such excitotoxicity. The blood-brain barrier, i.e., the endothelial lining of the brain capillaries...... cells. The mechanisms underlying transendothelial L-glutamate transport are however still not well understood. The present chapter summarizes the current knowledge on blood-brain barrier L-glutamate transporters and the suggested pathways for the brain-to-blood L-glutamate efflux......., regulates the exchange of nutrients, gases, and metabolic waste products between plasma and brain interstitial fluid. It has been suggested that brain capillary endothelial cells could play an important role in L-glutamate homeostasis by mediating brain-to-blood L-glutamate efflux. Both in vitro and in vivo...

Blood-brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood-central nervous system interface.

Science.gov (United States)

Phan, Duc Tt; Bender, R Hugh F; Andrejecsk, Jillian W; Sobrino, Agua; Hachey, Stephanie J; George, Steven C; Hughes, Christopher Cw

2017-11-01

The blood-brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood-brain barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer's disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface. Current research relies heavily on animal models (mostly mice) or on two-dimensional (2D) in vitro models, neither of which fully capture the complexities of the human blood-brain barrier. Physiological differences between humans and mice make translation to the clinic problematic, while monolayer cultures cannot capture the inherently three-dimensional (3D) nature of the blood-brain barrier, which includes close association of the abluminal side of the endothelium with astrocyte foot-processes and pericytes. Here we discuss the central nervous system diseases associated with blood-brain barrier pathology, recent advances in the development of novel 3D blood-brain barrier -on-a-chip systems that better mimic the physiological complexity and structure of human blood-brain barrier, and provide an outlook on how these blood-brain barrier-on-a-chip systems can be used for central nervous system disease modeling. Impact statement The field of microphysiological systems is rapidly evolving as new technologies are introduced and our understanding of organ physiology develops. In this review, we focus on Blood-Brain Barrier (BBB) models, with a particular emphasis on how they relate to neurological disorders such as Alzheimer's disease, multiple sclerosis, stroke, cancer, and vascular malformations. We emphasize the importance of capturing the three-dimensional nature of the brain and the unique architecture of the BBB - something that until recently

A Numerical Investigation of the Time Reversal Mirror Technique for Trans-skull Brain Cancer Ultrasound Surgery

Directory of Open Access Journals (Sweden)

H. Zahedmanesh

2007-06-01

Full Text Available Introduction: The medical applications of ultrasound on human brain are highly limited by the phase and amplitude aberrations induced by the heterogeneities of the skull. However, it has been shown that time reversing coupled with amplitude compensation can overcome these aberrations. In this work, a model for 2D simulation of the time reversal mirror technique is proposed to study the possibility of targeting any point within the brain without the need for craniotomy and to calculate the acoustic pressure field and the resulting temperature distribution within the skull and brain during a High Intensity Focused Ultrasound (HIFU transcranial therapy. Materials and Methods: To overcome the sensitivity of the wave pattern to the heterogeneous geometry of the skull, a real MRI derived 2D model is constructed. The model should include the real geometry of brain and skull. The model should also include the couplant medium which has the responsibility of coupling the transducer to the skull for the penetration of ultrasound. The clinical substance used as the couplant is water. The acoustic and thermal parameters are derived from the references. Next, the wave propagation through the skull is computed based on the Helmholtz equation, with a 2D finite element analysis. The acoustic simulation is combined with a 2D thermal diffusion analysis based on Pennes Bioheat equation and the temperature elevation inside the skull and brain is computed. The numerical simulations were performed using the FEMLAB 3.2 software on a PC having 8 GB RAM and a 2.4 MHz dual CPU. Results: It is seen that the ultrasonic waves are exactly focalized at the location where the hydrophone has been previously implanted. There is no penetration into the sinuses and the waves are reflected from their surface because of the high discrepancy between the speed of sound in bone and air.  Under the focal pressure of 2.5 MPa and after 4 seconds of sonication the temperature at the focus

High-intensity focused ultrasound for ex vivo kidney tissue ablation: influence of generator power and pulse duration.

Science.gov (United States)

Häcker, Axel; Köhrmann, Kai Uwe; Knoll, Thomas; Langbein, Sigrun; Steidler, Annette; Kraut, Oliver; Marlinghaus, Ernst; Alken, Peter; Michel, Maurice Stephan

2004-11-01

The therapeutic application of noninvasive tissue ablation by high-intensity focused ultrasound (HIFU) requires precise physical definition of the focal size and determination of control parameters. The objective of this study was to measure the extent of ex-vivo porcine kidney tissue ablation at variable generator parameters and to identify parameters to control lesion size. The ultrasound waves generated by a cylindrical piezoceramic element (1.04 MHz) were focused at a depth of 100 mm using a parabolic reflector (diameter 100 mm). A needle hydrophone was used to measure the field distribution of the sound pressure. The morphology and extent of tissue necrosis were examined at generator powers of up to 400 W (P(el)) and single pulse durations of as long as 8 seconds. The two-dimensional field distribution resulted in an approximately ellipsoidal focus of 32 x 4 mm (-6 dB). A sharp demarcation between coagulation necrosis and intact tissue was observed. Lesion size was controlled by both the variation of generator power and the pulse duration. At a constant pulse duration of 2 seconds, a generator power of 100 W remained below the threshold doses for inducing a reproducible lesion. An increase in power to as high as 400 W induced lesions with average dimensions of as much as 11.2 x 3 mm. At constant total energy (generator power x pulse duration), lesion size increased at higher generator power. This ultrasound generator can induce defined and reproducible necrosis in ex-vivo kidney tissue. Lesion size can be controlled by adjusting the generator power and pulse duration. Generator power, in particular, turned out to be a suitable control parameter for obtaining a lesion of a defined size.

Simulation Based Investigation of Focusing Phased Array Ultrasound in Dissimilar Metal Welds

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Hun-Hee Kim

2016-02-01

Full Text Available Flaws at dissimilar metal welds (DMWs, such as reactor coolant systems components, Control Rod Drive Mechanism (CRDM, Bottom Mounted Instrumentation (BMI etc., in nuclear power plants have been found. Notably, primary water stress corrosion cracking (PWSCC in the DMWs could cause significant reliability problems at nuclear power plants. Therefore, phased array ultrasound is widely used for inspecting surface break cracks and stress corrosion cracks in DMWs. However, inspection of DMWs using phased array ultrasound has a relatively low probability of detection of cracks, because the crystalline structure of welds causes distortion and splitting of the ultrasonic beams which propagates anisotropic medium. Therefore, advanced evaluation techniques of phased array ultrasound are needed for improvement in the probability of detection of flaws in DMWs. Thus, in this study, an investigation of focusing and steering phased array ultrasound in DMWs was carried out using a time reversal technique, and an adaptive focusing technique based on finite element method (FEM simulation. Also, evaluation of focusing performance of three different focusing techniques was performed by comparing amplitude of phased array ultrasonic signals scattered from the targeted flaw with three different time delays.

Magnetic resonance imaging of cold injury-induced brain edema in rats

International Nuclear Information System (INIS)

Houkin, Kiyohiro; Abe, Hiroshi; Hashiguchi, Yuji; Seri, Shigemi.

1996-01-01

The chronological changes of blood-brain barrier disruption, and diffusion and absorption of edema fluid were investigated in rats with cold-induced brain injury (vasogenic edema) using magnetic resonance imaging. Contrast medium was administered intravenously at 3 and 24 hours after lesioning as a tracer of edema fluid. Serial T 1 -weighted multiple-slice images were obtained for 180 minutes after contrast administration. Disruption of the blood-brain barrier was more prominent at 24 hours after lesioning than at 3 hours. Contrast medium leaked from the periphery of the injury and gradually diffused to the center of the lesion. Contrast medium diffused into the corpus callosum and the ventricular system (cerebrospinal fluid). Disruption of the blood-brain barrier induced by cold injury was most prominent at the periphery of the vasogenic edema. Edema fluid subsequently extended into the center of the lesion and was also absorbed by the ventricular system. Magnetic resonance imaging is a useful method to assess the efficacy of therapy for vasogenic edema. (author)

Application of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood-brain barrier: mechanisms of brain clearing

Science.gov (United States)

Semyachkina-Glushkovskaya, Oxana; Abdurashitov, Arkady; Dubrovsky, Alexander; Bragin, Denis; Bragina, Olga; Shushunova, Nataliya; Maslyakova, Galina; Navolokin, Nikita; Bucharskaya, Alla; Tuchin, Valery; Kurths, Juergen; Shirokov, Alexander

2017-12-01

The meningeal lymphatic vessels were discovered 2 years ago as the drainage system involved in the mechanisms underlying the clearance of waste products from the brain. The blood-brain barrier (BBB) is a gatekeeper that strongly controls the movement of different molecules from the blood into the brain. We know the scenarios during the opening of the BBB, but there is extremely limited information on how the brain clears the substances that cross the BBB. Here, using the model of sound-induced opening of the BBB, we clearly show how the brain clears dextran after it crosses the BBB via the meningeal lymphatic vessels. We first demonstrate successful application of optical coherence tomography (OCT) for imaging of the lymphatic vessels in the meninges after opening of the BBB, which might be a new useful strategy for noninvasive analysis of lymphatic drainage in daily clinical practice. Also, we give information about the depth and size of the meningeal lymphatic vessels in mice. These new fundamental data with the applied focus on the OCT shed light on the mechanisms of brain clearance and the role of lymphatic drainage in these processes that could serve as an informative platform for a development of therapy and diagnostics of diseases associated with injuries of the BBB such as stroke, brain trauma, glioma, depression, or Alzheimer disease.

Spatial filters for focusing ultrasound images

DEFF Research Database (Denmark)

Jensen, Jørgen Arendt; Gori, Paola

2001-01-01

, but the approach always yields point spread functions better or equal to a traditional dynamically focused image. Finally, the process was applied to in-vivo clinical images of the liver and right kidney from a 28 years old male. The data was obtained with a single element transducer focused at 100 mm....... A new method for making spatial matched filter focusing of RF ultrasound data is proposed based on the spatial impulse response description of the imaging. The response from a scatterer at any given point in space relative to the transducer can be calculated, and this gives the spatial matched filter...... for synthetic aperture imaging for single element transducers. It is evaluated using the Field II program. Data from a single 3 MHz transducer focused at a distance of 80 mm is processed. Far from the transducer focal region, the processing greatly improves the image resolution: the lateral slice...

The Blood-Brain Barrier: An Engineering Perspective

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Andrew eWong

2013-08-01

Full Text Available It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich’s first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and it remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore advances in our understanding of the structure and function of the blood-brain barrier are key to advances in treatment of a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

The effect of ultrasound on arterial blood flow: 1. Steady fully developed flow

International Nuclear Information System (INIS)

Bestman, A.R.

1990-12-01

The paper models the effects of ultrasound heating of the tissues and the resultant perturbation on blood flow in the arteries and veins. It is assumed that the blood vessel is rigid and the undisturbed flow is fully developed. Acoustical perturbation on this Poiseuille flow, for the general three-dimensional flow with heat transfer in an infinitely long pipe is considered. Closed form analytical solutions are obtained to the problem. It is discovered that the effects of the ultrasound heating are concentrated at the walls of the blood vessels. (author). 4 refs

Tanscranial Threshold of Inertial Cavitation Induced by Diagnosticc Ultrasound and Microbubbles

NARCIS (Netherlands)

Liu, J.; Gao, S.; Porter, T.R.; Everbach, C; Shi, W.; Vignon, F.; Powers, J.; Lof, J.; Turner, J.; Xie, F.

2011-01-01

Background: Inertial cavitation may cause hazardous bioeffects whileusing ultrasound and microbubble mediated thrombolysis. The purposeof this study was to investigate the influence of ultrasound pulselength and temporal bone on inertial cavitation thresholds within the brain utilizing transtemporal

Endothelial Proliferation and Increased Blood - Brain Barrier Permeability in the Basal Ganglia in a Rat Model of 3,4-Dihydrozyphenyl-L-Alanine-Induced Dyskinesia

DEFF Research Database (Denmark)

Westin, Jenny E.; Lindgren, Hanna S.; Gardi, Jonathan Eyal

2006-01-01

3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia is associated with molecular and synaptic plasticity in the basal ganglia, but the occurrence of structural remodeling through cell genesis has not been explored. In this study, rats with 6-hydroxydopamine lesions received injections of th...... of angiogenesis and blood-brain barrier dysfunction in an experimental model of L-DOPA-induced dyskinesia. These microvascular changes are likely to affect the kinetics of L-DOPA entry into the brain, favoring the occurrence of motor complications....... dyskinesia. The vast majority (60-80%) of the newborn cells stained positively for endothelial markers. This endothelial proliferation was associated with an upregulation of immature endothelial markers (nestin) and a downregulation of endothelial barrier antigen on blood vessel walls. In addition......, dyskinetic rats exhibited a significant increase in total blood vessel length and a visible extravasation of serum albumin in the two structures in which endothelial proliferation was most pronounced (substantia nigra pars reticulata and entopeduncular nucleus). The present study provides the first evidence...

Drug Release from Phase-Changeable Nanodroplets Triggered by Low-Intensity Focused Ultrasound

Science.gov (United States)

Cao, Yang; Chen, Yuli; Yu, Tao; Guo, Yuan; Liu, Fengqiu; Yao, Yuanzhi; Li, Pan; Wang, Dong; Wang, Zhigang; Chen, Yu; Ran, Haitao

2018-01-01

Background: As one of the most effective triggers with high tissue-penetrating capability and non-invasive feature, ultrasound shows great potential for controlling the drug release and enhancing the chemotherapeutic efficacy. In this study, we report, for the first time, construction of a phase-changeable drug-delivery nanosystem with programmable low-intensity focused ultrasound (LIFU) that could trigger drug-release and significantly enhance anticancer drug delivery. Methods: Liquid-gas phase-changeable perfluorocarbon (perfluoropentane) and an anticancer drug (doxorubicin) were simultaneously encapsulated in two kinds of nanodroplets. By triggering LIFU, the nanodroplets could be converted into microbubbles locally in tumor tissues for acoustic imaging and the loaded anticancer drug (doxorubicin) was released after the microbubble collapse. Based on the acoustic property of shell materials, such as shell stiffness, two types of nanodroplets (lipid-based nanodroplets and PLGA-based nanodroplets) were activated by different acoustic pressure levels. Ultrasound irradiation duration and power of LIFU were tested and selected to monitor and control the drug release from nanodroplets. Various ultrasound energies were introduced to induce the phase transition and microbubble collapse of nanodroplets in vitro (3 W/3 min for lipid nanodroplets; 8 W/3 min for PLGA nanodroplets). Results: We detected three steps in the drug-releasing profiles exhibiting the programmable patterns. Importantly, the intratumoral accumulation and distribution of the drug with LIFU exposure were significantly enhanced, and tumor proliferation was substantially inhibited. Co-delivery of two drug-loaded nanodroplets could overcome the physical barriers of tumor tissues during chemotherapy. Conclusion: Our study provides a new strategy for the efficient ultrasound-triggered chemotherapy by nanocarriers with programmable LIFU capable of achieving the on-demand drug release. PMID:29507623

Brain blood flow and blood pressure during hypoxia in the epaulette shark Hemiscyllium ocellatum, a hypoxia-tolerant elasmobranch.

Science.gov (United States)

Söderström, V; Renshaw, G M; Nilsson, G E

1999-04-01

The key to surviving hypoxia is to protect the brain from energy depletion. The epaulette shark (Hemiscyllium ocellatum) is an elasmobranch able to resist energy depletion and to survive hypoxia. Using epi-illumination microscopy in vivo to observe cerebral blood flow velocity on the brain surface, we show that cerebral blood flow in the epaulette shark is unaffected by 2 h of severe hypoxia (0.35 mg O2 l-1 in the respiratory water, 24 C). Thus, the epaulette shark differs from other hypoxia- and anoxia-tolerant species studied: there is no adenosine-mediated increase in cerebral blood flow such as that occurring in freshwater turtles and cyprinid fish. However, blood pressure showed a 50 % decrease in the epaulette shark during hypoxia, indicating that a compensatory cerebral vasodilatation occurs to maintain cerebral blood flow. We observed an increase in cerebral blood flow velocity when superfusing the normoxic brain with adenosine (making sharks the oldest vertebrate group in which this mechanism has been found). The adenosine-induced increase in cerebral blood flow velocity was reduced by the adenosine receptor antagonist aminophylline. Aminophylline had no effect upon the maintenance of cerebral blood flow during hypoxia, however, indicating that adenosine is not involved in maintaining cerebral blood flow in the epaulette shark during hypoxic hypotension.

Sonochemiluminescence observation of lipid- and polymer-shelled ultrasound contrast agents in 1.2 MHz focused ultrasound field.

Science.gov (United States)

Qiao, Yangzi; Cao, Hua; Zhang, Shusheng; Yin, Hui; Wan, Mingxi

2013-01-01

Ultrasound contrast agents (UCAs) are frequently added into the focused ultrasound field as cavitation nuclei to enhance the therapeutic efficiency. Since their presence will distort the pressure field and make the process unpredictable, comprehension of their behaviors especially the active zone spatial distribution is an important part of better monitoring and using of UCAs. As shell materials can strongly alter the acoustic behavior of UCAs, two different shells coated UCAs, lipid-shelled and polymer-shelled UCAs, in a 1.2 MHz focused ultrasound field were studied by the Sonochemiluminescence (SCL) method and compared. The SCL spatial distribution of lipid-shelled group differed from that of polymer-shelled group. The shell material and the character of focused ultrasound field work together to the SCL distribution, causing the lipid-shelled group to have a maximum SCL intensity in pre-focal region at lower input power than that of polymer-shelled group, and a brighter SCL intensity in post-focal region at high input power. The SCL inactive area of these two groups both increased with the input power. The general behavior of the UCAs can be studied by both the average SCL intensity and the backscatter signals. As polymer-shelled UCAs are more resistant to acoustic pressure, they had a higher destruction power and showed less reactivation than lipid-shelled ones. Copyright © 2012 Elsevier B.V. All rights reserved.

Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain--a primate study.

Science.gov (United States)

Hynynen, Kullervo; McDannold, Nathan; Clement, Greg; Jolesz, Ferenc A; Zadicario, Eyal; Killiany, Ron; Moore, Tara; Rosen, Douglas

2006-08-01

MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used.

Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system.

Science.gov (United States)

Plog, Benjamin A; Dashnaw, Matthew L; Hitomi, Emi; Peng, Weiguo; Liao, Yonghong; Lou, Nanhong; Deane, Rashid; Nedergaard, Maiken

2015-01-14

The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100β, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity. Copyright © 2015 the authors 0270-6474/15/350518-09$15.00/0.

Pulmonary Vein Isolation by High Intensity Focused Ultrasound

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Matthias Antz

2007-04-01

Full Text Available Pulmonary vein isolation (PVI using radiofrequency current (RFC ablation is a potentially curative treatment option for patients with atrial fibrillation (AF. The shortcomings of the RFC technology (technically challenging, long procedure times, complications steadily kindle the interest in new energy sources and catheter designs. High intensity focused ultrasound (HIFU has the ability to precisely focus ultrasound waves in a defined area with a high energy density. HIFU balloon catheters (BC positioned at the PV ostia appear to be an ideal tool to transmit the ablation energy in a circumferential manner to the PV ostia and may therefore bear substantial advantage over conventional ablation catheters in PVI procedures. In clinical trials the HIFU BC has shown promising success rates similar to RFC catheter ablation for PVI in patients with AF. However, procedure times are still long and serious complications have been observed. Therefore, it may be a valuable alternative to the conventional techniques in selected patients but further clinical trials have to be initiated.

Status epilepticus, blood-brain barrier disruption, inflammation, and epileptogenesis

NARCIS (Netherlands)

Gorter, Jan A.; van Vliet, Erwin A.; Aronica, Eleonora

2015-01-01

Over the last 15 years, attention has been focused on dysfunction of the cerebral vasculature and inflammation as important players in epileptogenic processes, with a specific emphasis on failure of the blood-brain barrier (BBB; Fig. 1) (Seiffert et al., 2004; Marchi et al., 2007; Oby and Janigro,

Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB1 receptors

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Loría Frida

2011-08-01

Full Text Available Abstract Background VCAM-1 represents one of the most important adhesion molecule involved in the transmigration of blood leukocytes across the blood-brain barrier (BBB that is an essential step in the pathogenesis of MS. Several evidences have suggested the potential therapeutic value of cannabinoids (CBs in the treatment of MS and their experimental models. However, the effects of endocannabinoids on VCAM-1 regulation are poorly understood. In the present study we investigated the effects of anandamide (AEA in the regulation of VCAM-1 expression induced by Theiler's virus (TMEV infection of brain endothelial cells using in vitro and in vivo approaches. Methods i in vitro: VCAM-1 was measured by ELISA in supernatants of brain endothelial cells infected with TMEV and subjected to AEA and/or cannabinoid receptors antagonist treatment. To evaluate the functional effect of VCAM-1 modulation we developed a blood brain barrier model based on a system of astrocytes and brain endothelial cells co-culture. ii in vivo: CB1 receptor deficient mice (Cnr1-/- infected with TMEV were treated with the AEA uptake inhibitor UCM-707 for three days. VCAM-1 expression and microglial reactivity were evaluated by immunohistochemistry. Results Anandamide-induced inhibition of VCAM-1 expression in brain endothelial cell cultures was mediated by activation of CB1 receptors. The study of leukocyte transmigration confirmed the functional relevance of VCAM-1 inhibition by AEA. In vivo approaches also showed that the inhibition of AEA uptake reduced the expression of brain VCAM-1 in response to TMEV infection. Although a decreased expression of VCAM-1 by UCM-707 was observed in both, wild type and CB1 receptor deficient mice (Cnr1-/-, the magnitude of VCAM-1 inhibition was significantly higher in the wild type mice. Interestingly, Cnr1-/- mice showed enhanced microglial reactivity and VCAM-1 expression following TMEV infection, indicating that the lack of CB1 receptor

MRI monitoring of lesions created at temperature below the boiling point and of lesions created above the boiling point using high intensity focused ultrasound

OpenAIRE

Damianou, C.; Ioannides, K.; Hadjisavvas, V.; Mylonas, N.; Couppis, A.; Iosif, D.; Kyriacou, P. A.

2010-01-01

Magnetic Resonance Imaging (MRI) was utilized to monitor lesions created at temperature below the boiling point and lesions created at temperature above the boiling point using High Intensity Focused Ultrasound (HIFU) in freshly excised kidney, liver and brain and in vivo rabbit kidney and brain. T2-weighted fast spin echo (FSE) was proven as an excellent MRI sequence that can detect lesions with temperature above the boiling point in kidney. This advantage is attributed to the significant di...

Evaluation of frequency-dependent ultrasound attenuation in transparent medium using focused shadowgraph technique

Science.gov (United States)

Iijima, Yukina; Kudo, Nobuki

2017-07-01

Acoustic fields of a short-pulsed ultrasound propagating through a transparent medium with ultrasound attenuation were visualized by the focused shadowgraph technique. A brightness waveform and its spatial integrations were derived from a visualized field image and compared with a pressure waveform measured by a membrane hydrophone. The experimental results showed that first-order integration of the brightness wave has good agreement with the pressure waveforms. Frequency-dependent attenuation of the pulse propagating through castor oil was derived from brightness and pressure waveforms, and attenuation coefficients determined from focused shadowgraphy and hydrophone techniques showed good agreement. The results suggest the usefulness of the shadowgraph technique not only for the visualization of ultrasound fields but also for noncontact estimation of rough pressure waveforms and correct ultrasound attenuation.

An experimental system for the study of ultrasound exposure of isolated blood vessels

International Nuclear Information System (INIS)

Tokarczyk, Anna; Rivens, Ian; Symonds-Tayler, Richard; Ter Haar, Gail; Van Bavel, E

2013-01-01

An experimental system designed for the study of the effects of diagnostic or therapeutic ultrasound exposure on isolated blood vessels in the presence or absence of intraluminal contrast agent is described. The system comprised several components. A microscope was used to monitor vessel size (and thus vessel functionality), and potential leakage of intraluminal 70 kDa FITC-dextran fluorescence marker. A vessel chamber allowed the mounting of an isolated vessel whilst maintaining its viability, with pressure regulation for the control of intraluminal pressure and induction of flow for the infusion of contrast microbubbles. A fibre-optic hydrophone sensor mounted on the vessel chamber using a micromanipulator allowed pre-exposure targeting of the vessel to within 150 µm, and monitoring of acoustic cavitation emissions during exposures. Acoustic cavitation was also detected using changes in the ultrasound drive voltage and by detection of audible emissions using a submerged microphone. The suitability of this system for studying effects in the isolated vessel model has been demonstrated using a pilot study of 6 sham exposed and 18 high intensity focused ultrasound exposed vessels, with or without intraluminal contrast agent (SonoVue) within the vessels. (paper)

Ultrasound tagged near infrared spectroscopy does not detect hyperventilation-induced reduction in cerebral blood flow

DEFF Research Database (Denmark)

Lund, Anton; Secher, Niels H.; Hirasawa, Ai

2016-01-01

Introduction: Continuous non-invasive monitoring of cerebral blood flow (CBF) may be important during anaesthesia and several options are available. We evaluated the CerOx monitor that employs ultrasound tagged near infrared spectroscopy to estimate changes in a CBF index (CFI).Methods: Seven...... healthy males (age 21-26 years) hyperventilated and were administered phenylephrine to increase mean arterial pressure by 20-30 mmHg. Frontal lobe tissue oxygenation (ScO2) and CFI were obtained using the CerOx and mean blood flow velocity in the middle cerebral artery (MCAvmean) was determined....... Administration of phenylephrine was not associated with any changes in MCAvmean, ICAf, ECAf, ScO2, SkBF, SskinO2, or CFI.Conclusion: The CerOx was able to detect a stable CBF during administration of phenylephrine. However, during hyperventilation MCAvmean and ICAf decreased while CFI increased, likely due...

Sorting Tubules Regulate Blood-Brain Barrier Transcytosis

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Roberto Villaseñor

2017-12-01

Full Text Available Transcytosis across the blood-brain barrier (BBB regulates key processes of the brain, but the intracellular sorting mechanisms that determine successful receptor-mediated transcytosis in brain endothelial cells (BECs remain unidentified. Here, we used Transferrin receptor-based Brain Shuttle constructs to investigate intracellular transport in BECs, and we uncovered a pathway for the regulation of receptor-mediated transcytosis. By combining live-cell imaging and mathematical modeling in vitro with super-resolution microscopy of the BBB, we show that intracellular tubules promote transcytosis across the BBB. A monovalent construct (sFab sorted for transcytosis was localized to intracellular tubules, whereas a bivalent construct (dFab sorted for degradation formed clusters with impaired transport along tubules. Manipulating tubule biogenesis by overexpressing the small GTPase Rab17 increased dFab transport into tubules and induced its transcytosis in BECs. We propose that sorting tubules regulate transcytosis in BECs and may be a general mechanism for receptor-mediated transport across the BBB.

Long-term streptozotocin-induced diabetes in rats leads to severe damage of brain blood vessels and neurons via enhanced oxidative stress.

Science.gov (United States)

Yang, Hongying; Fan, Shourui; Song, Dianping; Wang, Zhuo; Ma, Shungao; Li, Shuqing; Li, Xiaohong; Xu, Mian; Xu, Min; Wang, Xianmo

2013-02-01

The aim of this study was to investigate pathophysiological alterations and oxidative stress in various stages of streptozotocin (STZ)‑induced diabetes mellitus (DM) in rats. Male Sprague-Dawley rats (120) were randomized into DM and control groups. Body mass, plasma glucose, glycated hemoglobin (HbA1c), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels, as well as aldose reductase (AR) activities, in brain tissue and serum were determined. Electron microscopy was used to observe neuron and vessel changes in the brain. In STZ‑treated rats, blood glucose, low density lipoproteins, triglycerides and total cholesterol levels increased 1.43‑3.0‑fold and high density lipoprotein, HbA1c and insulin sensitivity index increased 1.1‑1.23‑fold compared with control. At week 16 following treatment, DM rat serum H2O2 concentration was increased, indicating oxidative stress and mRNA levels of GPx and SOD were 2‑fold higher than the control. Protein GPx and SOD levels were reduced (PNeuron cells and blood vessels in the DM rat brains became increasingly abnormal over time with altered Golgi bodies, mitochondria and endoplasmic reticulum cisterns, concurrent with SOD inactivation and AR protein accumulation. Disease progression in rats with STZ‑induced DM included brain pathologies with vascular and neuron cell abnormalities, associated with the reduction of SOD, CAT and GPx activities and also AR accumulation.

Induction by mercury compounds of brain metallothionein in rats: Hg{sup 0} exposure induces long-lived brain metallothionein

Energy Technology Data Exchange (ETDEWEB)

Yasutake, Akira; Nakano, Atsuhiro [Biochemistry Section, National Institute for Minamata Disease, Kumamoto (Japan); Hirayama, Kimiko [Kumamoto University, College of Medical Science (Japan)

1998-03-01

Metallothionein (MT) is one of the stress proteins which can easily be induced by various kind of heavy metals. However, MT in the brain is difficult to induce because of blood-brain barrier impermeability to most heavy metals. In this paper, we have attempted to induce brain MT in rats by exposure to methylmercury (MeHg) or metallic mercury vapor, both of which are known to penetrate the blood-brain barrier and cause neurological damage. Rats treated with MeHg (40 {mu}mol/kg per day x 5 days, p.o.) showed brain Hg levels as high as 18 {mu}g/g with slight neurological signs 10 days after final administration, but brain MT levels remained unchanged. However, rats exposed to Hg vapor for 7 days showed 7-8 {mu}g Hg/g brain tissue 24 h after cessation of exposure. At that time brain MT levels were about twice the control levels. Although brain Hg levels fell gradually with a half-life of 26 days, MT levels induced by Hg exposure remained unchanged for >2 weeks. Gel fractionation revealed that most Hg was in the brain cytosol fraction and thus bound to MT. Hybridization analysis showed that, despite a significant increase in MT-I and -II mRNA in brain, MT-III mRNA was less affected. Although significant Hg accumulation and MT induction were observed also in kidney and liver of Hg vapor-exposed rats, these decreased more quickly than in brain. The long-lived MT in brain might at least partly be accounted for by longer half-life of Hg accumulated there. The present results showed that exposure to Hg vapor might be a suitable procedure to provide an in vivo model with enhanced brain MT. (orig.) With 4 figs., 1 tab., 27 refs.

Effects of deferoxamine on blood-brain barrier disruption after subarachnoid hemorrhage.

Directory of Open Access Journals (Sweden)

Yanjiang Li

Full Text Available Blood brain barrier (BBB disruption is a key mechanism of subarachnoid hemorrhage (SAH-induced brain injury. This study examined the mechanism of iron-induced BBB disruption after SAH and investigated the potential therapeutic effect of iron chelation on SAH. Male adult Sprague-Dawley rats had an endovascular perforation of left internal carotid artery bifurcation or sham operation. The rats were treated with deferoxamine (DFX or vehicle (100mg/kg for a maximum of 7 days. Brain edema, BBB leakage, behavioral and cognitive impairment were examined. In SAH rat, the peak time of brain edema and BBB impairment in the cortex was at day 3 after SAH. SAH resulted in a significant increase in ferritin expression in the cortex. The ferritin positive cells were colocalized with endothelial cells, pericytes, astrocytes, microglia and neurons. Compared with vehicle, DFX caused less ferritin upregulation, brain water content, BBB impairment, behavioral and cognitive deficits in SAH rats. The results suggest iron overload could be a therapeutic target for SAH induced BBB damage.

Reduced clot debris size using standing waves formed via high intensity focused ultrasound

Science.gov (United States)

Guo, Shifang; Du, Xuan; Wang, Xin; Lu, Shukuan; Shi, Aiwei; Xu, Shanshan; Bouakaz, Ayache; Wan, Mingxi

2017-09-01

The feasibility of utilizing high intensity focused ultrasound (HIFU) to induce thrombolysis has been demonstrated previously. However, clinical concerns still remain related to the clot debris produced via fragmentation of the original clot potentially being too large and hence occluding downstream vessels, causing hazardous emboli. This study investigates the use of standing wave fields formed via HIFU to disintegrate the thrombus while achieving a reduced clot debris size in vitro. The results showed that the average diameter of the clot debris calculated by volume percentage was smaller in the standing wave mode than in the travelling wave mode at identical ultrasound thrombolysis settings. Furthermore, the inertial cavitation dose was shown to be lower in the standing wave mode, while the estimated cavitation bubble size distribution was similar in both modes. These results show that a reduction of the clot debris size with standing waves may be attributed to the particle trapping of the acoustic potential well which contributed to particle fragmentation.

Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles

Directory of Open Access Journals (Sweden)

Stephen Meairs

2015-08-01

Full Text Available Medical treatment options for central nervous system (CNS diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB. Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer’s disease is presented.

High-Intensity Focused Ultrasound Treatment for Advanced Pancreatic Cancer

Directory of Open Access Journals (Sweden)

Yufeng Zhou

2014-01-01

Full Text Available Pancreatic cancer is under high mortality but has few effective treatment modalities. High-intensity focused ultrasound (HIFU is becoming an emerging approach of noninvasively ablating solid tumor in clinics. A variety of solid tumors have been tried on thousands of patients in the last fifteen years with great success. The principle, mechanism, and clinical outcome of HIFU were introduced first. All 3022 clinical cases of HIFU treatment for the advanced pancreatic cancer alone or in combination with chemotherapy or radiotherapy in 241 published papers were reviewed and summarized for its efficacy, pain relief, clinical benefit rate, survival, Karnofsky performance scale (KPS score, changes in tumor size, occurrence of echogenicity, serum level, diagnostic assessment of outcome, and associated complications. Immune response induced by HIFU ablation may become an effective way of cancer treatment. Comments for a better outcome and current challenges of HIFU technology are also covered.

Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke.

Science.gov (United States)

Mao, Leilei; Li, Peiying; Zhu, Wen; Cai, Wei; Liu, Zongjian; Wang, Yanling; Luo, Wenli; Stetler, Ruth A; Leak, Rehana K; Yu, Weifeng; Gao, Yanqin; Chen, Jun; Chen, Gang; Hu, Xiaoming

2017-07-01

Delayed thrombolytic treatment with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier breakdown after ischaemic stroke and lead to lethal haemorrhagic transformation. The immune system is a dynamic modulator of stroke response, and excessive immune cell accumulation in the cerebral vasculature is associated with compromised integrity of the blood-brain barrier. We previously reported that regulatory T cells, which function to suppress excessive immune responses, ameliorated blood-brain barrier damage after cerebral ischaemia. This study assessed the impact of regulatory T cells in the context of tPA-induced brain haemorrhage and investigated the underlying mechanisms of action. The number of circulating regulatory T cells in stroke patients was dramatically reduced soon after stroke onset (84 acute ischaemic stroke patients with or without intravenous tPA treatment, compared to 115 age and gender-matched healthy controls). Although stroke patients without tPA treatment gradually repopulated the numbers of circulating regulatory T cells within the first 7 days after stroke, post-ischaemic tPA treatment led to sustained suppression of regulatory T cells in the blood. We then used the murine suture and embolic middle cerebral artery occlusion models of stroke to investigate the therapeutic potential of adoptive regulatory T cell transfer against tPA-induced haemorrhagic transformation. Delayed administration of tPA (10 mg/kg) resulted in haemorrhagic transformation in the ischaemic territory 1 day after ischaemia. When regulatory T cells (2 × 106/mouse) were intravenously administered immediately after delayed tPA treatment in ischaemic mice, haemorrhagic transformation was significantly decreased, and this was associated with improved sensorimotor functions. Blood-brain barrier disruption and tight junction damages were observed in the presence of delayed tPA after stroke, but were mitigated by regulatory T cell transfer. Mechanistic

Protective effects of monomethyl fumarate at the inflamed blood-brain barrier

NARCIS (Netherlands)

Lim, J.L.; van der Pol, S.M.A.; Di Dio, F.; van het Hof, B.; Kooij, G.; de Vries, H.E.; van Horssen, J.

2015-01-01

Background: Reactive oxygen species play a key role in the pathogenesis of multiple sclerosis as they induce blood-brain barrier disruption and enhance transendothelial leukocyte migration. Thus, therapeutic compounds with antioxidant and anti-inflammatory potential could have clinical value in

Continuous blood pressure recordings simultaneously with functional brain imaging: studies of the glymphatic system

Science.gov (United States)

Zienkiewicz, Aleksandra; Huotari, Niko; Raitamaa, Lauri; Raatikainen, Ville; Ferdinando, Hany; Vihriälä, Erkki; Korhonen, Vesa; Myllylä, Teemu; Kiviniemi, Vesa

2017-03-01

The lymph system is responsible for cleaning the tissues of metabolic waste products, soluble proteins and other harmful fluids etc. Lymph flow in the body is driven by body movements and muscle contractions. Moreover, it is indirectly dependent on the cardiovascular system, where the heart beat and blood pressure maintain force of pressure in lymphatic channels. Over the last few years, studies revealed that the brain contains the so-called glymphatic system, which is the counterpart of the systemic lymphatic system in the brain. Similarly, the flow in the glymphatic system is assumed to be mostly driven by physiological pulsations such as cardiovascular pulses. Thus, continuous measurement of blood pressure and heart function simultaneously with functional brain imaging is of great interest, particularly in studies of the glymphatic system. We present our MRI compatible optics based sensing system for continuous blood pressure measurement and show our current results on the effects of blood pressure variations on cerebral brain dynamics, with a focus on the glymphatic system. Blood pressure was measured simultaneously with near-infrared spectroscopy (NIRS) combined with an ultrafast functional brain imaging (fMRI) sequence magnetic resonance encephalography (MREG, 3D brain 10 Hz sampling rate).

Extraction of water labeled with oxygen 15 during single-capillary transit. Influence of blood pressure, osmolarity, and blood-brain barrier damage

International Nuclear Information System (INIS)

Go, K.G.; Lammertsma, A.A.; Paans, A.M.; Vaalburg, W.; Woldring, M.G.

1981-01-01

By external detection, the influence of arterial blood pressure (BP), osmolarity, and cold-induced blood-brain barrier damage was assessed on the extraction of water labeled with oxygen 15 during single-capillary transit in the rat. There was an inverse relation between arterial BP and extraction that was attributable to the influence of arterial BP on cerebral blood flow (CBF) and the relation between CBF and extraction. Neither arterial BP nor osmolarity of the injected bolus had any direct effect on extraction of water 15O, signifying that the diffusional exchange component (determined by blood flow) of extraction greatly surpasses the convection flow contribution by hydrostatic or osmotic forces. Damage to the blood-brain barrier did not change its permeability to water

Algorithms for estimating blood velocities using ultrasound

DEFF Research Database (Denmark)

Jensen, Jørgen Arendt

2000-01-01

Ultrasound has been used intensively for the last 15 years for studying the hemodynamics of the human body. Systems for determining both the velocity distribution at one point of interest (spectral systems) and for displaying a map of velocity in real time have been constructed. A number of schemes...... have been developed for performing the estimation, and the various approaches are described. The current systems only display the velocity along the ultrasound beam direction and a velocity transverse to the beam is not detected. This is a major problem in these systems, since most blood vessels...... are parallel to the skin surface. Angling the transducer will often disturb the flow, and new techniques for finding transverse velocities are needed. The various approaches for determining transverse velocities will be explained. This includes techniques using two-dimensional correlation (speckle tracking...

Gaussian representation of high-intensity focused ultrasound beams.

Science.gov (United States)

Soneson, Joshua E; Myers, Matthew R

2007-11-01

A method for fast numerical simulation of high-intensity focused ultrasound beams is derived. The method is based on the frequency-domain representation of the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation, and assumes for each harmonic a Gaussian transverse pressure distribution at all distances from the transducer face. The beamwidths of the harmonics are constrained to vary inversely with the square root of the harmonic number, and as such this method may be viewed as an extension of a quasilinear approximation. The technique is capable of determining pressure or intensity fields of moderately nonlinear high-intensity focused ultrasound beams in water or biological tissue, usually requiring less than a minute of computer time on a modern workstation. Moreover, this method is particularly well suited to high-gain simulations since, unlike traditional finite-difference methods, it is not subject to resolution limitations in the transverse direction. Results are shown to be in reasonable agreement with numerical solutions of the full KZK equation in both tissue and water for moderately nonlinear beams.

Increased blood-brain transfer in a rabbit model of acute liver failure

International Nuclear Information System (INIS)

Horowitz, M.E.; Schafer, D.F.; Molnar, P.; Jones, E.A.; Blasberg, R.G.; Patlak, C.S.; Waggoner, J.; Fenstermacher, J.D.

1983-01-01

The blood-to-brain transfer of [ 14 C]alpha-aminoisobutyric acid was investigated by quantitative autoradiography in normal rabbits and rabbits with acute liver failure induced by the selective hepatotoxin galactosamine. The blood-to-brain transfer of alpha-aminoisobutyric acid was similar in control animals and animals 2 and 7 h after galactosamine injections, but was increased five- to tenfold in certain gray-matter areas of the brain in animals 11 and 18 h after galactosamine treatment. No detectable differences in white-matter uptake of [ 14 C]alpha-aminoisobutyric acid were found between the control and treated groups. The increase in alpha-aminoisobutyric acid transfer within the gray-matter areas suggested that a general or nonspecific increase in brain capillary permeability occurred in these areas. No clinical signs of early hepatic encephalopathy were observed in the treated rabbits, except for 1 animal from the 18-h postgalactosamine group. Thus, enhanced blood-brain transfer of alpha-aminoisobutyric acid preceded the development of overt hepatic encephalopathy. The distribution of radioactivity after the intravenous administration of [ 14 C]galactosamine showed that virtually none of the hepatotoxin localized in the brain, suggesting that the drug itself does not have a direct effect upon the blood-brain barrier or the brain. The increased uptake of alpha-aminoisobutyric acid at 11 and 18 h implies that the transfer of other solutes would also be enhanced, that central nervous system homeostasis would be compromised, and that the resulting changes in brain fluid composition could contribute to or cause hepatic encephalopathy

Glutamate Efflux at the Blood-Brain Barrier

DEFF Research Database (Denmark)

Cederberg-Helms, Hans Christian; Uhd-Nielsen, Carsten; Brodin, Birger

2014-01-01

is well known, however endothelial cells may also play an important role through mediating brain-to-blood L-glutamate efflux. Expression of excitatory amino acid transporters has been demonstrated in brain endothelial cells of bovine, human, murine, rat and porcine origin. These can account for high...... affinity concentrative uptake of L-glutamate from the brain interstitial fluid into the capillary endothelial cells. The mechanisms in between L-glutamate uptake in the endothelial cells and L-glutamate appearing in the blood are still unclear and may involve a luminal transporter for L......-glutamate, metabolism of L-glutamate and transport of metabolites or a combination of the two. However, both in vitro and in vivo studies have demonstrated blood-to-brain transport of L-glutamate, at least during pathological events. This review summarizes the current knowledge on the brain-to-blood L-glutamate efflux...

MR-Guided Focused Ultrasound for the Treatment of Uterine Fibroids

International Nuclear Information System (INIS)

Hesley, Gina K.; Gorny, Krzysztof R.; Woodrum, David A.

2013-01-01

Magnetic resonance imaging–guided focused ultrasound (MRgFUS) ablation of uterine fibroids provides a minimally invasive outpatient technique for targeting and treating symptomatic uterine fibroids. Magnetic resonance imaging provides a guidance platform that has high temporal and spatial resolution for guiding, as well as thermal monitoring of the procedure. The high-intensity focused ultrasound provides a mechanism for delivering large amounts of energy directly into the fibroid without causing detrimental effects to the nontarget tissues. Early and intermediate follow-up of patients treated with MRgFUS provided promising results on the efficacy of the technique for providing symptom relief to patients. As more long-term follow-up data are published, the efficacy of this technique can be compared to more invasive surgical and minimally invasive catheter treatments.

WE-H-209-01: Advances in Ultrasound Therapy

Energy Technology Data Exchange (ETDEWEB)

Hynynen, K. [University of Toronto (Canada)

2016-06-15

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives: Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments.

WE-H-209-01: Advances in Ultrasound Therapy

International Nuclear Information System (INIS)

Hynynen, K.

2016-01-01

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives: Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments

Feasibility of MRI-guided Focused Ultrasound as Organ-Sparing Treatment for Testicular Cancer

Science.gov (United States)

Staruch, Robert; Curiel, Laura; Chopra, Rajiv; Hynynen, Kullervo

2009-04-01

High cure rates for testicular cancer have prompted interest in organ-sparing surgery for patients with bilateral disease or single testis. Focused ultrasound (FUS) ablation could offer a noninvasive approach to organ-sparing surgery. The objective of this study was to determine the feasibility of using MR thermometry to guide organ-sparing focused ultrasound surgery in the testis. The testes of anesthetized rabbits were sonicated in several discrete locations using a single-element focused transducer operating at 2.787MHz. Focal heating was visualized with MR thermometry, using a measured PRF thermal coefficient of -0.0089±0.0003 ppm/° C. Sonications at 3.5-14 acoustic watts applied for 30 seconds produced maximum temperature elevations of 10-80° C, with coagulation verified by histology. Coagulation of precise volumes in the testicle is feasible with MRI-guided focused ultrasound. Variability in peak temperature for given sonication parameters suggests the need for online temperature feedback control.

Cofilin Knockdown Attenuates Hemorrhagic Brain Injury-induced Oxidative Stress and Microglial Activation in Mice.

Science.gov (United States)

Alhadidi, Qasim; Nash, Kevin M; Alaqel, Saleh; Sayeed, Muhammad Shahdaat Bin; Shah, Zahoor A

2018-05-08

Intracerebral hemorrhage (ICH) resulting from the rupture of the blood vessels in the brain is associated with significantly higher mortality and morbidity. Clinical studies focused on alleviating the primary injury, hematoma formation and expansion, were largely ineffective, suggesting that secondary injury-induced inflammation and the formation of reactive species also contribute to the overall injury process. In this study, we explored the effects of cofilin knockdown in a mouse model of ICH. Animals given stereotaxic injections of cofilin siRNA, 72-h prior to induction of ICH by collagenase injection within the area of siRNA administration showed significantly decreased cofilin expression levels and lower hemorrhage volume and edema, and the animals performed significantly better in neurobehavioral tasks i.e., rotarod, grip strength and neurologic deficit scores. Cofilin siRNA knocked-down mice had reduced ICH-induced DNA fragmentation, blood-brain barrier disruption and microglial activation, with a concomitant increase in astrocyte activation. Increased expression of pro-survival proteins and decreased markers of oxidative stress were also observed in cofilin siRNA-treated mice possibly due to the reduced levels of cofilin. Our results suggest that cofilin plays a major role in ICH-induced secondary injury, and could become a potential therapeutic target. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Spatial and temporal observation of phase-shift nano-emulsions assisted cavitation and ablation during focused ultrasound exposure.

Science.gov (United States)

Qiao, Yangzi; Zong, Yujin; Yin, Hui; Chang, Nan; Li, Zhaopeng; Wan, Mingxi

2014-09-01

Phase-shift nano-emulsions (PSNEs) with a small initial diameter in nanoscale have the potential to leak out of the blood vessels and to accumulate at the target point of tissue. At desired location, PSNEs can undergo acoustic droplet vaporization (ADV) process, change into gas bubbles and enhance focused ultrasound efficiency. The threshold of droplet vaporization and influence of acoustic parameters have always been research hotspots in order to spatially control the potential of bioeffects and optimize experimental conditions. However, when the pressure is much higher than PSNEs' vaporization threshold, there were little reports on their cavitation and thermal effects. In this study, PSNEs induced cavitation and ablation effects during pulsed high-intensity focused ultrasound (HIFU) exposure were investigated, including the spatial and temporal information and the influence of acoustic parameters. Two kinds of tissue-mimicking phantoms with uniform PSNEs were prepared because of their optical transparency. The Sonoluminescence (SL) method was employed to visualize the cavitation activities. And the ablation process was observed as the heat deposition could produce white lesion. Precisely controlled HIFU cavitation and ablation can be realized at a relatively low input power. But when the input power was high, PSNEs can accelerate cavitation and ablation in pre-focal region. The cavitation happened layer by layer advancing the transducer. While the lesion appeared to be separated into two parts, one in pre-focal region stemmed from one point and grew quickly, the other in focal region grew much more slowly. The influence of duty cycle has also been examined. Longer pulse off time would cause heat transfer to the surrounding media, and generate smaller lesion. On the other hand, this would give outer layer bubbles enough time to dissolve, and inner bubbles can undergo violent collapse and emit bright light. Copyright © 2014 Elsevier B.V. All rights reserved.

Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-weighted MRI at 3 tesla

DEFF Research Database (Denmark)

Larsson, Henrik B W; Courivaud, Frédéric; Rostrup, Egill

2009-01-01

Assessment of vascular properties is essential to diagnosis and follow-up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood-brain permeability from dynamic T(1)-weighted...... on a pixel-by-pixel basis of cerebral perfusion, cerebral blood volume, and blood-brain barrier permeability.......Assessment of vascular properties is essential to diagnosis and follow-up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood-brain permeability from dynamic T(1)-weighted...... imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model-free deconvolution using Tikhonov's method (gray matter/white matter/tumor: 72 +/- 16/30 +/- 8/56 +/- 45 mL/100 g...

Plasmalemmal Vesicle Associated Protein-1 (PV-1 is a marker of blood-brain barrier disruption in rodent models

Directory of Open Access Journals (Sweden)

Ali Zarina S

2008-02-01

Full Text Available Abstract Background Plasmalemmal vesicle associated protein-1 (PV-1 is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state. Results We demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated. Conclusion Our results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.

How does the blood leave the brain? A systematic ultrasound analysis of cerebral venous drainage patterns

International Nuclear Information System (INIS)

Doepp, Florian; Schreiber, Stephan J.; Muenster, Thomas von; Rademacher, Joerg; Valdueza, Jose M.; Klingebiel, Randolf

2004-01-01

The internal jugular veins are considered to be the main pathways of cerebral blood drainage. However, angiographic and anatomical studies show a wide anatomical variability and varying degrees of jugular and non-jugular venous drainage. The study systematically analyses the types and prevalence of human cerebral venous outflow patterns by ultrasound and MRI. Fifty healthy volunteers (21 females; 29 males; mean age 27±7 years) were studied by color-coded duplex sonography. Venous blood volume flow was measured in both internal jugular and vertebral veins in the supine position. Furthermore, the global arterial cerebral blood volume flow was calculated as the sum of volume flows in both internal carotid and vertebral arteries. Three types of venous drainage patterns were defined: a total jugular volume flow of more than 2/3 (type 1), between 1/3 and 2/3 (type 2) and less than 1/3 (type 3) of the global arterial blood flow. 2D TOF MR-venography was performed exemplarily in one subject with type-1 and in two subjects with type-3 drainage. Type-1 drainage was present in 36 subjects (72%), type 2 in 11 subjects (22%) and type 3 in 3 subjects (6%). In the majority of subjects in our study population, the internal jugular veins were indeed the main drainage vessels in the supine body position. However, a predominantly non-jugular drainage pattern was found in approximately 6% of subjects. (orig.)

Treatment of near-skull brain tissue with a focused device using shear-mode conversion: a numerical study

International Nuclear Information System (INIS)

Pichardo, Samuel; Hynynen, Kullervo

2007-01-01

Shear mode transmission through the skull has been previously proposed as a new trans-skull propagation technique for noninvasive therapeutic ultrasound (Clement 2004 J. Acoust. Soc. Am. 115 1356-64). The main advantage of choosing shear over longitudinal mode resides on the fact that there is less wavefront distortion with the former. In the present study, the regions of the brain suitable for shear-mode transmission were established for a simple focused ultrasound device. The device consists of a spherically curved transducer that has a focal length of 10 cm, an aperture between 30 0 and 60 0 and operates at 0.74 MHz. The regions suitable for shear-mode transmission were determined by the shear wave acoustic windows that matched the shape of the device acoustic field. The acoustic windows were calculated using segmentation and triangulation of outer and inner faces of skull from 3D-MRI head datasets. Nine heads of healthy adults were analyzed. The surface considered for the calculations was the head region found above the supra-orbital margin. For every inspected point in the brain volume, the axis of the device was determined by the vector between this inspection point and a point located in the center of the brain. Numerical predictions of the acoustic field, where shear-mode conversion through the skull was considered, were obtained and compared to the case of water-only conditions. The brain tissue that is close to the skull showed suitable acoustic windows for shear waves. The central region of the brain seems to be unreachable using shear-mode. Analysis of the acoustic fields showed a proportional relation between the acoustic window for shear mode and the effective degree of focusing. However, this relation showed significant differences among specimens. In general, highly focused fields were obtained when the acoustic window for shear waves (A SW ) intersected more than 67% of the entering acoustic window (A TX ) of the device. The average depth from the

Radiation-induced brain injury: A review

Directory of Open Access Journals (Sweden)

Michael eRobbins

2012-07-01

Full Text Available Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (> 6 months to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses > 30 Gy; white matter necrosis occurs at fractionated doses > 60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain

Ultrasound, liposomes, and drug delivery: principles for using ultrasound to control the release of drugs from liposomes.

Science.gov (United States)

Schroeder, Avi; Kost, Joseph; Barenholz, Yechezkel

2009-11-01

Ultrasound is used in many medical applications, such as imaging, blood flow analysis, dentistry, liposuction, tumor and fibroid ablation, and kidney stone disruption. In the past, low frequency ultrasound (LFUS) was the main method to downsize multilamellar (micron range) vesicles into small (nano scale) unilamellar vesicles. Recently, the ability of ultrasound to induce localized and controlled drug release from liposomes, utilizing thermal and/or mechanical effects, has been shown. This review, deals with the interaction of ultrasound with liposomes, focusing mainly on the mechanical mechanism of drug release from liposomes using LFUS. The effects of liposome lipid composition and physicochemical properties, on one hand, and of LFUS parameters, on the other, on liposomal drug release, are addressed. Acoustic cavitation, in which gas bubbles oscillate and collapse in the medium, thereby introducing intense mechanical strains, increases release substantially. We suggest that the mechanism of release may involve formation and collapse of small gas nuclei in the hydrophobic region of the lipid bilayer during exposure to LFUS, thereby inducing the formation of transient pores through which drugs are released. Introducing PEG-lipopolymers to the liposome bilayer enhances responsivity to LFUS, most likely due to absorption of ultrasonic energy by the highly hydrated PEG headgroups. The presence of amphiphiles, such as phospholipids with unsaturated acyl chains, which destabilize the lipid bilayer, also increases liposome susceptibility to LFUS. Application of these principles to design highly LFUS-responsive liposomes is discussed.

Concepts and strategies for clinical management of blast-induced traumatic brain injury and posttraumatic stress disorder.

Science.gov (United States)

Chen, Yun; Huang, Wei; Constantini, Shlomi

2013-01-01

After exposure of the human body to blast, kinetic energy of the blast shock waves might be transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood (a volumetric blood surge). The volumetric blood surge moves through blood vessels from the high-pressure body cavity to the low-pressure cranial cavity, causing damage to tiny cerebral blood vessels and the blood-brain barrier (BBB). Large-scale cerebrovascular insults and BBB damage that occur globally throughout the brain may be the main causes of non-impact, blast-induced brain injuries, including the spectrum of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). The volumetric blood surge may be a major contributor not only to blast-induced brain injuries resulting from physical trauma, but may also be the trigger to psychiatric disorders resulting from emotional and psychological trauma. Clinical imaging technologies, which are able to detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema, may help diagnose both TBI and PTSD in the victims exposed to blasts. Potentially, prompt medical treatment aiming at prevention of secondary neuronal damage may slow down or even block the cascade of events that lead to progressive neuronal damage and subsequent long-term neurological and psychiatric impairment.

Magnetic Resonance-Guided High-Intensity-Focused Ultrasound for Palliation of Painful Skeletal Metastases: A Pilot Study.

Science.gov (United States)

Chan, Michael; Dennis, Kristopher; Huang, Yuexi; Mougenot, Charles; Chow, Edward; DeAngelis, Carlo; Coccagna, Jennifer; Sahgal, Arjun; Hynynen, Kullervo; Czarnota, Gregory; Chu, William

2017-10-01

Bone is one of the most common sites of metastases, with bone metastases-related pain representing a significant source of morbidity among patients with cancer. Magnetic resonance-guided focused ultrasound is a noninvasive, outpatient modality with the potential for treating painful bone metastases. The aim of this study is to report our initial experience with magnetic resonance-guided focused ultrasound in the treatment of bone metastases and our preliminary analysis of urinary cytokine levels after therapy. This was a single-center pilot study of 10 patients with metastatic cancer to investigate the feasibility of magnetic resonance-guided focused ultrasound for primary pain control in device-accessible skeletal metastases. Treatments were performed on a clinical magnetic resonance-guided focused ultrasound system using a volumetric ablation technique. Primary efficacy was assessed using Brief Pain Inventory scores and morphine equivalent daily dose intake at 3 time points: before, day 14, and day 30 after the magnetic resonance-guided focused ultrasound treatment. Urine cytokines were measured 3 days before treatment and 2 days after the treatment. Of the 10 patients, 8 were followed up 14 days and 6 were followed up 30 days after the treatment. At day 14, 3 patients (37.5%) exhibited partial pain response and 4 patients (50%) exhibited an indeterminate response, and at day 30 after the treatment, 5 patients (83%) exhibited partial pain response. No treatment-related adverse events were recorded. Of the urine cytokines measured, only Transforming growth factor alpha (TGFα) demonstrated an overall decrease, with a trend toward statistical significance ( P = .078). Our study corroborates magnetic resonance-guided focused ultrasound as a feasible and safe modality as a primary, palliative treatment for painful bone metastases and contributes to the limited body of literature using magnetic resonance-guided focused ultrasound for this clinical indication.

Proinflammatory Adhesion Molecules Facilitate Polychlorinated Biphenyl–Mediated Enhancement of Brain Metastasis Formation

OpenAIRE

Sipos, Eszter; Chen, Lei; András, Ibolya E.; Wrobel, Jagoda; Zhang, Bei; Pu, Hong; Park, Minseon; Eum, Sung Yong; Toborek, Michal

2012-01-01

Polychlorinated biphenyls (PCBs) are environmental toxicants that cause vascular inflammation and facilitate the development of brain metastases. The crucial event in metastasis formation is adhesion of blood-borne tumor cells to the vascular endothelium, followed by their transcapillary migration. The aim of the present study was to examine the mechanisms of PCB118-induced brain metastasis formation at the blood-brain barrier level with the focus on tumor cell adhesion to the brain endotheli...

Muscle blood volume assessment during exercise with Power Doppler Ultrasound

NARCIS (Netherlands)

Heres, H.M.; Tchang, B.C.Y.; Schoots, T.; Rutten, M.C.M.; van de Vosse, F.N.; Lopata, R.G.P.

2016-01-01

Assessment of perfusion adaptation in muscle during exercise can provide diagnostic information on cardiac and endothelial diseases. Power Doppler Ultrasound (PDUS) is known for its feasibility in the non-invasive measurement of moving blood volume (MBV), a perfusion related parameter. In this

Driving Circuitry for Focused Ultrasound Noninvasive Surgery and Drug Delivery Applications

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Kullervo Hynynen

2011-01-01

Full Text Available Recent works on focused ultrasound (FUS have shown great promise for cancer therapy. Researchers are continuously trying to improve system performance, which is resulting in an increased complexity that is more apparent when using multi-element phased array systems. This has led to significant efforts to reduce system size and cost by relying on system integration. Although ideas from other fields such as microwave antenna phased arrays can be adopted in FUS, the application requirements differ significantly since the frequency range used in FUS is much lower. In this paper, we review recent efforts to design efficient power monitoring, phase shifting and output driving techniques used specifically for high intensity focused ultrasound (HIFU.

Pharmacokinetics and In Vitro Blood-Brain Barrier Screening of the Plant-Derived Alkaloid Tryptanthrin.

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Jähne, Evelyn A; Eigenmann, Daniela E; Sampath, Chethan; Butterweck, Veronika; Culot, Maxime; Cecchelli, Roméo; Gosselet, Fabien; Walter, Fruzsina R; Deli, Mária A; Smieško, Martin; Hamburger, Matthias; Oufir, Mouhssin

2016-07-01

The indolo[2,1-b]quinazoline alkaloid tryptanthrin was previously identified as a potent anti-inflammatory compound with a unique pharmacological profile. It is a potent inhibitor of cyclooxygenase-2, 5-lipooxygenase-catalyzed leukotriene synthesis, and nitric oxide production catalyzed by the inducible nitric oxide synthase. To characterize the pharmacokinetic properties of tryptanthrin, we performed a pilot in vivo study in male Sprague-Dawley rats (2 mg/kg bw i. v.). Moreover, the ability of tryptanthrin to cross the blood-brain barrier was evaluated in three in vitro human and animal blood-brain barrier models. Bioanalytical UPLC-MS/MS methods used were validated according to current international guidelines. A half-life of 40.63 ± 6.66 min and a clearance of 1.00 ± 0.36 L/h/kg were found in the in vivo pharmacokinetic study. In vitro data obtained with the two primary animal blood-brain barrier models showed a good correlation with an immortalized human monoculture blood-brain barrier model (hBMEC cell line), and were indicative of a high blood-brain barrier permeation potential of tryptanthrin. These findings were corroborated by the in silico prediction of blood-brain barrier penetration. P-glycoprotein interaction of tryptanthrin was assessed by calculation of the efflux ratio in bidirectional permeability assays. An efflux ratio below 2 indicated that tryptanthrin is not subjected to active efflux. Georg Thieme Verlag KG Stuttgart · New York.

Moderately nonlinear ultrasound propagation in blood-mimicking fluid.

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Kharin, Nikolay A; Vince, D Geoffrey

2004-04-01

In medical diagnostic ultrasound (US), higher than-in-water nonlinearity of body fluids and tissue usually does not produce strong nonlinearly distorted waves because of the high absorption. The relative influence of absorption and nonlinearity can be characterized by the Gol'dberg number Gamma. There are two limiting cases in nonlinear acoustics: weak waves (Gamma 1). However, at diagnostic frequencies in tissue and body fluids, the nonlinear effects and effects of absorption more likely are comparable (Gol'dberg number Gamma approximately 1). The aim of this work was to study the nonlinear propagation of a moderately nonlinear US second harmonic signal in a blood-mimicking fluid. Quasilinear solutions to the KZK equation are presented, assuming radiation from a flat and geometrically focused circular Gaussian source. The solutions are expressed in a new simplified closed form and are in very good agreement with those of previous studies measuring and modeling Gaussian beams. The solutions also show good agreement with the measurements of the beams produced by commercially available transducers, even without special Gaussian shading.

Protective/detoxicative function of metallothionein in the rat brain and blood induced by controlled cadmium doses

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H. N. Shiyntum

2015-09-01

Full Text Available Cadmiumclassified as a major carcinogen is considered a poisonous and unwanted heavy metal to a lot of tissues in many organisms. Of many publications already available, the general consensus is that the cadmium attenuating element is metallothionein (MT through its interchangeable mechanism with Zn triggered by the presence of Cd, providing binding sites for Cd ions. MT was first discovered in the kidney cortex of the horse; it represents a low molecular weight protein, rich in cysteine residues which effectively bind with metals. Its functions consist in detoxification of heavy metals like mercury, arsenic, cadmium, homeostasis of essential metals including copper and zinc, anti-oxidation against reactive oxygen species, protection against DNA damage, oxidative stress, cell survival, angiogenesis, apoptosis, and increase of proliferation. In this work, we sought to highlight the protective function of MT in the brain and serum of rats by means of detoxification under induced effects of controlled Cd doses. We have done this by exposing Wistar rats to Cd at different doses in drinking water at different time intervals. In two independent experiments, 58 rats were subjected to 0.1 or 1.0 µg Cd2+/kg of body weight for 15 or 36 days under different conditions. The obtained data indicates the different functioning systems for the brain and the blood for MT metabolism under Cd effect. Our results indicate significant loss of metallothionein level in the brain and important increases in the amount of MT in serum proving that even minimal ingestion of toxic Cd is enough to trigger the release of MT protein in blood.

Functional photoacoustic imaging to observe regional brain activation induced by cocaine hydrochloride

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Jo, Janggun; Yang, Xinmai

2011-09-01

Photoacoustic microscopy (PAM) was used to detect small animal brain activation in response to drug abuse. Cocaine hydrochloride in saline solution was injected into the blood stream of Sprague Dawley rats through tail veins. The rat brain functional change in response to the injection of drug was then monitored by the PAM technique. Images in the coronal view of the rat brain at the locations of 1.2 and 3.4 mm posterior to bregma were obtained. The resulted photoacoustic (PA) images showed the regional changes in the blood volume. Additionally, the regional changes in blood oxygenation were also presented. The results demonstrated that PA imaging is capable of monitoring regional hemodynamic changes induced by drug abuse.

Histological and Ultrastructural Effects of Ultrasound-induced Cavitation on Human Skin Adipose Tissue.

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Bani, Daniele; Quattrini Li, Alessandro; Freschi, Giancarlo; Russo, Giulia Lo

2013-09-01

In aesthetic medicine, the most promising techniques for noninvasive body sculpturing purposes are based on ultrasound-induced fat cavitation. Liporeductive ultrasound devices afford clinically relevant subcutaneous fat pad reduction without significant adverse reactions. This study aims at evaluating the histological and ultrastructural changes induced by ultrasound cavitation on the different cell components of human skin. Control and ultrasound-treated ex vivo abdominal full-thickness skin samples and skin biopsies from patients pretreated with or without ultrasound cavitation were studied histologically, morphometrically, and ultrastructurally to evaluate possible changes in adipocyte size and morphology. Adipocyte apoptosis and triglyceride release were also assayed. Clinical evaluation of the effects of 4 weekly ultrasound vs sham treatments was performed by plicometry. Compared with the sham-treated control samples, ultrasound cavitation induced a statistically significant reduction in the size of the adipocytes (P ultrasound treatment caused a significant reduction of abdominal fat. This study further strengthens the current notion that noninvasive transcutaneous ultrasound cavitation is a promising and safe technology for localized reduction of fat and provides experimental evidence for its specific mechanism of action on the adipocytes.

Acoustic radiation force induced resonance elastography of coagulating blood: theoretical viscoelasticity modeling and ex vivo experimentation

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Bhatt, Manish; Montagnon, Emmanuel; Destrempes, François; Chayer, Boris; Kazemirad, Siavash; Cloutier, Guy

2018-03-01

Deep vein thrombosis is a common vascular disease that can lead to pulmonary embolism and death. The early diagnosis and clot age staging are important parameters for reliable therapy planning. This article presents an acoustic radiation force induced resonance elastography method for the viscoelastic characterization of clotting blood. The physical concept of this method relies on the mechanical resonance of the blood clot occurring at specific frequencies. Resonances are induced by focusing ultrasound beams inside the sample under investigation. Coupled to an analytical model of wave scattering, the ability of the proposed method to characterize the viscoelasticity of a mimicked venous thrombosis in the acute phase is demonstrated. Experiments with a gelatin-agar inclusion sample of known viscoelasticity are performed for validation and establishment of the proof of concept. In addition, an inversion method is applied in vitro for the kinetic monitoring of the blood coagulation process of six human blood samples obtained from two volunteers. The computed elasticity and viscosity values of blood samples at the end of the 90 min kinetics were estimated at 411  ±  71 Pa and 0.25  ±  0.03 Pa · s for volunteer #1, and 387  ±  35 Pa and 0.23  ±  0.02 Pa · s for volunteer #2, respectively. The proposed method allowed reproducible time-varying thrombus viscoelastic measurements from samples having physiological dimensions.

Application of nonlinear phenomena induced by focused ultrasound to bone imaging.

Science.gov (United States)

Callé, Samuel; Remenieras, Jean-Pierre; Bou Matar, Olivier; Defontaine, Marielle; Patat, Frederic

2003-03-01

A tissue deformability image is obtained with the vibroacoustography imaging method using mechanical low-frequency (LF) excitation. This ultrasonic excitation is created locally by means of a focused annular array emitting two primary beams at two close frequencies, f(1) and f(2) (f(2) = f(1) + f(LF)). The LF acoustic emission resulting from the vibration of the medium is detected by a sensitive hydrophone and then used to form the image. This noninvasive imaging method was demonstrated in this study to be suitable for bone imaging, with x and y transverse resolutions less than 300 micro m. Two bone sites susceptible to demineralization were tested: the calcaneus and the neck of the femur. The vibroacoustic method provides valuable ultrasonic images regarding the structure and the elastic properties of bone tissue. Correlation was made between vibroacoustic bone images, performed in vitro, and images acquired by other imaging methods (i.e., bone ultrasound attenuation and x-ray computerized tomography (CT)). Moreover, the amplitudes of vibroacoustic signals radiating from phosphocalcic ceramic samples (bone substitute) of different porosity were evaluated. The good correlation between these results and the description of our images and the quality of vibroacoustic images indicate that bone decalcification could be detected using vibroacoustography.

Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood–brain barrier

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Wang X

2014-10-01

Full Text Available Xiang Wang,1 Ping Liu,1 Weixiao Yang,1 Lu Li,1 Peijing Li,2 Zheng Liu,1 Zhongxiong Zhuo,1 Yunhua Gao1 1Department of Ultrasound, Xinqiao Hospital of the Third Military Medical University, Chongqing, 2Department of Ultrasound, General Hospital of the Jinan Military Area, Jinan, People’s Republic of China Abstract: Methotrexate (MTX is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%±0.86%, and their size (2.64±0.93 µm in diameter was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood–brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3±2.4 µg/g > unmodified ZHIFUXIAN + MTX + ultrasound (18.6±2.2 µg/g > MTX alone (6.97±0.75 µg/g > MTX-liposome-coupled microbubbles (2.92±0.39 µg/g. Therefore

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats.

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Shi, Xudan; Doycheva, Desislava Met; Xu, Liang; Tang, Jiping; Yan, Min; Zhang, John H

2016-11-01

Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injuries. Rat pups underwent common carotid artery ligation followed by either 150min (severe model) or 100min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) was used to examine their roles on BBB permeability. Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α's effects as a prodeath or prosurvival signal were influenced by the severity of HI injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Non-invasive peripheral nerve stimulation via focused ultrasound in vivo

Science.gov (United States)

Downs, Matthew E.; Lee, Stephen A.; Yang, Georgiana; Kim, Seaok; Wang, Qi; Konofagou, Elisa E.

2018-02-01

Focused ultrasound (FUS) has been employed on a wide range of clinical applications to safely and non-invasively achieve desired effects that have previously required invasive and lengthy procedures with conventional methods. Conventional electrical neuromodulation therapies that are applied to the peripheral nervous system (PNS) are invasive and/or non-specific. Recently, focused ultrasound has demonstrated the ability to modulate the central nervous system and ex vivo peripheral neurons. Here, for the first time, noninvasive stimulation of the sciatic nerve eliciting a physiological response in vivo is demonstrated with FUS. FUS was applied on the sciatic nerve in mice with simultaneous electromyography (EMG) on the tibialis anterior muscle. EMG signals were detected during or directly after ultrasound stimulation along with observable muscle contraction of the hind limb. Transecting the sciatic nerve downstream of FUS stimulation eliminated EMG activity during FUS stimulation. Peak-to-peak EMG response amplitudes and latency were found to be comparable to conventional electrical stimulation methods. Histology along with behavioral and thermal testing did not indicate damage to the nerve or surrounding regions. The findings presented herein demonstrate that FUS can serve as a targeted, safe and non-invasive alternative to conventional peripheral nervous system stimulation to treat peripheral neuropathic diseases in the clinic.

Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound

Science.gov (United States)

Mueller, Jerel K.; Ai, Leo; Bansal, Priya; Legon, Wynn

2017-12-01

Objective. Transcranial focused ultrasound is an emerging field for human non-invasive neuromodulation, but its dosing in humans is difficult to know due to the skull. The objective of the present study was to establish modeling methods based on medical images to assess skull differences between individuals on the wave propagation of ultrasound. Approach. Computational models of transcranial focused ultrasound were constructed using CT and MR scans to solve for intracranial pressure. We explored the effect of including the skull base in models, different transducer placements on the head, and differences between 250 kHz or 500 kHz acoustic frequency for both female and male models. We further tested these features using linear, nonlinear, and elastic simulations. To better understand inter-subject skull thickness and composition effects we evaluated the intracranial pressure maps between twelve individuals at two different skull sites. Main results. Nonlinear acoustic simulations resulted in virtually identical intracranial pressure maps with linear acoustic simulations. Elastic simulations showed a difference in max pressures and full width half maximum volumes of 15% at most. Ultrasound at an acoustic frequency of 250 kHz resulted in the creation of more prominent intracranial standing waves compared to 500 kHz. Finally, across twelve model human skulls, a significant linear relationship to characterize intracranial pressure maps was not found. Significance. Despite its appeal, an inherent problem with the use of a noninvasive transcranial ultrasound method is the difficulty of knowing intracranial effects because of the skull. Here we develop detailed computational models derived from medical images of individuals to simulate the propagation of neuromodulatory ultrasound across the skull and solve for intracranial pressure maps. These methods allow for a much better understanding of the intracranial effects of ultrasound for an individual in order to

Cold injury, blood-brain barrier changes, and leukotriene synthesis: Inhibition by phenidone

International Nuclear Information System (INIS)

Robichaud, L.J.; Marcoux, F.W.

1990-01-01

Transcranial cold injury in rats and guinea pigs induced cerebral extravasation of albumin labeled with Evans blue dye or 125 I, respective indicators of the area and amount of blood-brain barrier (BBB) disruption. Radioimmunoassay of brain extracts showed that cold injury induced leukotriene (LT)C4 in rat and guinea pig brains 15 min after injury. In guinea pigs, the LT synthesis inhibitor phenidone (30 mg/kg, i.p.) completely blocked cold-induced LTC4 in brain. Phenidone (30 and 100 mg/kg) also inhibited cerebral tissue accumulation of 125 I-albumin and dye in rats and guinea pigs. Phenidone is reported to show antioxidant properties and selective lipoxygenase inhibition of arachidonic acid metabolism compared to cyclooxygenase inhibitors, meclofenamate sodium, and other nonsteroidal anti-inflammatory agents. Since several oxygen and hydroxyl radical scavengers and the cyclooxygenase inhibitor, meclofenamate sodium, did not inhibit protein extravasation, the findings support a role for LT as a mediator of cold-induced changes in BBB permeability in rats and guinea pigs and suggest that the inhibitory effects of phenidone on BBB permeability may be due to inhibition of LT production

Ultrasound guided double injection of blood into cisterna magna: a rabbit model for treatment of cerebral vasospasm.

Science.gov (United States)

Chen, Yongchao; Zhu, Youzhi; Zhang, Yu; Zhang, Zixuan; Lian, Juan; Luo, Fucheng; Deng, Xuefei; Wong, Kelvin K L

2016-02-06

Double injection of blood into cisterna magna using a rabbit model results in cerebral vasospasm. An unacceptably high mortality rate tends to limit the application of model. Ultrasound guided puncture can provide real-time imaging guidance for operation. The aim of this paper is to establish a safe and effective rabbit model of cerebral vasospasm after subarachnoid hemorrhage with the assistance of ultrasound medical imaging. A total of 160 New Zealand white rabbits were randomly divided into four groups of 40 each: (1) manual control group, (2) manual model group, (3) ultrasound guided control group, and (4) ultrasound guided model group. The subarachnoid hemorrhage was intentionally caused by double injection of blood into their cisterna magna. Then, basilar artery diameters were measured using magnetic resonance angiography before modeling and 5 days after modeling. The depth of needle entering into cisterna magna was determined during the process of ultrasound guided puncture. The mortality rates in manual control group and model group were 15 and 23 %, respectively. No rabbits were sacrificed in those two ultrasound guided groups. We found that the mortality rate in ultrasound guided groups decreased significantly compared to manual groups. Compared with diameters before modeling, the basilar artery diameters after modeling were significantly lower in manual and ultrasound guided model groups. The vasospasm aggravated and the proportion of severe vasospasms was greater in ultrasound guided model group than that of manual group. In manual model group, no vasospasm was found in 8 % of rabbits. The ultrasound guided double injection of blood into cisterna magna is a safe and effective rabbit model for treatment of cerebral vasospasm.

Human umbilical cord blood cells restore brain damage induced changes in rat somatosensory cortex.

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Maren Geissler

Full Text Available Intraperitoneal transplantation of human umbilical cord blood (hUCB cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury.

High-intensity focused ultrasound ablation around the tubing.

Science.gov (United States)

Siu, Jun Yang; Liu, Chenhui; Zhou, Yufeng

2017-01-01

High-intensity focused ultrasound (HIFU) has been emerging as an effective and noninvasive modality in cancer treatment with very promising clinical results. However, a small vessel in the focal region could be ruptured, which is an important concern for the safety of HIFU ablation. In this study, lesion formation in the polyacrylamide gel phantom embedded with different tubing (inner diameters of 0.76 mm and 3 mm) at varied flow speeds (17-339 cm/s) by HIFU ablation was photographically recorded. Produced lesions have decreased length (~30%) but slightly increased width (~6%) in comparison to that without the embedded tubing. Meanwhile, bubble activities during the exposures were measured by passive cavitation detection (PCD) at the varied pulse repetition frequency (PRF, 10-30 Hz) and duty cycle (DC, 10%-20%) of the HIFU bursts. High DC and low flow speed were found to produce stronger bubble cavitation whereas no significant influence of the PRF. In addition, high-speed photography illustrated that the rupture of tubing was produced consistently after the first HIFU burst within 20 ms and then multiple bubbles would penetrate into the intraluminal space of tubing through the rupture site by the acoustic radiation force. Alignment of HIFU focus to the anterior surface, middle, and posterior surface of tubing led to different characteristics of vessel rupture and bubble introduction. In summary, HIFU-induced vessel rupture is possible as shown in this phantom study; produced lesion sizes and shapes are dependent on the focus alignment to the tubing, flow speed, and tubing properties; and bubble cavitation and the formation liquid jet may be one of the major mechanisms of tubing rupture as shown in the high-speed photography.

Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice.

Science.gov (United States)

Cheng, Zhuo; Wang, Liping; Qu, Meijie; Liang, Huaibin; Li, Wanlu; Li, Yongfang; Deng, Lidong; Zhang, Zhijun; Yang, Guo-Yuan

2018-05-03

Ischemic stroke induced matrixmetallo-proteinase-9 (MMP-9) upregulation, which increased blood-brain barrier permeability. Studies demonstrated that mesenchymal stem cell therapy protected blood-brain barrier disruption from several cerebrovascular diseases. However, the underlying mechanism was largely unknown. We therefore hypothesized that mesenchymal stem cells reduced blood-brain barrier destruction by inhibiting matrixmetallo-proteinase-9 and it was related to intercellular adhesion molecule-1 (ICAM-1). Adult ICR male mice (n = 118) underwent 90-min middle cerebral artery occlusion and received 2 × 10 5 mesenchymal stem cell transplantation. Neurobehavioral outcome, infarct volume, and blood-brain barrier permeability were measured after ischemia. The relationship between myeloperoxidase (MPO) activity and ICAM-1 release was further determined. We found that intracranial injection of mesenchymal stem cells reduced infarct volume and improved behavioral function in experimental stroke models (p mesenchymal stem cell-treated mice compared to the control group following ischemia (p cells and myeloperoxidase activity were decreased in mesenchymal stem cell-treated mice (p mesenchymal stem cell therapy attenuated blood-brain barrier disruption in mice after ischemia. Mesenchymal stem cells attenuated the upward trend of MMP-9 and potentially via downregulating ICAM-1 in endothelial cells. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway may influence MMP-9 expression of neutrophils and resident cells, and ICAM-1 acted as a key factor in the paracrine actions of mesenchymal stem cell.

Venous or arterial blood components trigger more brain swelling, tissue death after acute subdural hematoma compared to elderly atrophic brain with subdural effusion (SDE) model rats.

Science.gov (United States)

Wajima, Daisuke; Sato, Fumiya; Kawamura, Kenya; Sugiura, Keisuke; Nakagawa, Ichiro; Motoyama, Yasushi; Park, Young-Soo; Nakase, Hiroyuki

2017-09-01

Acute subdural hematoma (ASDH) is a frequent complication of severe head injury, whose secondary ischemic lesions are often responsible for the severity of the disease. We focused on the differences of secondary ischemic lesions caused by the components, 0.4ml venous- or arterial-blood, or saline, infused in the subdural space, evaluating the differences in vivo model, using rats. The saline infused rats are made for elderly atrophic brain with subdural effusion (SDE) model. Our data showed that subdural blood, both venous- and arterial-blood, aggravate brain edema and lesion development more than SDE. This study is the first study, in which different fluids in rats' subdural space, ASDH or SDE are compared with the extension of early and delayed brain damage by measuring brain edema and histological lesion volume. Blood constituents started to affect the degree of ischemia underneath the subdural hemorrhage, leading to more pronounced breakdown of the blood-brain barrier and brain damage. This indicates that further strategies to treat blood-dependent effects more efficiently are in view for patients with ASDH. Copyright © 2017 Elsevier B.V. All rights reserved.

Radiation-induced brain injury: A review

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Greene-Schloesser, Dana; Robbins, Mike E.; Peiffer, Ann M.; Shaw, Edward G. [Department of Radiation Oncology, Wake Forest School of Medicine,, Winston-Salem, NC (United States); Brain Tumor Center of Excellence, Wake Forest School of Medicine,, Winston-Salem, NC (United States); Wheeler, Kenneth T. [Brain Tumor Center of Excellence, Wake Forest School of Medicine,, Winston-Salem, NC (United States); Department of Radiology, Wake Forest School of Medicine,, Winston-Salem, NC (United States); Chan, Michael D., E-mail: mrobbins@wakehealth.edu [Department of Radiation Oncology, Wake Forest School of Medicine,, Winston-Salem, NC (United States); Brain Tumor Center of Excellence, Wake Forest School of Medicine,, Winston-Salem, NC (United States)

2012-07-19

Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their

Radiation-induced brain injury: A review

International Nuclear Information System (INIS)

Greene-Schloesser, Dana; Robbins, Mike E.; Peiffer, Ann M.; Shaw, Edward G.; Wheeler, Kenneth T.; Chan, Michael D.

2012-01-01

Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their

Focusing of high power ultrasound beams and limiting values of shock wave parameters

Science.gov (United States)

Bessonova, O. V.; Khokhlova, V. A.; Bailey, M. R.; Canney, M. S.; Crum, L. A.

2009-10-01

In this work, the influence of nonlinear and diffraction effects on amplification factors of focused ultrasound systems is investigated. The limiting values of acoustic field parameters obtained by focusing of high power ultrasound are studied. The Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation was used for the numerical modeling. Solutions for the nonlinear acoustic field were obtained at output levels corresponding to both pre- and post-shock formation conditions in the focal area of the beam in a weakly dissipative medium. Numerical solutions were compared with experimental data as well as with known analytic predictions.

Neocortical Transplants in the Mammalian Brain Lack a Blood-Brain Barrier to Macromolecules

Science.gov (United States)

Rosenstein, Jeffrey M.

1987-02-01

In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

[Estimation of Time-Dependent microRNA Expression Patterns in Brain Tissue, Leukocytes, and Blood Plasma of Rats under Photochemically Induced Focal Cerebral Ischemia].

Science.gov (United States)

Gusar, V A; Timofeeva, A V; Zhanin, I S; Shram, S I; Pinelis, V G

2017-01-01

miRNA expression over different time periods (24 and 48 h) using the quantitative RT-PCR and deep sequencing has been evaluated in a model of photochemically induced thrombosis. A combination of two approaches allowed us to determine the miRNA expression patterns caused by ischemia. Nine miRNAs, including let-7f-5p, miR-221-3p, miR-21-5p, miR-30c-5p, miR-30a-3p, miR-223-3p, miR-23a-3p, miR-22-5p, and miR-99a-5p, were differentially expressed in brain tissue and leukocytes of rats 48 h after onset of ischemia. In addition, six miRNAs were differentially expressed in the brain tissue and blood plasma of rats 24 h after exposure, among which miR-145-3p and miR-375-3p were downregulated and miR-19a-3p, miR-92a-3p, miR-188-5p, and miR-532-5p were upregulated. In our opinion, miR-188-5p and miR-532-5p may be considered to be new potential markers of ischemic injury. The level of miRNA expression tended to increase 48 h after the onset of ischemia in brain tissue and leukocytes, which reflects not only the local response in brain tissue due to inflammation, vascular endothelial dysfunction, and disorders of the permeability of the blood-brain barrier, but also the systemic response of the organism to multifactor molecular processes induced by ischemic injury.

Markers for blood-brain barrier integrity

DEFF Research Database (Denmark)

Saunders, Norman R; Dziegielewska, Katarzyna M; Møllgård, Kjeld

2015-01-01

In recent years there has been a resurgence of interest in brain barriers and various roles their intrinsic mechanisms may play in neurological disorders. Such studies require suitable models and markers to demonstrate integrity and functional changes at the interfaces between blood, brain......, and cerebrospinal fluid. Studies of brain barrier mechanisms and measurements of plasma volume using dyes have a long-standing history, dating back to the late nineteenth-century. Their use in blood-brain barrier studies continues in spite of their known serious limitations in in vivo applications. These were well...... known when first introduced, but seem to have been forgotten since. Understanding these limitations is important because Evans blue is still the most commonly used marker of brain barrier integrity and those using it seem oblivious to problems arising from its in vivo application. The introduction...

Lysosomal storage diseases and the blood-brain barrier.

Science.gov (United States)

Begley, David J; Pontikis, Charles C; Scarpa, Maurizio

2008-01-01

The blood-brain barrier becomes a crucial issue in neuronopathic lysosomal storage diseases for three reasons. Firstly, the function of the blood-brain barrier may be compromised in many of the lysosomal storage diseases and this barrier dysfunction may contribute to the neuropathology seen in the diseases and accelerate cell death. Secondly, the substrate reduction therapies, which successfully reduce peripheral lysosomal storage, because of the blood-brain barrier may not have as free an access to brain cells as they do to peripheral cells. And thirdly, enzyme replacement therapy appears to have little access to the central nervous system as the mannose and mannose-6-phosphate receptors involved in their cellular uptake and transport to the lysosome do not appear to be expressed at the adult blood-brain barrier. This review will discuss in detail these issues and their context in the development of new therapeutic strategies.

Cranial Ultrasound/Head Ultrasound

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... used to screen for brain conditions associated with prematurity, such as bleeding or brain tissue damage as ... or crying child will slow the examination process. Large patients are more difficult to image by ultrasound, ...

Modeling Group B Streptococcus and Blood-Brain Barrier Interaction by Using Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells

OpenAIRE

Kim, Brandon J.; Bee, Olivia B.; McDonagh, Maura A.; Stebbins, Matthew J.; Palecek, Sean P.; Doran, Kelly S.; Shusta, Eric V.

2017-01-01

ABSTRACT Bacterial meningitis is a serious infection of the central nervous system (CNS) that occurs after bacteria interact with and penetrate the blood-brain barrier (BBB). The BBB is comprised of highly specialized brain microvascular endothelial cells (BMECs) that function to separate the circulation from the CNS and act as a formidable barrier for toxins and pathogens. Certain bacteria, such as Streptococcus agalactiae (group B Streptococcus [GBS]), possess the ability to interact with a...

Transcranial cavitation-mediated ultrasound therapy at sub-MHz frequency via temporal interference modulation

Science.gov (United States)

Sun, Tao; Sutton, Jonathan T.; Power, Chanikarn; Zhang, Yongzhi; Miller, Eric L.; McDannold, Nathan J.

2017-10-01

Sub-megahertz transmission is not usually adopted in pre-clinical small animal experiments for focused ultrasound (FUS) brain therapy due to the large focal size. However, low frequency FUS is vital for preclinical evaluations due to the frequency-dependence of cavitation behavior. To maximize clinical relevance, a dual-aperture FUS system was designed for low-frequency (274.3 kHz) cavitation-mediated FUS therapy. Combining two spherically curved transducers provides significantly improved focusing in the axial direction while yielding an interference pattern with strong side lobes, leading to inhomogeneously distributed cavitation activities. By operating the two transducers at slightly offset frequencies to modulate this interference pattern over the period of sonication, the acoustic energy was redistributed and resulted in a spatially homogenous treatment profile. Simulation and pressure field measurements in water were performed to assess the beam profiles. In addition, the system performance was demonstrated in vivo in rats via drug delivery through microbubble-mediated blood-brain barrier disruption. This design resulted in a homogenous treatment profile that was fully contained within the rat brain at a clinically relevant acoustic frequency.

Ultrasound-mediated Optical Imaging and Focusing in Scattering Media

Science.gov (United States)

Suzuki, Yuta

Because of its non-ionizing and molecular sensing nature, light has been an attractive tool in biomedicine. Scanning an optical focus allows not only high-resolution imaging but also manipulation and therapy. However, due to multiple photon scattering events, conventional optical focusing using an ordinary lens is limited to shallow depths of one transport mean free path (lt'), which corresponds to approximately 1 mm in human tissue. To overcome this limitation, ultrasonic modulation (or encoding ) of diffuse light inside scattering media has enabled us to develop both deep-tissue optical imaging and focusing techniques, namely, ultrasound-modulated optical tomography (UOT) and time-reversed ultrasonically encoded (TRUE) optical focusing. While UOT measures the power of the encoded light to obtain an image, TRUE focusing generates a time-reversed (or phase-conjugated) copy of the encoded light, using a phase-conjugate mirror to focus light inside scattering media beyond 1 lt'. However, despite extensive progress in both UOT and TRUE focusing, the low signal-to-noise ratio in encoded-light detection remains a challenge to meeting both the speed and depth requirements for in vivo applications. This dissertation describes technological advancements of both UOT and TRUE focusing, in terms of their signal detection sensitivities, operational depths, and operational speeds. The first part of this dissertation describes sensitivity improvements of encoded-light detection in UOT, achieved by using a large area (˜5 cm x 5 cm) photorefractive polymer. The photorefractive polymer allowed us to improve the detection etendue by more than 10 times that of previous detection schemes. It has enabled us to resolve absorbing objects embedded inside diffused media thicker than 80 lt', using moderate light power and short ultrasound pulses. The second part of this dissertation describes energy enhancement and fluorescent excitation using TRUE focusing in turbid media, using

Influence of CO2 on ultrasound-induced polymerizations in high-pressure fluids

NARCIS (Netherlands)

Kuijpers, M.W.A.; Jacobs, L.J.M.; Kemmere, M.F.; Keurentjes, J.T.F.

2005-01-01

A strong viscosity increase upon polymerization hinders cavitation and subsequent radical formation during an ultrasound-induced bulk polymerization. Ultrasound-induced radical polymerizations of methyl methacrylate (MMA) have been performed in CO2-expanded MMA, as well as in bulk MMA. For this

Effects of intracarotid ioxaglate on the normal blood-brain barrier

International Nuclear Information System (INIS)

Wilcox, J.; Sage, M.R.

1985-01-01

Using two different models, the effect on the blood-brain barrier of intracarotid injections of sodium/meglumine ioxaglate at similar iodine concentrations (280 mgI/ml) was investigated. In both models the degree of blood-brain barrier damage was assessed visually using Evans' Blue stain. Quantitative assessment of blood-brain barrier disruption was made by contrast enhancement as measured by CT of the dog brain, and by 99m Tc-pertechnetate uptake by the brain in the rabbit model. No Evans' Blue staining was observed in any study using the canine/CT model. Slight staining was observed in two studies with ioxaglate using the rabbit/pertechnetate model. Statistical analysis of results from the canine/CT model did not detect any damage to the blood-brain barrier with either ioxaglate or saline control studies (P>0.1). However, in the rabbit/pertechnetate model a slight increase in disruption of the blood-brain barrier was observed with ioxaglate compared with control studies, but this was only significant at the 0.1 level. The results suggest that the rabbit/pertechnetate model is a more sensitive measure of blood-brain barrier disruption than the canine/CT model. This study also demonstrates that blood-brain barrier disruption following intracarotid injection of ioxaglate is minimal. (orig.)

Thrombolysis using multi-frequency high intensity focused ultrasound at MHz range: an in vitro study

International Nuclear Information System (INIS)

Suo, Dingjie; Guo, Sijia; Jiang, Xiaoning; Jing, Yun; Lin, Weili

2015-01-01

High intensity focused ultrasound (HIFU) based thrombolysis has emerged as a promising drug-free treatment approach for ischemic stroke. The large amount of acoustic power required by this approach, however, poses a critical challenge to the future clinical translation. In this study, multi-frequency acoustic waves at MHz range (near 1.5 MHz) were introduced as HIFU excitations to reduce the required power for treatment as well as the treatment time. In vitro bovine blood clots weighing around 150 mg were treated by single-frequency and multi-frequency HIFU. The pulse length was 2 ms for all experiments except the ones where the duty cycle was changed. It was found that dual-frequency thrombolysis efficiency was statistically better than single-frequency under the same acoustic power and excitation condition. When varying the acoustic power but fixing the duty cycle at 5%, it was found that dual-frequency ultrasound can save almost 30% power in order to achieve the same thrombolysis efficiency. In the experiment where the duty cycle was increased from 0.5% to 10%, it was shown that dual-frequency ultrasound can achieve the same thrombolysis efficiency with only half of the duty cycle of single-frequency. Dual-frequency ultrasound could also accelerate the thrombolysis by a factor of 2–4 as demonstrated in this study. No significant differences were found between dual-frequencies with different frequency differences (0.025, 0.05, and 0.1 MHz) and between dual-frequency and triple-frequency. The measured cavitation doses of dual-frequency and triple-frequency excitations were at about the same level but both were significantly higher than that of single-frequency. (paper)

High-intensity focused ultrasound in the treatment of breast tumours.

Science.gov (United States)

Peek, Mirjam C L; Wu, Feng

2018-01-01

High-intensity focused ultrasound (HIFU) is a minimally invasive technique that has been used for the treatment of both benign and malignant tumours. With HIFU, an ultrasound (US) beam propagates through soft tissue as a high-frequency pressure wave. The US beam is focused at a small target volume, and due to the energy building up at this site, the temperature rises, causing coagulative necrosis and protein denaturation within a few seconds. HIFU is capable of providing a completely non-invasive treatment without causing damage to the directly adjacent tissues. HIFU can be either guided by US or magnetic resonance imaging (MRI). Guided imaging is used to plan the treatment, detect any movement during the treatment and monitor response in real-time. This review describes the history of HIFU, the HIFU technique, available devices and gives an overview of the published literature in the treatment of benign and malignant breast tumours with HIFU.

Ultrashort echo-time MRI versus CT for skull aberration correction in MR-guided transcranial focused ultrasound: In vitro comparison on human calvaria.

Science.gov (United States)

Miller, G Wilson; Eames, Matthew; Snell, John; Aubry, Jean-François

2015-05-01

Transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) brain treatment systems compensate for skull-induced beam aberrations by adjusting the phase and amplitude of individual ultrasound transducer elements. These corrections are currently calculated based on a preacquired computed tomography (CT) scan of the patient's head. The purpose of the work presented here is to demonstrate the feasibility of using ultrashort echo-time magnetic resonance imaging (UTE MRI) instead of CT to calculate and apply aberration corrections on a clinical TcMRgFUS system. Phantom experiments were performed in three ex-vivo human skulls filled with tissue-mimicking hydrogel. Each skull phantom was imaged with both CT and UTE MRI. The MR images were then segmented into "skull" and "not-skull" pixels using a computationally efficient, threshold-based algorithm, and the resulting 3D binary skull map was converted into a series of 2D virtual CT images. Each skull was mounted in the head transducer of a clinical TcMRgFUS system (ExAblate Neuro, Insightec, Israel), and transcranial sonications were performed using a power setting of approximately 750 acoustic watts at several different target locations within the electronic steering range of the transducer. Each target location was sonicated three times: once using aberration corrections calculated from the actual CT scan, once using corrections calculated from the MRI-derived virtual CT scan, and once without applying any aberration correction. MR thermometry was performed in conjunction with each 10-s sonication, and the highest single-pixel temperature rise and surrounding-pixel mean were recorded for each sonication. The measured temperature rises were ∼ 45% larger for aberration-corrected sonications than for noncorrected sonications. This improvement was highly significant (p skull-induced ultrasound aberration corrections. Their results suggest that UTE MRI could be used instead of CT to implement such corrections on

The design of a focused ultrasound transducer array for the treatment of stroke: a simulation study

International Nuclear Information System (INIS)

Pajek, Daniel; Hynynen, Kullervo

2012-01-01

High intensity focused ultrasound (HIFU) is capable of mechanically disintegrating blood clots at high pressures. Safe thrombolysis may require frequencies higher than those currently utilized by transcranial HIFU. Since the attenuation and focal distortion of ultrasound in bone increases at higher frequencies, resulting focal pressures are diminished. This study investigated the feasibility of using transcranial HIFU for the non-invasive treatment of ischemic stroke. The use of large aperture, 1.1–1.5 MHz phased arrays in targeting four clinically relevant vessel locations was simulated. Resulting focal sizes decreased with frequency, producing a maximum –3 dB depth of field and lateral width of 2.0 and 1.2 mm, respectively. Mean focal gains above an order of magnitude were observed in three of four targets and transducer intensities required to achieve thrombolysis were determined. Required transducer element counts are about an order of magnitude higher than what currently exists and so, although technically feasible, new arrays would need to be developed to realize this as a treatment modality for stroke. (paper)

Examination of Blood-Brain Barrier (BBB) Integrity In A Mouse Brain Tumor Model

Science.gov (United States)

On, Ngoc; Mitchell, Ryan; Savant, Sanjot D.; Bachmeier, Corbin. J.; Hatch, Grant M.; Miller, Donald W.

2013-01-01

The present study evaluates, both functionally and biochemically, brain tumor-induced alterations in brain capillary endothelial cells. Brain tumors were induced in Balb/c mice via intracranial injection of Lewis Lung carcinoma (3LL) cells into the right hemisphere of the mouse brain using stereotaxic apparatus. Blood-brain barrier (BBB) permeability was assessed at various stages of tumor development, using both radiolabeled tracer permeability and magnetic resonance imaging (MRI) with gadolinium diethylene-triamine-pentaacetate contrast enhancement (Gad-DTPA). The expression of the drug efflux transporter, P-glycoprotein (P-gp), in the BBB at various stages of tumor development was also evaluated by Western blot and immunohistochemistry. Median mouse survival following tumor cell injection was 17 days. The permeability of the BBB to 3H-mannitol was similar in both brain hemispheres at 7 and 10 days post-injection. By day 15, there was a 2-fold increase in 3H-mannitol permeability in the tumor bearing hemispheres compared to the non-tumor hemispheres. Examination of BBB permeability with Gad-DTPA contrast enhanced MRI indicated cerebral vascular permeability changes were confined to the tumor area. The permeability increase observed at the later stages of tumor development correlated with an increase in cerebral vascular volume suggesting angiogenesis within the tumor bearing hemisphere. Furthermore, the Gad-DPTA enhancement observed within the tumor area was significantly less than Gad-DPTA enhancement within the circumventricular organs not protected by the BBB. Expression of P-gp in both the tumor bearing and non-tumor bearing portions of the brain appeared similar at all time points examined. These studies suggest that although BBB integrity is altered within the tumor site at later stages of development, the BBB is still functional and limiting in terms of solute and drug permeability in and around the tumor. PMID:23184143

Magnetic resonance imaging indicators of blood-brain barrier and brain water changes in young rats with kaolin-induced hydrocephalus.

Science.gov (United States)

Del Bigio, Marc R; Slobodian, Ili; Schellenberg, Angela E; Buist, Richard J; Kemp-Buors, Tanya L

2011-08-11

Hydrocephalus is associated with enlargement of cerebral ventricles. We hypothesized that magnetic resonance (MR) imaging parameters known to be influenced by tissue water content would change in parallel with ventricle size in young rats and that changes in blood-brain barrier (BBB) permeability would be detected. Hydrocephalus was induced by injection of kaolin into the cisterna magna of 4-week-old rats, which were studied 1 or 3 weeks later. MR was used to measure longitudinal and transverse relaxation times (T1 and T2) and apparent diffusion coefficients in several regions. Brain tissue water content was measured by the wet-dry weight method, and tissue density was measured in Percoll gradient columns. BBB permeability was measured by quantitative imaging of changes on T1-weighted images following injection of gadolinium diethylenetriamine penta-acetate (Gd-DTPA) tracer and microscopically by detection of fluorescent dextran conjugates. In nonhydrocephalic rats, water content decreased progressively from age 3 to 7 weeks. T1 and T2 and apparent diffusion coefficients did not exhibit parallel changes and there was no evidence of BBB permeability to tracers. The cerebral ventricles enlarged progressively in the weeks following kaolin injection. In hydrocephalic rats, the dorsal cortex was more dense and the white matter less so, indicating that the increased water content was largely confined to white matter. Hydrocephalus was associated with transient elevation of T1 in gray and white matter and persistent elevation of T2 in white matter. Changes in the apparent diffusion coefficients were significant only in white matter. Ventricle size correlated significantly with dorsal water content, T1, T2, and apparent diffusion coefficients. MR imaging showed evidence of Gd-DTPA leakage in periventricular tissue foci but not diffusely. These correlated with microscopic leak of larger dextran tracers. MR characteristics cannot be used as direct surrogates for water

Magnetic resonance imaging indicators of blood-brain barrier and brain water changes in young rats with kaolin-induced hydrocephalus

Directory of Open Access Journals (Sweden)

Del Bigio Marc R

2011-08-01

Full Text Available Abstract Background Hydrocephalus is associated with enlargement of cerebral ventricles. We hypothesized that magnetic resonance (MR imaging parameters known to be influenced by tissue water content would change in parallel with ventricle size in young rats and that changes in blood-brain barrier (BBB permeability would be detected. Methods Hydrocephalus was induced by injection of kaolin into the cisterna magna of 4-week-old rats, which were studied 1 or 3 weeks later. MR was used to measure longitudinal and transverse relaxation times (T1 and T2 and apparent diffusion coefficients in several regions. Brain tissue water content was measured by the wet-dry weight method, and tissue density was measured in Percoll gradient columns. BBB permeability was measured by quantitative imaging of changes on T1-weighted images following injection of gadolinium diethylenetriamine penta-acetate (Gd-DTPA tracer and microscopically by detection of fluorescent dextran conjugates. Results In nonhydrocephalic rats, water content decreased progressively from age 3 to 7 weeks. T1 and T2 and apparent diffusion coefficients did not exhibit parallel changes and there was no evidence of BBB permeability to tracers. The cerebral ventricles enlarged progressively in the weeks following kaolin injection. In hydrocephalic rats, the dorsal cortex was more dense and the white matter less so, indicating that the increased water content was largely confined to white matter. Hydrocephalus was associated with transient elevation of T1 in gray and white matter and persistent elevation of T2 in white matter. Changes in the apparent diffusion coefficients were significant only in white matter. Ventricle size correlated significantly with dorsal water content, T1, T2, and apparent diffusion coefficients. MR imaging showed evidence of Gd-DTPA leakage in periventricular tissue foci but not diffusely. These correlated with microscopic leak of larger dextran tracers. Conclusions MR

Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage.

Directory of Open Access Journals (Sweden)

Kyeung Min Joo

Full Text Available Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.

Effects of high-fat diet and losartan on renal cortical blood flow using contrast ultrasound imaging.

Science.gov (United States)

Declèves, Anne-Emilie; Rychak, Joshua J; Smith, Dan J; Sharma, Kumar

2013-11-01

Obesity-related kidney disease occurs as a result of complex interactions between metabolic and hemodynamic effects. Changes in microvascular perfusion may play a major role in kidney disease; however, these changes are difficult to assess in vivo. Here, we used perfusion ultrasound imaging to evaluate cortical blood flow in a mouse model of high-fat diet-induced kidney disease. C57BL/6J mice were randomized to a standard diet (STD) or a high-fat diet (HFD) for 30 wk and then treated either with losartan or a placebo for an additional 6 wk. Noninvasive ultrasound perfusion imaging of the kidney was performed during infusion of a microbubble contrast agent. Blood flow within the microvasculature of the renal cortex and medulla was derived from imaging data. An increase in the time required to achieve full cortical perfusion was observed for HFD mice relative to STD. This was reversed following treatment with losartan. These data were concurrent with an increased glomerular filtration rate in HFD mice compared with STD- or HFD-losartan-treated mice. Losartan treatment also abrogated fibro-inflammatory disease, assessed by markers at the protein and messenger level. Finally, a reduction in capillary density was found in HFD mice, and this was reversed upon losartan treatment. This suggests that alterations in vascular density may be responsible for the elevated perfusion time observed by imaging. These data demonstrate that ultrasound contrast imaging is a robust and sensitive method for evaluating changes in renal microvascular perfusion and that cortical perfusion time may be a useful parameter for evaluating obesity-related renal disease.

Anti-inflammatory effect with high intensity focused ultrasound-mediated pulsatile delivery of diclofenac.

Science.gov (United States)

Wang, Chih-Yu; Yang, Chih-Hui; Lin, Yung-Sheng; Chen, Chih-Hsin; Huang, Keng-Shiang

2012-02-01

A pulsatile ultrasound controlled drug release platform with diclofenac-loaded alginate microcapsules (fabricated with a home-made electrostatic device, 75% embedded rate) was established to evaluate anti-inflammation efficiency. Better anti-inflammation efficiency was found using the ultrasound system and the drug delivery can be adjusted based on the programmed ultrasound cycle. The results of the in vitro study show that an approx. 30% higher drug release rate was obtained by using continuous ultrasound irradiation (9-Watt, 180 min), and an approx. 16% higher drug release rate was obtained by using pulsatile ultrasound irradiation (9-Watt, 60 min) compared to without ultrasound activation. For the in vivo study, the anti-inflammatory test with carrageenan-induced rat's paw edema shows that diclofenac-loaded microcapsules followed by ultrasound irradiation (9-Watt, 60 min) contributed to an 81% inhibition rate, which was significantly higher than diclofenac only (approx. 60% higher). In addition, because of their heat conducting properties, gold nanoparticles encapsulated in the diclofenac-loaded microcapsules resulted in better drug release efficiency, but tended to depress the anti-inflammation effect. Copyright © 2011 Elsevier Ltd. All rights reserved.

MRI feedback temperature control for focused ultrasound surgery

International Nuclear Information System (INIS)

Vanne, A; Hynynen, K

2003-01-01

A temperature feedback controller routine using a physical model for temperature evolution was developed for use with focused ultrasound surgery. The algorithm for the controller was a multi-input, single-output linear quadratic regulator (LQR) derived from Pennes' bioheat transfer equation. The controller was tested with simulated temperature data that had the same characteristics as those obtained with magnetic resonance imaging (MRI). The output of the controller was the appropriate power level to be used by the transducer. Tissue parameters estimated prior to the simulated treatments were used to determine the controller parameters. The controller performance was simulated in three dimensions with varying system parameters, and sufficient temperature tracking was achieved. The worst-case overshoot was 7 deg. C and the steady-state error was 5 deg. C. The simulated behaviour of the controller suggests satisfactory performance and that the controller may be useful in controlling the power output during MRI-monitored ultrasound surgery

The effect of blood acceleration on the ultrasound power Doppler spectrum

Science.gov (United States)

Matchenko, O. S.; Barannik, E. A.

2017-09-01

The purpose of the present work was to study the influence of blood acceleration and time window length on the power Doppler spectrum for Gaussian ultrasound beams. The work has been carried out on the basis of continuum model of the ultrasound scattering from inhomogeneities in fluid flow. Correlation function of fluctuations has been considered for uniformly accelerated scatterers, and the resulting power Doppler spectra have been calculated. It is shown that within the initial phase of systole uniformly accelerated slow blood flow in pulmonary artery and aorta tends to make the correlation function about 4.89 and 7.83 times wider, respectively, than the sensitivity function of typical probing system. Given peak flow velocities, the sensitivity function becomes, vice versa, about 4.34 and 3.84 times wider, respectively, then the correlation function. In these limiting cases, the resulting spectra can be considered as Gaussian. The optimal time window duration decreases with increasing acceleration of blood flow and equals to 11.62 and 7.54 ms for pulmonary artery and aorta, respectively. The width of the resulting power Doppler spectrum is shown to be defined mostly by the wave vector of the incident field, the duration of signal and the acceleration of scatterers in the case of low flow velocities. In the opposite case geometrical properties of probing field and the average velocity itself are more essential. In the sense of signal-noise ratio, the optimal duration of time window can be found. Abovementioned results may contribute to the improved techniques of Doppler ultrasound diagnostics of cardiovascular system.

Cranial nerve threshold for thermal injury induced by MRI-guided high-intensity focused ultrasound (MRgHIFU): preliminary results on an optic nerve model.

Science.gov (United States)

Harnof, Sagi; Zibly, Zion; Cohen, Zvi; Shaw, Andrew; Schlaff, Cody; Kassel, Neal F

2013-04-01

Future clinical applications of magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) are moving toward the management of different intracranial pathologies. We sought to validate the production, safety, and efficacy of thermal injury to cranial nerves generated by MRgHIFU. In this study, five female domestic pigs underwent a standard bifrontal craniectomy under general anesthesia. Treatment was then given using an MRgHIFU system to induce hyperthermic ablative sonication (6 to 10 s; 50 to 2000 J.) Histological analyses were done to confirm nerve damage; temperature measured on the optic nerve was approximately 53.4°C (range: 39°C to 70°C.) Histology demonstrated a clear definition between a necrotic, transitional zone, and normal tissue. MRgHIFU induces targeted thermal injury to nervous tissue within a specific threshold of 50°C to 60°C with the tissue near the sonication center yielding the greatest effect; adjacent tissue showed minimal changes. Additional studies utilizing this technology are required to further establish accurate threshold parameters for optic nerve thermo-ablation.

Enhanced tumor cell killing following BNCT with hyperosmotic mannitol-induced blood-brain barrier disruption and intracarotid injection of boronophenylalanine

International Nuclear Information System (INIS)

Hsieh, C.H.; Hwang, J.J.; Chen, F.D.; Liu, R.S.; Liu, H.M.; Hsueh, Y.W.; Kai, J.J.

2006-01-01

The delivery of boronophenylalanine (BPA) by means of intracarotid injection combined with opening the blood-brain barrier (BBB) have been shown significantly enhanced the tumor boron concentration and the survival time of glioma-bearing rats. However, no direct evidence demonstrates whether this treatment protocol can enhance the cell killing of tumor cells or infiltrating tumor cells and the magnitude of enhanced cell killing. The purpose of the present study was to determine if the tumor cell killing of boron neutron capture therapy could be enhanced by hyperosmotic mannitol-induced BBB disruption using BPA-Fr as the capture agent. F98 glioma-bearing rats were injected intravenously or intracarotidly with BPA at doses of 500 mg/kg body weight (b.w.) and with or without mannitol-induced hyperosmotic BBB disruption. The rats were irradiated with an epithermal neutron beam at the reactor of National Tsing-Hua University (THOR). After neutron beam irradiation, the rats were euthanized and the ipsilateral brains containing intracerebral F98 glioma were removed to perform in vivo/in vitro soft agar clonogenic assay. The results demonstrate BNCT with optimizing the delivery of BPA by means of intracarotid injection combined with opening the BBB by infusing a hyperosmotic solution of mannitol significantly enhanced the cell killing of tumor cells and infiltrating tumor cells, the tumor boron concentration and the boron ratio of tumor to normal brain tissues. (author)

Blood velocity estimation using ultrasound and spectral iterative adaptive approaches

DEFF Research Database (Denmark)

Gudmundson, Erik; Jakobsson, Andreas; Jensen, Jørgen Arendt

2011-01-01

-mode images are interleaved with the Doppler emissions. Furthermore, the techniques are shown, using both simplified and more realistic Field II simulations as well as in vivo data, to outperform current state-of-the-art techniques, allowing for accurate estimation of the blood velocity spectrum using only 30......This paper proposes two novel iterative data-adaptive spectral estimation techniques for blood velocity estimation using medical ultrasound scanners. The techniques make no assumption on the sampling pattern of the emissions or the depth samples, allowing for duplex mode transmissions where B...

Inferring common cognitive mechanisms from brain blood-flow lateralization data: a new methodology for fTCD analysis.

Science.gov (United States)

Meyer, Georg F; Spray, Amy; Fairlie, Jo E; Uomini, Natalie T

2014-01-01

Current neuroimaging techniques with high spatial resolution constrain participant motion so that many natural tasks cannot be carried out. The aim of this paper is to show how a time-locked correlation-analysis of cerebral blood flow velocity (CBFV) lateralization data, obtained with functional TransCranial Doppler (fTCD) ultrasound, can be used to infer cerebral activation patterns across tasks. In a first experiment we demonstrate that the proposed analysis method results in data that are comparable with the standard Lateralization Index (LI) for within-task comparisons of CBFV patterns, recorded during cued word generation (CWG) at two difficulty levels. In the main experiment we demonstrate that the proposed analysis method shows correlated blood-flow patterns for two different cognitive tasks that are known to draw on common brain areas, CWG, and Music Synthesis. We show that CBFV patterns for Music and CWG are correlated only for participants with prior musical training. CBFV patterns for tasks that draw on distinct brain areas, the Tower of London and CWG, are not correlated. The proposed methodology extends conventional fTCD analysis by including temporal information in the analysis of cerebral blood-flow patterns to provide a robust, non-invasive method to infer whether common brain areas are used in different cognitive tasks. It complements conventional high resolution imaging techniques.

Glial and neuronal control of brain blood flow

DEFF Research Database (Denmark)

Attwell, David; Buchan, Alastair M; Charpak, Serge

2010-01-01

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...... in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches....

Curcumin attenuates blood-brain barrier disruption after subarachnoid hemorrhage in mice.

Science.gov (United States)

Yuan, Jichao; Liu, Wei; Zhu, Haitao; Zhang, Xuan; Feng, Yang; Chen, Yaxing; Feng, Hua; Lin, Jiangkai

2017-01-01

Early brain injury, one of the most important mechanisms underlying subarachnoid hemorrhage (SAH), comprises edema formation and blood-brain barrier (BBB) disruption. Curcumin, an active extract from the rhizomes of Curcuma longa, alleviates neuroinflammation by as yet unknown neuroprotective mechanisms. In this study, we examined whether curcumin treatment ameliorates SAH-induced brain edema and BBB permeability changes, as well as the mechanisms underlying this phenomenon. We induced SAH in mice via endovascular perforation, administered curcumin 15 min after surgery and evaluated neurologic scores, brain water content, Evans blue extravasation, Western blot assay results, and immunohistochemical analysis results 24 h after surgery. Curcumin significantly improved neurologic scores and reduced brain water content in treated mice compared with SAH mice. Furthermore, curcumin decreased Evans blue extravasation, matrix metallopeptidase-9 expression, and the number of Iba-1-positive microglia in treated mice compared with SAH mice. At last, curcumin treatment increased the expression of the tight junction proteins zonula occludens-1 and occludin in treated mice compared with vehicle-treated and sample SAH mice. We demonstrated that curcumin inhibits microglial activation and matrix metallopeptidase-9 expression, thereby reducing brain edema and attenuating post-SAH BBB disruption in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Blood-brain transfer of Pittsburgh compound B in humans

DEFF Research Database (Denmark)

Gjedde, Albert; Aanerud, Joel; Braendgaard, Hans

2013-01-01

-brain barrier is held to be high but the permeability-surface area product and extraction fractions in patients or healthy volunteers are not known. We used PET to determine the clearance associated with the unidrectional blood-brain transfer of [(11)C]PiB and the corresponding cerebral blood flow rates...... with the observation that numerically, but insignificantly, unidirectional blood-brain clearances are lower and extraction fractions higher in the patients. The evidence of unchanged permeability-surface area products in the patients implies that blood flow changes can be deduced from the unidirectional blood......In the labeled form, the Pittsburgh compound B (2-(4'-{N-methyl-[(11)C]}methyl-aminophenyl)-6-hydroxy-benzothiazole, [(11)C]PiB), is used as a biomarker for positron emission tomography (PET) of brain β-amyloid deposition in Alzheimer's disease (AD). The permeability of [(11)C]PiB in the blood...

[Chromogranin A derived peptide CGA47-66 inhibits hyper-permeability of blood brain barrier in mice with sepsis].

Science.gov (United States)

Zeng, Yan; Zhang, Dan; Jiang, Liping; Wei, Fu; Xu, Shan

2016-02-01

To explore the effect of chromofungin (CHR), a chromogranin A (CGA) derived peptide CGA47-66, on hyper-permeability of blood brain barrier in septic mice. 120 healthy male C57BL/6 mice were randomly divided into groups, with 12 mice in each group. Seventy-two mice were used for dynamic observation of the contents of water and Evan blue (EB) in brain tissue after being treated with lipopolysaccharide (LPS). Another 48 mice were divided into normal saline control group (NS group), LPS induced sepsis model group (LPS group), low-dose CHR pretreatment group (CL+LPS group), and high-dose CHR pretreatment group (CH+LPS group). The septic model was reproduced by intraperitoneal injection of 10 mg/kg LPS 0.1 mL, and the mice in NS group was given equal volume of normal saline. The mice in CL+LPS group and CH+LPS group were intraperitoneally injected with 15.5 μg/kg and 77.5 μg/kg CHR 10 minutes before LPS injection. Six hours after LPS injection, 4 mL/kg of 2% EB was injected via caudal vein, the contents of water and EB in brain tissue were determined, and EB immune fluorescence in brain tissue was determined to assess the changes in permeability of blood brain barrier. Brain pathology was observed with hematoxylin and eosin (HE) staining. With the extension of time after LPS injection, the contents of water and EB in brain tissue were gradually increased, and the time of difference with statistical significance appeared earlier when compared with that of control group in the contents of water than that in EB contents (3 hours and 6 hours, respectively). The contents of water and EB in brain tissue in LPS group were significantly increased as compared with NS group [water content: (79.77±0.62)% vs. (78.28±0.44)%, P water and EB contents in brain tissue induced by LPS, and the effect was more significant in CH+LPS group [water content: (78.15±0.73)% vs. (79.77±0.62)%, EB (μg/g): 7.09±2.59 vs. 13.87±4.50, both P leakage in LPS group was more marked than that of NS

Thymoquinone ameliorates lead-induced brain damage in Sprague Dawley rats.

Science.gov (United States)

Radad, Khaled; Hassanein, Khaled; Al-Shraim, Mubarak; Moldzio, Rudolf; Rausch, Wolf-Dieter

2014-01-01

The present study aims to investigate the protective effects of thymoquinone, the major active ingredient of Nigella sativa seeds, against lead-induced brain damage in Sprague-Dawley rats. In which, 40 rats were divided into four groups (10 rats each). The first group served as control. The second, third and fourth groups received lead acetate, lead acetate and thymoquinone, and thymoquinone only, respectively, for one month. Lead acetate was given in drinking water at a concentration of 0.5 g/l (500 ppm). Thymoquinone was given daily at a dose of 20mg/kg b.w. in corn oil by gastric tube. Control and thymoquinone-treated rats showed normal brain histology. Treatment of rats with lead acetate was shown to produce degeneration of endothelial lining of brain blood vessels with peri-vascular cuffing of mononuclear cells consistent to lymphocytes, congestion of choroid plexus blood vessels, ischemic brain infarction, chromatolysis and neuronal degeneration, microglial reaction and neuronophagia, degeneration of hippocampal and cerebellar neurons, and axonal demyelination. On the other hand, co-administration of thymoquinone with lead acetate markedly decreased the incidence of lead acetate-induced pathological lesions. Thus the current study shed some light on the beneficial effects of thymoquinone against neurotoxic effects of lead in rats. Copyright © 2013 Elsevier GmbH. All rights reserved.

Sleep restriction impairs blood-brain barrier function.

Science.gov (United States)

He, Junyun; Hsuchou, Hung; He, Yi; Kastin, Abba J; Wang, Yuping; Pan, Weihong

2014-10-29

The blood-brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice. Copyright © 2014 the authors 0270-6474/14/3414697-10$15.00/0.

Glial and neuronal control of brain blood flow

DEFF Research Database (Denmark)

Attwell, David; Buchan, Alastair M; Charpak, Serge

2010-01-01

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...... recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts...

Blood BDNF concentrations reflect brain-tissue BDNF levels across species

DEFF Research Database (Denmark)

Klein, Anders B; Williamson, Rebecca; Santini, Martin A

2011-01-01

Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been...... no studies directly comparing blood BDNF levels to brain BDNF levels in different species. We examined blood, serum, plasma and brain-tissue BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method. As a control, we included an analysis of blood and brain tissue from...... conditional BDNF knockout mice and their wild-type littermates. Whereas BDNF could readily be measured in rat blood, plasma and brain tissue, it was undetectable in mouse blood. In pigs, whole-blood levels of BDNF could not be measured with a commercially available ELISA kit, but pig plasma BDNF levels (mean...

Blood BDNF concentrations reflect brain-tissue BDNF levels across species

DEFF Research Database (Denmark)

Klein, Anders B; Williamson, Rebecca; Santini, Martin A

2011-01-01

no studies directly comparing blood BDNF levels to brain BDNF levels in different species. We examined blood, serum, plasma and brain-tissue BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method. As a control, we included an analysis of blood and brain tissue from......Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been...... conditional BDNF knockout mice and their wild-type littermates. Whereas BDNF could readily be measured in rat blood, plasma and brain tissue, it was undetectable in mouse blood. In pigs, whole-blood levels of BDNF could not be measured with a commercially available ELISA kit, but pig plasma BDNF levels (mean...

Estrogen and insulin transport through the blood-brain barrier.

Science.gov (United States)

May, Aaron A; Bedel, Nicholas D; Shen, Ling; Woods, Stephen C; Liu, Min

2016-09-01

Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS. Copyright © 2016 Elsevier Inc. All rights reserved.

Postmortem Quetiapine Reference Concentrations in Brain and Blood

DEFF Research Database (Denmark)

Skov, Louise; Johansen, Sys Stybe; Linnet, Kristian

2015-01-01

and related to concentrations in postmortem blood. For cases, where quetiapine was unrelated to the cause of death (N 5 36), the 10–90 percentiles for quetiapine concentrations in brain tissue were 0.030 – 1.54 mg/kg (median 0.48 mg/kg, mean 0.79 mg/kg). Corresponding blood 10 –90 percentile values were 0.......007 – 0.39 mg/kg (median 0.15 mg/kg, mean 0.19 mg/kg), giving brain –blood ratio 10 –90 percentiles of 2.31 – 6.54 (median 3.87, mean 4.32). Both correspond well to the limited amount of data found in the literature. For cases where quetiapine was a contributing factor to death (N 5 5), the median value......Brain tissue is a useful alternative to blood in postmortem forensic investigations, but scarcity of information on reference concentrations in brain tissue makes interpretation challenging. Here we present a study of 43 cases where the antipsychotic drug quetiapine was quantified in brain tissue...

Quantitative measurement of total cerebral blood flow using 2D phase-contrast MRI and doppler ultrasound

Energy Technology Data Exchange (ETDEWEB)

Seo, Keum Soo; Choi, Sun Seob; Lee, Young Il [Dong-A Univ., College of Medicine, Busan (Korea, Republic of)

2001-12-01

To compare of quantitative measurement of the total cerebral blood flow using two-dimensional phase-contrast MR imaging and Doppler ultrasound. In 16 volunteers (mean age, 26 years; mean body weight, 66 kg) without abnormal medical histories, two-dimensional phase-contrast MR imaging was performed at the level of the C2-3 inter vertebral disc for flow measurement of the internal carotid arteries and the vertebral arteries. Volume flow measurements using Doppler ultrasound were also performed at the internal carotid arteries 2cm above the carotid bifurcation, and at the vertebral arteries at the level of the upper pole of the thyroid gland. Flows in the four vessels measured by the two methods were compared using Wilcoxon's correlation analysis and the median score. Total cerebral blood flows were calculated by summing these four vessel flows, and mean values for the 16 volunteers were calculated. Cerebral blood flows measured by 2-D phase-contrast MR imaging and Doppler ultrasounds were 233 and 239 ml/min in the right internal carotid artery, 250 and 248 ml/min in the left internal carotid artery, 62 and 56 ml/min in the right vertebral artery, and 83 and 68 ml/min in the left vertebral artery. Correlation coefficients of the blood flows determined by the two methods were 0.48, 0.54, 0.49, and 0.62 in each vessel, while total cerebral blood flows were 628{+-}68 (range, 517 to 779) ml/min and 612{+-}79 (range, 482 to 804)ml/min, respectively. Total cerebral blood flow was easily measured using 2-D phase-contrast MR imaging and Doppler ultrasound, and the two noninvasive methods can therefore be used clinically for the measurement of total cerebral blood flow.

Ultrasound -- Pelvis

Medline Plus

Full Text Available ... image. Ultrasound examinations do not use ionizing radiation (as used in x-rays ), thus there is no ... structure and movement of the body's internal organs, as well as blood flowing through blood vessels. Ultrasound ...

Heterogeneity of brain blood flow and permeability during acute hypertension

International Nuclear Information System (INIS)

Baumbach, G.L.; Heistad, D.D.

1985-01-01

The purpose of this study was to examine regional autoregulation of blood flow in the brain during acute hypertension. In anesthetized cats severe hypertension increased blood flow more in cerebrum (159%) and cerebellum (106%) than brain stem (58%). In contrast to the heterogeneous autoregulatory response, hypocapnia produced uniform vasoconstriction in the brain. The authors also compared vasodilatation during severe hypertension with vasodilatation during hypercapnia. During hypercapnia, blood flow increased as much in brain stem, as in cerebrum and cerebellum. Thus, regional differences in autoregulation appear to be specific for autoregulatory stimulus and are not secondary to nonspecific differences in vasoconstrictor or vasodilator capacity. To determine whether the blood-brain barrier is more susceptible to hypertensive disruption in regions with less effective autoregulation, permeability of the barrier was quantitated with 125 I-albumin. Severe hypertension produced disruption of the barrier in cerebrum but not in brain stem. Thus, there are parallel differences in effectiveness of autoregulation and susceptibility to disruption of the blood-brain barrier in different regions of the brain

Verapamil-induced breakdown of the blood-brain barrier presenting as a transient right middle cerebral artery syndrome.

Science.gov (United States)

Pace, Jonathan; Nelson, Jeffrey; Ray, Abhishek; Hu, Yin

2017-12-01

A middle-aged patient presented for elective embolization of an incidentally found right internal carotid aneurysm. An angiogram was performed, during which the left internal carotid artery was visualized to evaluate a second, small aneurysm. During the embolization of the right internal carotid artery aneurysm, a catheter-induced vasospasm was identified that prompted treatment with intra-arterial verapamil. The procedure was uncomplicated; a postoperative rotational flat-panel computed tomography scan was performed on the angiography table that demonstrated right hemisphere contrast staining. The patient developed a right middle cerebral artery (MCA) syndrome after extubation with repeat cerebral angiography negative for occlusion and magnetic resonance imaging negative for stroke. The patient was observed for 48 hours, during which time the patient had slowly improved. At a six-week follow up visit, the patient had fully recovered. We present an interesting case of a verapamil-induced breakdown of the blood-brain barrier and self-limited right MCA syndrome.

Cerebrospinal fluid aquaporin-4-immunoglobulin G disrupts blood brain barrier

DEFF Research Database (Denmark)

Asgari, Nasrin; Berg, Carsten Tue; Mørch, Marlene Thorsen

2015-01-01

associated with blood-borne horseradish peroxidase leakage indicating blood-brain barrier breakdown. The cerebrospinal fluid aquaporin-4-immunoglobulin G therefore distributes widely in brain to initiate astrocytopathy and blood-brain barrier breakdown....... was evaluated. A distinct distribution pattern of aquaporin-4-immunoglobulin G deposition was observed in the subarachnoid and subpial spaces where vessels penetrate the brain parenchyma, via a paravascular route with intraparenchymal perivascular deposition. Perivascular astrocyte-destructive lesions were...

3D ultrasound Nakagami imaging for radiation-induced vaginal fibrosis

Science.gov (United States)

Yang, Xiaofeng; Rossi, Peter; Shelton, Joseph; Bruner, Debrorah; Tridandapani, Srini; Liu, Tian

2014-03-01

Radiation-induced vaginal fibrosis is a debilitating side-effect affecting up to 80% of women receiving radiotherapy for their gynecological (GYN) malignancies. Despite the significant incidence and severity, little research has been conducted to identify the pathophysiologic changes of vaginal toxicity. In a previous study, we have demonstrated that ultrasound Nakagami shape and PDF parameters can be used to quantify radiation-induced vaginal toxicity. These Nakagami parameters are derived from the statistics of ultrasound backscattered signals to capture the physical properties (e.g., arrangement and distribution) of the biological tissues. In this paper, we propose to expand this Nakagami imaging concept from 2D to 3D to fully characterize radiation-induced changes to the vaginal wall within the radiation treatment field. A pilot study with 5 post-radiotherapy GYN patients was conducted using a clinical ultrasound scanner (6 MHz) with a mechanical stepper. A serial of 2D ultrasound images, with radio-frequency (RF) signals, were acquired at 1 mm step size. The 2D Nakagami shape and PDF parameters were calculated from the RF signal envelope with a sliding window, and then 3D Nakagami parameter images were generated from the parallel 2D images. This imaging method may be useful as we try to monitor radiation-induced vaginal injury, and address vaginal toxicities and sexual dysfunction in women after radiotherapy for GYN malignancies.

Control of treatment size in cavitation-enhanced high-intensity focused ultrasound using radio-frequency echo signals

Science.gov (United States)

Tomiyasu, Kentaro; Takagi, Ryo; Iwasaki, Ryosuke; Yoshizawa, Shin; Umemura, Shin-ichiro

2017-07-01

In high-intensity focused ultrasound (HIFU) treatment, controlling the ultrasound dose at each focal target spot is important because it is a problem that the length of the coagulated region in front of the focal point deviates owing to the differences in absorption in each focal target spot and attenuation in the intervening tissues. In this study, the detected changes in the power spectra of HIFU echoes were used by controlling the HIFU duration in the “trigger HIFU” sequence with the aim to increase coagulation size through the enhancement of the ultrasonic heating by the cavitation induced by the preceding extremely high intensity short “trigger” pulse. The result shows that this method can be used to detect boiling bubbles and the following generated cavitation bubbles at their early stage. By automatically stopping HIFU exposure immediately after detecting the bubbles, overheating was prevented and the deviation of the length of the coagulated region was reduced.

Beacon signal in transcranial color coded ultrasound: A sign for brain death

Directory of Open Access Journals (Sweden)

Mehmet Akif Topçuoğlu

2014-04-01

Full Text Available A widely under-recognized brain-death confirming transcranial ultrasonography pattern resembling the red-blue beacon signal was demonstrated. Familiarity to this distinct and characteristic ultrasonic pattern seems to be important in the perspective of point-of-care neurological ultrasound use and knobology.

High-Intensity Focused Ultrasound (HIFU) in Localized Prostate Cancer Treatment

International Nuclear Information System (INIS)

Alkhorayef, Mohammed; Mahmoud, Mustafa Z.; Alzimami, Khalid S.; Sulieman, Abdelmoneim; Fagiri, Maram A.

2015-01-01

High-intensity focused ultrasound (HIFU) applies high-intensity focused ultrasound energy to locally heat and destroy diseased or damaged tissue through ablation. This study intended to review HIFU to explain the fundamentals of HIFU, evaluate the evidence concerning the role of HIFU in the treatment of prostate cancer (PC), review the technologies used to perform HIFU and the published clinical literature regarding the procedure as a primary treatment for PC. Studies addressing HIFU in localized PC were identified in a search of internet scientific databases. The analysis of outcomes was limited to journal articles written in English and published between 2000 and 2013. HIFU is a non-invasive approach that uses a precisely delivered ultrasound energy to achieve tumor cell necrosis without radiation or surgical excision. In current urological oncology, HIFU is used clinically in the treatment of PC. Clinical research on HIFU therapy for localized PC began in the 1990s, and the majority of PC patients were treated with the Ablatherm device. HIFU treatment for localized PC can be considered as an alternative minimally invasive therapeutic modality for patients who are not candidates for radical prostatectomy. Patients with lower pre-HIFU PSA level and favourable pathologic Gleason score seem to present better oncologic outcomes. Future advances in technology and safety will undoubtedly expand the HIFU role in this indication as more of patient series are published, with a longer follow-up period

Current status of high-intensity focused ultrasound for the management of uterine adenomyosis

Energy Technology Data Exchange (ETDEWEB)

Cheng, Vincent Y. T. [Dept. of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong (China)

2017-04-15

While high-intensity focused ultrasound has been used for some time in the management of uterine fibroids, its effectiveness and safety in managing adenomyosis is less well established. A literature review was performed of all eligible reports using this modality as a treatment for adenomyosis. Relevant publications were obtained from the PubMed electronic database from inception through March 2016. Eleven articles, including information from 1,150 treatments and follow-up data from 990 patients, were reviewed. High-intensity focused ultrasound appears to be effective and safe in the management of symptomatic adenomyosis, and can be considered as an alternative uterine-sparing option for women with this condition.

Current status of high-intensity focused ultrasound for the management of uterine adenomyosis

International Nuclear Information System (INIS)

Cheng, Vincent Y. T.

2017-01-01

While high-intensity focused ultrasound has been used for some time in the management of uterine fibroids, its effectiveness and safety in managing adenomyosis is less well established. A literature review was performed of all eligible reports using this modality as a treatment for adenomyosis. Relevant publications were obtained from the PubMed electronic database from inception through March 2016. Eleven articles, including information from 1,150 treatments and follow-up data from 990 patients, were reviewed. High-intensity focused ultrasound appears to be effective and safe in the management of symptomatic adenomyosis, and can be considered as an alternative uterine-sparing option for women with this condition

Prostate Ultrasound

Medline Plus

Full Text Available ... through blood vessels. Ultrasound imaging is a noninvasive medical test that helps physicians diagnose and treat medical conditions. Prostate ultrasound, also called transrectal ultrasound, provides ...

Multi-parametric monitoring and assessment of high-intensity focused ultrasound (HIFU) boiling by harmonic motion imaging for focused ultrasound (HMIFU): an ex vivo feasibility study

International Nuclear Information System (INIS)

Hou, Gary Y; Marquet, Fabrice; Wang, Shutao; Konofagou, Elisa E

2014-01-01

Harmonic motion imaging for focused ultrasound (HMIFU) is a recently developed high-intensity focused ultrasound (HIFU) treatment monitoring method with feasibilities demonstrated in vitro and in vivo. Here, a multi-parametric study is performed to investigate both elastic and acoustics-independent viscoelastic tissue changes using the Harmonic Motion Imaging (HMI) displacement, axial compressive strain and change in relative phase shift during high energy HIFU treatment with tissue boiling. Forty three (n = 43) thermal lesions were formed in ex vivo canine liver specimens (n = 28). Two-dimensional (2D) transverse HMI displacement maps were also obtained before and after lesion formation. The same method was repeated in 10 s, 20 s and 30 s HIFU durations at three different acoustic powers of 8, 10, and 11 W, which were selected and verified as treatment parameters capable of inducing boiling using both thermocouple and passive cavitation detection (PCD) measurements. Although a steady decrease in the displacement, compressive strain, and relative change in the focal phase shift (Δϕ) were obtained in numerous cases, indicating an overall increase in relative stiffness, the study outcomes also showed that during boiling, a reverse lesion-to-background displacement contrast was detected, indicating potential change in tissue absorption, geometrical change and/or, mechanical gelatification or pulverization. Following treatment, corresponding 2D HMI displacement images of the thermal lesions also mapped consistent discrepancy in the lesion-to-background displacement contrast. Despite the expectedly chaotic changes in acoustic properties with boiling, the relative change in phase shift showed a consistent decrease, indicating its robustness to monitor biomechanical properties independent of the acoustic property changes throughout the HIFU treatment. In addition, the 2D HMI displacement images confirmed and indicated the increase in the thermal lesion size with

Ultrasound -- Pelvis

Medline Plus

Full Text Available ... internal organs, as well as blood flowing through blood vessels. Ultrasound imaging is a noninvasive medical test that helps physicians diagnose and treat medical conditions. There are three types of pelvic ultrasound: abdominal ( transabdominal ) vaginal ( transvaginal / endovaginal ) ...

P-shaped Coiled Stator Ultrasound Motor for Rotating Intravascular Surgery Device

Directory of Open Access Journals (Sweden)

Toshinobu ABE

2015-01-01

Full Text Available The primary focus of this paper is the development of an ultra-miniature ultrasound motor for use in the human blood vessel. Since the size of the drive source for rotating the atherectomy device and intravascular ultrasonography system are large currently in practical use, it is installed outside the body, and the rotational power for the atherectomy device and intravascular ultrasonography system are transmitted through the long tortuous blood vessel. Such systems suffer from the problem that the rotation becomes non-uniform, and the problem that the available time is limited. We have therefore developed a P-shaped coiled stator ultrasound motor as a miniature ultrasound motor for rotating the ultrasound sensor for use in blood vessels in order to solve these problems. In this paper, we describe measurement of the torque, revolution speed, output power, efficiency, and particle motion on acoustic waveguide of the P-shaped coiled stator ultrasound motor.

Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura.

Science.gov (United States)

Hougaard, Anders; Amin, Faisal M; Christensen, Casper E; Younis, Samaira; Wolfram, Frauke; Cramer, Stig P; Larsson, Henrik B W; Ashina, Messoud

2017-06-01

See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability in any of the investigated regions. There was no correlation between blood-brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood-brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood-brain barrier

WE-H-209-00: Carson/Zagzebski Distinguished Lectureship: Image Guided Ultrasound Therapy

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NONE

2016-06-15

Focused ultrasound has been shown to be the only method that allows noninvasive thermal coagulation of tissues and recently this potential has been explored for image-guided drug delivery. In this presentation, the advances in ultrasound phased array technology for energy delivery, exposure monitoring and control will be discussed. Experimental results from novel multi-frequency transmit/receive arrays will be presented. In addition, the feasibility of fully electronically focused and steered high power arrays with many thousands of transducer elements will be discussed. Finally, some of the recent clinical and preclinical results for the treatment of brain disease will be reviewed. Learning Objectives: Introduce FUS therapy principles and modern techniques Discuss use of FUS for drug delivery Cover the technology required to deliver FUS and monitor therapy Present clinical examples of the uses of these techniques This research was supported by funding from The Canada Research Chair Program, Grants from CIHR and NIH (no. EB003268).; K. Hynynen, Canada Foundation for Innovation; Canadian Institutes of Health Research; Focused Ultrasound Surgery Foundation; Canada Research Chair Program; Natural Sciences and Engineering Research Council of Canada; Ontario Research Fund; National Institutes of Health; Canadian Cancer Society Research Institute; The Weston Brain Institute; Harmonic Medical; Focused Ultrasound Instruments.

A novel process for ultrasound-induced radical polymerization in CO2-expanded fluids

NARCIS (Netherlands)

Kemmere, M.F.; Kuijpers, M.W.A.; Prickaerts, R.M.H.; Keurentjes, J.T.F.

2005-01-01

A strong viscosity increase upon polymerization hinders cavitation and subsequent radical formation during an ultrasound-induced bulk polymerization. In this work, ultrasound-induced radical polymerizations of methyl methacrylate (MMA) have been performed in CO2-expanded MMA in order to reduce the

Jet formation and shock wave emission during collapse of ultrasound-induced cavitation bubbles and their role in the therapeutic applications of high-intensity focused ultrasound.

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Brujan, E A; Ikeda, T; Matsumoto, Y

2005-10-21

The dynamics of inertial cavitation bubbles produced by short pulses of high-intensity focused ultrasound near a rigid boundary are studied to get a better understanding of the role of jet formation and shock wave emission during bubble collapse in the therapeutic applications of ultrasound. The bubble dynamics are investigated by high-speed photography with up to 2 million frames/s and acoustic measurements, as well as by numerical calculations. The significant parameter of this study is the dimensionless stand-off, gamma, which is defined as the distance of the bubble centre at its maximum expansion scaled by the maximum bubble radius. High-speed photography is applied to observe the bubble motion and the velocity of the liquid jet formed during bubble collapse. Hydrophone measurements are used to determine the pressure and the duration of the shock wave emitted during bubble rebound. Calculations yield the variation with time of the bubble wall, the maximum velocity and the kinetic energy of the re-entrant jet. The comparisons between experimental and numerical data are favourable with regard to both shape history and translational motion of the bubble. The acoustic energy constitutes the largest individual amount in the energy balance of bubble collapse. The ratio of the shock wave energy, measured at 10 mm from the emission centre, to the cavitation bubble energy was 1:2.4 at gamma = 1.55 and 1:3.5 at gamma = 1. At this distance, the shock wave pressure ranges from 0.122 MPa, at gamma = 1, to 0.162 MPa, at gamma = 1.55, and the temporal duration at the half maximum level is 87 ns. The maximum jet velocity ranges from 27 m s(-1), at gamma = 1, to 36 m s(-1), at gamma = 1.55. For gamma < 1.2, the re-entrant jet can generate an impact pressure on the nearby boundary larger than 50 MPa. We discuss the implications of the results for the therapeutic applications of high-intensity focused ultrasound.

Jet formation and shock wave emission during collapse of ultrasound-induced cavitation bubbles and their role in the therapeutic applications of high-intensity focused ultrasound

International Nuclear Information System (INIS)

Brujan, E A; Ikeda, T; Matsumoto, Y

2005-01-01

The dynamics of inertial cavitation bubbles produced by short pulses of high-intensity focused ultrasound near a rigid boundary are studied to get a better understanding of the role of jet formation and shock wave emission during bubble collapse in the therapeutic applications of ultrasound. The bubble dynamics are investigated by high-speed photography with up to 2 million frames/s and acoustic measurements, as well as by numerical calculations. The significant parameter of this study is the dimensionless stand-off, γ, which is defined as the distance of the bubble centre at its maximum expansion scaled by the maximum bubble radius. High-speed photography is applied to observe the bubble motion and the velocity of the liquid jet formed during bubble collapse. Hydrophone measurements are used to determine the pressure and the duration of the shock wave emitted during bubble rebound. Calculations yield the variation with time of the bubble wall, the maximum velocity and the kinetic energy of the re-entrant jet. The comparisons between experimental and numerical data are favourable with regard to both shape history and translational motion of the bubble. The acoustic energy constitutes the largest individual amount in the energy balance of bubble collapse. The ratio of the shock wave energy, measured at 10 mm from the emission centre, to the cavitation bubble energy was 1:2.4 at γ = 1.55 and 1:3.5 at γ = 1. At this distance, the shock wave pressure ranges from 0.122 MPa, at γ = 1, to 0.162 MPa, at γ 1.55, and the temporal duration at the half maximum level is 87 ns. The maximum jet velocity ranges from 27 m s -1 , at γ = 1, to 36 m s -1 , at γ = 1.55. For γ < 1.2, the re-entrant jet can generate an impact pressure on the nearby boundary larger than 50 MPa. We discuss the implications of the results for the therapeutic applications of high-intensity focused ultrasound

Glucose transporter of the human brain and blood-brain barrier

International Nuclear Information System (INIS)

Kalaria, R.N.; Gravina, S.A.; Schmidley, J.W.; Perry, G.; Harik, S.I.

1988-01-01

We identified and characterized the glucose transporter in the human cerebral cortex, cerebral microvessels, and choroid plexus by specific D-glucose-displaceable [3H]cytochalasin B binding. The binding was saturable, with a dissociation constant less than 1 microM. Maximal binding capacity was approximately 7 pmol/mg protein in the cerebral cortex, approximately 42 pmol/mg protein in brain microvessels, and approximately 27 pmol/mg protein in the choroid plexus. Several hexoses displaced specific [3H]cytochalasin B binding to microvessels in a rank-order that correlated well with their known ability to cross the blood-brain barrier; the only exception was 2-deoxy-D-glucose, which had much higher affinity for the glucose transporter than the natural substrate, D-glucose. Irreversible photoaffinity labeling of the glucose transporter of microvessels with [3H]cytochalasin B, followed by solubilization and polyacrylamide gel electrophoresis, labeled a protein band with an average molecular weight of approximately 55,000. Monoclonal and polyclonal antibodies specific to the human erythrocyte glucose transporter immunocytochemically stained brain blood vessels and the few trapped erythrocytes in situ, with minimal staining of the neuropil. In the choroid plexus, blood vessels did not stain, but the epithelium reacted positively. We conclude that human brain microvessels are richly endowed with a glucose transport moiety similar in molecular weight and antigenic characteristics to that of human erythrocytes and brain microvessels of other mammalian species

Intranasal administration of dopamine attenuates unconditioned fear in that it reduces restraint-induced ultrasound vocalizations and escape from bright light.

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Talbot, Teddy; Mattern, Claudia; de Souza Silva, Maria Angelica; Brandão, Marcus Lira

2017-06-01

Although substantial evidence suggests that dopamine (DA) enhances conditioned fear responses, few studies have examined the role of DA in unconditioned fear states. Whereas DA does not cross the blood-brain barrier, intranasally-applied dopamine reaches the brain directly via the nose-brain pathways in rodents, providing an alternative means of targeting DA receptors. Intranasal dopamine (IN-DA) has been demonstrated to bind to DA transporters and to increase extracellular DA in the striatum as well as having memory-promoting effects in rats. The purpose of this study was to examine the influence of IN-DA in three tests of fear/anxiety. The three doses of DA hydrochloride (0.03, 0.3, or 1 mg/kg) were applied in a viscous castor oil gel in a volume of 5 µl to each of both nostrils of adult Wistar rats prior to testing of (a) escape from a bright light, using a two-chamber procedure, (b) restraint-induced 22 kHz ultrasound vocalizations (USVs), and (c) exploratory behavior in the elevated plus-maze (EPM). IN-DA dose-dependently reduced escape from bright light and the number of USV responses to restraint. It had no influence on the exploratory behavior in the EPM. IN-DA application reduced escape behavior in two tests of unconditioned fear (escape from bright light and USV response to immobilization). These findings may be interpreted in light of the known antidepressant action of IN-DA and DA reuptake blockers. The results also confirm the promise of the nasal route as an alternative means for targeting the brain's dopaminergic receptors with DA.

[Neurological disorders and the blood-brain barrier. Strategies and limitations for drug delivery to the brain].

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Domínguez, Alazne; Álvarez, Antonia; Suárez-Merino, Blanca; Goñi-de-Cerio, Felipe

2014-03-01

The incidence in the central nervous system diseases has increased with a growing elderly population. Unfortunately, conventional treatments used to treat the mentioned diseases are frequently ineffective due to the presence of the blood brain barrier. To illustrate the blood-brain barrier properties that limit drug transport into the brain and the main strategies employed to treat neurologic disorders. The blood-brain barrier is mainly composed of a specialized microvascular endothelium and of glial cells. It constitutes a valuable tool to separate the central nervous system from the rest of the body. Nevertheless, it also represents an obstacle to the delivery of therapeutic drugs to the brain. To be effective, drugs must reach their target in the brain. On one hand, therapeutic agents could be designed to be able to cross the blood brain barrier. On the other hand, drug delivery systems could be employed to facilitate the therapeutic agents' entry into the central nervous system. In vivo models of neurological diseases, in addition to in vitro models of the blood brain barrier, have been widely employed for the evaluation of drugs utilized to treat central nervous system diseases.

Droplets, Bubbles and Ultrasound Interactions.

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Shpak, Oleksandr; Verweij, Martin; de Jong, Nico; Versluis, Michel

2016-01-01

The interaction of droplets and bubbles with ultrasound has been studied extensively in the last 25 years. Microbubbles are broadly used in diagnostic and therapeutic medical applications, for instance, as ultrasound contrast agents. They have a similar size as red blood cells, and thus are able to circulate within blood vessels. Perfluorocarbon liquid droplets can be a potential new generation of microbubble agents as ultrasound can trigger their conversion into gas bubbles. Prior to activation, they are at least five times smaller in diameter than the resulting bubbles. Together with the violent nature of the phase-transition, the droplets can be used for local drug delivery, embolotherapy, HIFU enhancement and tumor imaging. Here we explain the basics of bubble dynamics, described by the Rayleigh-Plesset equation, bubble resonance frequency, damping and quality factor. We show the elegant calculation of the above characteristics for the case of small amplitude oscillations by linearizing the equations. The effect and importance of a bubble coating and effective surface tension are also discussed. We give the main characteristics of the power spectrum of bubble oscillations. Preceding bubble dynamics, ultrasound propagation is introduced. We explain the speed of sound, nonlinearity and attenuation terms. We examine bubble ultrasound scattering and how it depends on the wave-shape of the incident wave. Finally, we introduce droplet interaction with ultrasound. We elucidate the ultrasound-focusing concept within a droplets sphere, droplet shaking due to media compressibility and droplet phase-conversion dynamics.

Weakening Pin Bone Attachment in Fish Fillets Using High-Intensity Focused Ultrasound.

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Skjelvareid, Martin H; Stormo, Svein Kristian; Þórarinsdóttir, Kristín Anna; Heia, Karsten

2017-09-18

High Intensity Focused Ultrasound (HIFU) can be used for the localized heating of biological tissue through the conversion of sound waves into heat. Although originally developed for human medicine, HIFU may also be used to weaken the attachment of pin bones in fish fillets to enable easier removal of such bones. This was shown in the present study, where a series of experiments were performed on HIFU phantoms and fillets of cod and salmon. In thin objects such as fish fillets, the heat is mainly dissipated at the surfaces. However, bones inside the fillet absorb ultrasound energy more efficiently than the surrounding tissue, resulting in a "self-focusing" heating of the bones. Salmon skin was found to effectively block the ultrasound, resulting in a significantly lower heating effect in fillets with skin. Cod skin partly blocked the ultrasound, but only to a small degree, enabling HIFU treatment through the skin. The treatment of fillets to reduce the pin bone attachment yielded an average reduction in the required pulling force by 50% in cod fillets with skin, with little muscle denaturation, and 72% in skinned fillets, with significant muscle denaturation. Salmon fillets were treated from the muscle side of the fillet to circumvent the need for penetration through skin. The treatment resulted in a 30% reduction in the peak pulling force and 10% reduction in the total pulling work, with a slight denaturation of the fillet surface.

Focused Ultrasound for Essential Tremor: Review of the Evidence and Discussion of Current Hurdles

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Mohammad Rohani

2017-05-01

Full Text Available Background. While there is no breakthrough progress in the medical treatment of essential tremor (ET, in the past decades several remarkable achievements happened in the surgical field, such as radiofrequency thalamotomy, thalamic deep brain stimulation and gamma knife thalamotomy. The most recent advance in this area is magnetic resonance-guided focused ultrasound (MRgFUS. Methods. Purpose of this review is to discuss the new developments and trials of MRgFUS in the treatment of ET and other tremor disorders. Results. MRgFUS is an incision-less surgery performed without anesthesia and ionizing radiation (no risk of cumulative dose and delayed side effects. Studies have shown the safety and effectiveness of unilateral MRgFUS-thalamotomy in the treatment of ET. It has been successfully used in few patients with Parkinson's disease-related tremor and fewer patients with Fragile X-associated Tremor/Ataxia Syndrome. Safety and long-term effects of the procedure are still unclear, as temporary and permanent adverse events have been reported as well as reoccurrence of tremor. Discussion. MRgFUS is a promising new surgical approach with still a number of unknowns and unsolved issues. It represents a valuable option particularly for patients who refused or could not be candidate for other procedures, deep brain stimulation in particular. 

Effect of ultrasound on the interleukin content in blood of rats with experimental inflammation

International Nuclear Information System (INIS)

Nurishchenko, N.Je.

2015-01-01

The aim was to determine the effectiveness of anti-inflammatory action of ultrasound by the interleukin-6, interleukin-8 and tumor necrosis factor alpha content in the blood of rats with experimental inflammation. The study was performed using conventional models of inflammation - carrageenan- induced edema of the limbs of rats. Content interleukins Il-6 and Il-8 were determined by enzyme immunoassay (ELISA) according to a standard protocol Immunoassay kit, Biosourse (USA). The content of TNF-α was determined by cytotoxic effect on sensitive mouse fibroblast line L- 929. It was shown that in the group of rats with carrageenan-induced edema contents of IL-6 increase in 2.8 times, IL-8 - in 5.6 times, and TNF-α- in 3 times compared to the control. Course influence of ultra sound contributed to reduction of the studied parameters. The content of IL-6 decreased in 1.7 times, IL-8 and TNF-α- in 1.6 times in comparison with inflammation

Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury.

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Russell, K L; Berman, N E J; Gregg, P R A; Levant, B

2014-01-01

The effects of an oral fish oil treatment regimen on sensorimotor, blood-brain barrier, and biochemical outcomes of traumatic brain injury (TBI) were investigated in a juvenile rat model. Seventeen-day old Long-Evans rats were given a 15mL/kg fish oil (2.01g/kg EPA, 1.34g/kg DHA) or soybean oil dose via oral gavage 30min prior to being subjected to a controlled cortical impact injury or sham surgery, followed by daily doses for seven days. Fish oil treatment resulted in less severe hindlimb deficits after TBI as assessed with the beam walk test, decreased cerebral IgG infiltration, and decreased TBI-induced expression of the Mmp9 gene one day after injury. These results indicate that fish oil improved functional outcome after TBI resulting, at least in part from decreased disruption of the blood-brain barrier through a mechanism that includes attenuation of TBI-induced expression of Mmp9. © 2013 Elsevier Ltd. All rights reserved.

MRI-induced heating of deep brain stimulation leads

International Nuclear Information System (INIS)

Mohsin, Syed A; Sheikh, Noor M; Saeed, Usman

2008-01-01

The radiofrequency (RF) field used in magnetic resonance imaging is scattered by medical implants. The scattered field of a deep brain stimulation lead can be very intense near the electrodes stimulating the brain. The effect is more pronounced if the lead behaves as a resonant antenna. In this paper, we examine the resonant length effect. We also use the finite element method to compute the near field for (i) the lead immersed in inhomogeneous tissue (fat, muscle, and brain tissues) and (ii) the lead connected to an implantable pulse generator. Electric field, specific absorption rate and induced temperature rise distributions have been obtained in the brain tissue surrounding the electrodes. The worst-case scenario has been evaluated by neglecting the effect of blood perfusion. The computed values are in good agreement with in vitro measurements made in the laboratory.

Blood-Brain Glucose Transfer: Repression in Chronic Hyperglycemia

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Gjedde, Albert; Crone, Christian

1981-10-01

Diabetic patients with increased plasma glucose concentrations may develop cerebral symptoms of hypoglycemia when their plasma glucose is rapidly lowered to normal concentrations. The symptoms may indicate insufficient transport of glucose from blood to brain. In rats with chronic hyperglycemia the maximum glucose transport capacity of the blood-brain barrier decreased from 400 to 290 micromoles per 100 grams per minute. When plasma glucose was lowered to normal values, the glucose transport rate into brain was 20 percent below normal. This suggests that repressive changes of the glucose transport mechanism occur in brain endothelial cells in response to increased plasma glucose.

Protection of the blood-brain barrier by hypercapnia during acute hypertension

International Nuclear Information System (INIS)

Baumbach, G.L.; Mayhan, W.G.; Heistad, D.D.

1986-01-01

The purpose of this study was to examine effects of hypercapnia on susceptibility of the blood-brain barrier to disruption during acute hypertension. Two methods were used to test the hypothesis that cerebral vasodilation during hypercapnia increases disruption of the blood-brain barrier. First, permeability of the blood-brain barrier was measured in anesthetized cats with 125 I-labeled serum albumin. Severe hypertension markedly increased permeability of the blood-brain barrier during normocapnia, but not during hypercapnia. The protective effect of hypercapnia was not dependent on sympathetic nerves. Second, in anesthetized rats, permeability of the barrier was quantitated by clearance of fluorescent dextran. Disruption of the blood-brain barrier during hypertension was decreased by hypercapnia. Because disruption of the blood-brain barrier occurred primarily in pial venules, the authors also measured pial venular diameter and pressure. Acute hypertension increased pial venular pressure and diameter in normocapnic rats. Hypercapnia alone increased pial venular pressure and pial venular diameter, and acute hypertension during hypercapnia further increased venular pressure. The magnitude of increase in pial venular pressure during acute hypertension was significantly less in hypercapnic than in normocapnic rats. They conclude that hypercapnia protects the blood-brain barrier. Possible mechanisms of this effect include attenuation of the incremental increase in pial venular pressure by hypercapnia or a direct effect on the blood-brain barrier not related to venous pressure

Blood brain barrier permeability and tPA-mediated neurotoxicity

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Nassar, Taher; Yarovoi, Sergey; Rayan, Anwar; Lamensdorf, Itschak; Karakoveski, Michael; Vadim, Polianski; Fanne, Rami Abu; Jamal, Mahmud; Cines, Douglas B.; Higazi, Abd Al-Roof

2015-01-01

Tissue type plasminogen activator (tPA) induces neuronal apoptosis, disrupt the blood-brain-barrier (BBB), and promotes dilation of the cerebral vasculature. The timing, sequence and contributions of these and other deleterious effects of tPA and their contribution to post-ischemic brain damage after stroke, have not been fully elucidated. To dissociate the effects of tPA on BBB permeability, cerebral vasodilation and protease-dependent pathways, we developed several tPA mutants and PAI-1 derived peptides constructed by computerized homology modeling of tPA. Our data show that intravenous administration of human tPA to rats increases BBB permeability through a non-catalytic process, which is associated with reversible neurotoxicity, brain damage, edema, mortality and contributes significantly to its brief therapeutic window. Furthermore, our data show that inhibiting the effect of tPA on BBB function without affecting its catalytic activity, improves outcome and significantly extends its therapeutic window in mechanical as well as thromboembolic models of stroke. PMID:20060006

High Intensity Focused Ultrasound for Cancer Therapy--harnessing its non-linearity

International Nuclear Information System (INIS)

Haar, Gail ter

2008-01-01

In medicine in general, and for cancer treatments in particular, there is a drive to find effective non-invasive therapies. High Intensity Focused Ultrasound (HIFU) represents one such technique. In principle, it is simple--a high energy ultrasound beam is brought to a tight focus within a target which may lie several centimetres below the skin surface (for example, in a tumour of the liver), and is used to destroy a selected tissue volume. The main mechanism for cell killing in a HIFU beam is heat. Ultrasound energy absorption is frequency dependent, the higher frequencies being absorbed most strongly. Significant thermal advantage may therefore be gained from non-linear propagation, which generates higher harmonics, in tissue. Acoustic cavitation and thermal exsolution of gas (boiling) also contribute to tissue damage. This activity leads to the local mechanical disruption of cells. In addition, the non-linear oscillation of these bubbles leads to enhanced energy deposition. The acoustic emissions from such bubbles are characteristic of their behaviour and may be correlated to some extent with the appearance of the disruption produced. The more widespread clinical acceptance of HIFU is awaiting faster, and more efficient, energy delivery and treatment monitoring. A better understanding of the nonlinear aspects of HIFU propagation in tissue is thus important if this technique is to benefit more patients

Effect of delta sleep-inducing peptide on the expression of antioxidant enzyme genes in the brain and blood of rats during physiological aging.

Science.gov (United States)

Kutilin, D S; Bondarenko, T I; Kornienko, I V; Mikhaleva, I I

2014-09-01

Subcutaneous injections of exogenous delta sleep-inducing peptide in a dose of 100 μg/kg (monthly, 5-day courses) to rats of various age groups (2-24 months) were followed by an increase in the expression of genes for SOD 1 (Sod1) and glutathione peroxidase 1 (Gpx1) in the brain and nucleated blood cells. The expression of these genes was shown to decrease during physiological aging of the body.

SU-E-J-03: Characterization of the Precision and Accuracy of a New, Preclinical, MRI-Guided Focused Ultrasound System for Image-Guided Interventions in Small-Bore, High-Field Magnets

International Nuclear Information System (INIS)

Ellens, N; Farahani, K

2015-01-01

Purpose: MRI-guided focused ultrasound (MRgFUS) has many potential and realized applications including controlled heating and localized drug delivery. The development of many of these applications requires extensive preclinical work, much of it in small animal models. The goal of this study is to characterize the spatial targeting accuracy and reproducibility of a preclinical high field MRgFUS system for thermal ablation and drug delivery applications. Methods: The RK300 (FUS Instruments, Toronto, Canada) is a motorized, 2-axis FUS positioning system suitable for small bore (72 mm), high-field MRI systems. The accuracy of the system was assessed in three ways. First, the precision of the system was assessed by sonicating regular grids of 5 mm squares on polystyrene plates and comparing the resulting focal dimples to the intended pattern, thereby assessing the reproducibility and precision of the motion control alone. Second, the targeting accuracy was assessed by imaging a polystyrene plate with randomly drilled holes and replicating the hole pattern by sonicating the observed hole locations on intact polystyrene plates and comparing the results. Third, the practicallyrealizable accuracy and precision were assessed by comparing the locations of transcranial, FUS-induced blood-brain-barrier disruption (BBBD) (observed through Gadolinium enhancement) to the intended targets in a retrospective analysis of animals sonicated for other experiments. Results: The evenly-spaced grids indicated that the precision was 0.11 +/− 0.05 mm. When image-guidance was included by targeting random locations, the accuracy was 0.5 +/− 0.2 mm. The effective accuracy in the four rodent brains assessed was 0.8 +/− 0.6 mm. In all cases, the error appeared normally distributed (p<0.05) in both orthogonal axes, though the left/right error was systematically greater than the superior/inferior error. Conclusions: The targeting accuracy of this device is sub-millimeter, suitable for many

SU-E-J-03: Characterization of the Precision and Accuracy of a New, Preclinical, MRI-Guided Focused Ultrasound System for Image-Guided Interventions in Small-Bore, High-Field Magnets

Energy Technology Data Exchange (ETDEWEB)

Ellens, N [Johns Hopkins University, Baltimore, Maryland (United States); Farahani, K [National Cancer Institute, Bethesda, MD (United States)

2015-06-15

Purpose: MRI-guided focused ultrasound (MRgFUS) has many potential and realized applications including controlled heating and localized drug delivery. The development of many of these applications requires extensive preclinical work, much of it in small animal models. The goal of this study is to characterize the spatial targeting accuracy and reproducibility of a preclinical high field MRgFUS system for thermal ablation and drug delivery applications. Methods: The RK300 (FUS Instruments, Toronto, Canada) is a motorized, 2-axis FUS positioning system suitable for small bore (72 mm), high-field MRI systems. The accuracy of the system was assessed in three ways. First, the precision of the system was assessed by sonicating regular grids of 5 mm squares on polystyrene plates and comparing the resulting focal dimples to the intended pattern, thereby assessing the reproducibility and precision of the motion control alone. Second, the targeting accuracy was assessed by imaging a polystyrene plate with randomly drilled holes and replicating the hole pattern by sonicating the observed hole locations on intact polystyrene plates and comparing the results. Third, the practicallyrealizable accuracy and precision were assessed by comparing the locations of transcranial, FUS-induced blood-brain-barrier disruption (BBBD) (observed through Gadolinium enhancement) to the intended targets in a retrospective analysis of animals sonicated for other experiments. Results: The evenly-spaced grids indicated that the precision was 0.11 +/− 0.05 mm. When image-guidance was included by targeting random locations, the accuracy was 0.5 +/− 0.2 mm. The effective accuracy in the four rodent brains assessed was 0.8 +/− 0.6 mm. In all cases, the error appeared normally distributed (p<0.05) in both orthogonal axes, though the left/right error was systematically greater than the superior/inferior error. Conclusions: The targeting accuracy of this device is sub-millimeter, suitable for many

A review of suspension-Scattered particles used in blood-mimicking fluid for doppler ultrasound imaging

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Ammar A Oglat

2018-01-01

Full Text Available Doppler ultrasound imaging system description and calibration need blood-mimicking fluids (BMFs for the test target of medical ultrasound diagnostic tools, with known interior features and acoustic and physical properties of this fluid (BMF. Physical and acoustical properties determined in the International Electrotechnical Commission (IEC standard are specified as constant values, the materials used in the BMF preparation should have values similar to the IEC standard values. However, BMF is ready-made commercially from a field of medical usage, which may not be appropriate in the layout of ultrasound system or for an estimate of novel imaging mechanism. It is often eligible to have the capability to make sound properties and mimic blood arrangement for specific applications. In this review, sufficient BMF materials, liquids, and measures are described which have been generated by utilizing diverse operation mechanism and materials that have sculptured a range of biological systems.

Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles

OpenAIRE

Meairs, Stephen

2015-01-01

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This techni...

Transmigration of neural stem cells across the blood brain barrier induced by glioma cells.

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Mónica Díaz-Coránguez

Full Text Available Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-α, TNF-α, IL-12p70, IL-1β, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2.

Transmigration of neural stem cells across the blood brain barrier induced by glioma cells.

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Díaz-Coránguez, Mónica; Segovia, José; López-Ornelas, Adolfo; Puerta-Guardo, Henry; Ludert, Juan; Chávez, Bibiana; Meraz-Cruz, Noemi; González-Mariscal, Lorenza

2013-01-01

Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB) was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs) cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM) from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-α, TNF-α, IL-12p70, IL-1β, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2.

Blood-brain barrier alterations provide evidence of subacute diaschisis in an ischemic stroke rat model.

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Svitlana Garbuzova-Davis

Full Text Available Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas.In ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO, significant BBB alterations characterized by large Evans Blue (EB parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices.These results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke.

Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole

Directory of Open Access Journals (Sweden)

Akanuma Shin-ichi

2011-10-01

Full Text Available Abstract Background Peripheral administration of lipopolysaccharide (LPS induces inflammation and increases cerebral prostaglandin E2 (PGE2 concentration. PGE2 is eliminated from brain across the blood-brain barrier (BBB in mice, and this process is inhibited by intracerebral or intravenous pre-administration of anti-inflammatory drugs and antibiotics such as cefmetazole and cefazolin that inhibit multidrug resistance-associated protein 4 (Mrp4/Abcc4-mediated PGE2 transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE2 elimination from brain, and whether antibiotics further inhibit PGE2 elimination in LPS-treated mice. Methods [3H]PGE2 elimination across the BBB of intraperitoneally LPS-treated mice was assessed by the brain efflux index (BEI method. Transporter protein amounts in brain capillaries were quantified by liquid chromatography-tandem mass spectrometry. Results The apparent elimination rate of [3H]PGE2 from brain was lower by 87%, in LPS-treated mice compared with saline-treated mice. The Mrp4 protein amount was unchanged in brain capillaries of LPS-treated mice compared with saline-treated mice, while the protein amounts of organic anion transporter 3 (Oat3/Slc22a8 and organic anion transporting polypeptide 1a4 (Oatp1a4/Slco1a4 were decreased by 26% and 39%, respectively. Either intracerebral or intravenous pre-administration of cefmetazole further inhibited PGE2 elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE2 elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE2 elimination across the BBB in LPS-treated mice. Conclusion PGE2 elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE2 elimination in LPS

Ang-(1-7) exerts protective role in blood-brain barrier damage by the balance of TIMP-1/MMP-9.

Science.gov (United States)

Wu, Jitao; Zhao, Duo; Wu, Shuang; Wang, Dan

2015-02-05

Cerebrovascular disease (CVD) ranks as the top three health risks, specially cerebral ischemia characterized with the damage of blood-brain barrier (BBB). The angiotensin Ang-(1-7) was proven to have a protective effect on cerebrovascular diseases. However, its role on blood-brain barrier and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved damage of ischemia reperfusion injury on blood-brain barrier in cerebral ischemia reperfusion injury (IRI) rats. Furthermore, its treatment attenuated BBB permeability and brain edema. Similarly, Ang-(1-7) also decreased the barrier permeability of brain endothelial cell line RBE4. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and zonula occludens ZO-1) expression levels both in IRI-rats and hypoxia-induced RBE4 cells. Furthermore, Ang-(1-7) stimulation down-regulated hypoxia-induced matrix metalloproteinase-9 (MMP-9) levels, whose silencing with (matrix metalloproteinase-9 hemopexin domain) MMP9-PEX inhibitor significantly increased the expression of claudin-5 and ZO-1. Further mechanism analysis demonstrated that Ang-(1-7) might junction protein levels by tissue inhibitor of metalloproteinase 1 (TIMP1)-MMP9 pathway, because Ang-(1-7) enhanced TIMP1 expression, whose silencing obviously attenuated the inhibitor effect of Ang-(1-7) on MMP-9 levels and decreased Ang-(1-7)-triggered increase in claudin-5 and ZO-1. Together, this study demonstrated a protective role of Ang-(1-7) in IRI-induced blood-brain barrier damage by TIMP1-MMP9-regulated tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against IRI and its complications. Copyright © 2014 Elsevier B.V. All rights reserved.

Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior

Directory of Open Access Journals (Sweden)

Samantha J. Hindle

2017-10-01

Full Text Available Summary: Central nervous system (CNS chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB. Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in controlling drug and endogenous molecule CNS homeostasis. If this is true, then brain-impermeable drugs could induce behavioral changes by affecting brain levels of endogenous molecules. Using computational, genetic, and pharmacologic approaches across diverse organisms, we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice. Furthermore, we show that MDR1-interacting drugs are associated with anxiety-related behaviors in humans. We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates and implicates the BBB in behavioral regulation. : Hindle et al. shed light on the curious finding that some drugs cause behavioral side-effects despite negligible access into the brain. These authors propose a unifying hypothesis that links blood-brain barrier drug transporter function and brain access of circulating steroids to common CNS adverse drug responses. Keywords: drug side effect mechanisms, central nervous system, blood brain barrier, behavior, toxicology, drug transporters, endobiotics, steroid hormones

Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development.

Directory of Open Access Journals (Sweden)

Keith M Godfrey