The objective of this work was to determine whether diagnostic ultrasound and contrast agent could be used to transcranially and nondestructively disrupt the blood-brain barrier (BBB) in mice under ultrasound image guidance, and to quantify that disruption using MRI and MR contrast agent. Each mouse was placed under isoflurane anesthesia and the hair on top of its skull was removed before treatment. A diagnostic ultrasound transducer was placed in a water bag coupled with gel to the mouse skull. Definity (US contrast) and Magnevist (MR contrast) were injected concurrent with the start of a custom ultrasound transmission sequence. The transducer was translated along the rostralcaudal axis to insonify three spatial locations (2 mm apart) along one half of the brain for each sequence. T1-weighted MR images were used to quantify the volume of tissue over which the BBB disruption allowed Magnevist to enter the brain, based upon increases in MR contrast-to-noise ratio (CNR) as compared to the noninsonified portions of the brain. Ultrasonic frequency, pressure, and pulse duration, as well as Definity dose and injection time were varied. Preliminary results suggest that a threshold exists for BBB opening dependent upon both pressure and pulse duration (consistent with reports in the literature performed at lower frequencies). A range of typical diagnostic frequencies (e.g., 5.0-8.0 MHz) generated BBB disruption. Comparable BBB opening was noted with varied delays between Definity injection and insonification (0-2 min) for a range of Definity concentrations (400-2400 μL/kg). The low-pressure, custom sequences (MI≤0.65) had minimal blood cell extravasation as determined by histological evaluation. This study has shown the ability of a diagnostic ultrasound system, in conjunction with Definity, to open the BBB transcranially in a mouse model for molecules approximately 0.5 kDa in size. Opening was achieved at higher frequencies than previously reported and was localized under ultrasound image guidance. A typical, ultrasound imaging mode (PW Doppler) with specific settings (transmit frequency=5.7 MHz, gate size=15 mm, pulse repetition frequency=100 Hz, system power=15%) successfully opened the BBB, which facilitates implementation using the majority of commercially available clinical diagnostic scanners. Localized opening of the BBB may have potential clinical utility for the delivery of diagnostic or therapeutic agents to the brain.
The use of contrast agents for neuroimaging is limited by the blood-brain barrier (BBB), which restricts entry into the brain. To administer imaging agents to the brain of rats, intracarotid infusions of hypertonic mannitol have been used to open the BBB. However, this technically challenging approach is invasive, opens only a limited region of the BBB, and is difficult to extend to mice. In this work, the BBB was opened in mice, using unfocused ultrasound combined with an injection of microbubbles. This technique has several notable features: it (a) can be performed transcranially in mice; (b) takes only 3 min and uses only commercially available components; (c) opens the BBB throughout the brain; (d) causes no observed histologic damage or changes in behavior (with peak-negative acoustic pressures of 0.36 MPa); and (e) allows recovery of the BBB within 4 h. Using this technique, Gadopentetate Dimeglumine (Gd-DTPA) was administered to the mouse brain parenchyma, thereby shortening T 1 and enabling the acquisition of high-resolution (52 3 52 3 100 micrometers 3 ) images in 51 min in vivo. By enabling the administration of both existing anatomic contrast agents and the newer molecular/sensing contrast agents, this technique may be useful for the study of mouse models of neurologic function and pathology with MRI. Magn Reson Med 64:995-1004,
The goal of this work is to demonstrate the feasibility of using a diagnostic ultrasound system (Siemens Antares™ and CH6-2 curvilinear array) 1) to ablate ex vivo liver with a custom M-mode sequence and 2) to monitor the resulting tissue stiffening with 2-D Acoustic Radiation Force Impulse (ARFI) imaging. Images were taken before and after ablation, as well as in 5 s intervals during the ablation sequence in order to monitor the ablation lesion formation temporally. Ablation lesions were generated at depths up to 1.5 cm from the surface of the liver and were not visible in B-mode. ARFI images showed liver stiffening with heating that corresponded to discolored regions in gross pathology. As expected, the contrast of ablation lesions in ARFI images is observed to increase with ablation lesion size. This study demonstrated the ability of a diagnostic system using custom beam sequences to localize an ablation site, heat the site to the point of irreversible damage, and monitor the formation of the ablation lesion with ARFI imaging.
Bonded multilayer ceramics and composites incorporating low-loss piezoceramics have been applied to arrays for ultrasound imaging to improve acoustic transmit power levels and to reduce internal heating. Commercially available hard PZT from multiple vendors has been characterized for microstructure, ability to be processed, and electroacoustic properties. Multilayers using the best materials demonstrate the tradeoffs compared with the softer PZT5-H typically used for imaging arrays. Three-layer PZT4 composites exhibit an effective dielectric constant that is three times that of single layer PZT5H, a 50% higher mechanical Q, a 30% lower acoustic impedance, and only a 10% lower coupling coefficient. Application of low-loss multilayers to linear phased and large curved arrays results in equivalent or better element performance. A 3-layer PZT4 composite array achieved the same transmit intensity at 40% lower transmit voltage and with a 35% lower face temperature increase than the PZT-5 control. Although B-mode images show similar quality, acoustic radiation force impulse (ARFI) images show increased displacement for a given drive voltage. An increased failure rate for the multilayers following extended operation indicates that further development of the bond process will be necessary. In conclusion, bonded multilayer ceramics and composites allow additional design freedom to optimize arrays and improve the overall performance for increased acoustic output while maintaining image quality.
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