Meaghan A. O’Reilly

Blood-Brain Barrier: Real-time Feedback-controlled Focused Ultrasound Disruption by Using an Acoustic Emissions–based Controller

PURPOSE To determine if focused ultrasound disruption of the blood-brain barrier (BBB) can be safely controlled by using real-time modulation of treatment pressures on the basis of acoustic emissions from the exposed microbubbles. MATERIALS AND METHODS All experiments were performed with the approval of the institutional animal care committee. Transcranial focused ultrasound (551.5 kHz, 10-msec bursts, 2-Hz pulse repetition frequency, 2 minute sonication) in conjunction with circulating microbubbles was applied in 86 locations in 27 rats to disrupt the BBB. Acoustic emissions captured during each burst by using a wideband polyvinylidene fluoride hydrophone were analyzed for spectral content and used to adjust treatment pressures. Pressures were increased incrementally after each burst until ultraharmonic emissions were detected, at which point the pressure was reduced to a percentage of the pressure required to induce the ultraharmonics and was maintained for the remainder of the sonication. Disruption was evaluated at contrast material-enhanced T1-weighted magnetic resonance (MR) imaging. Mean enhancement was calculated by averaging the signal intensity at the focus over a 3 × 3-pixel region of interest and comparing it with that in nonsonicated tissue. Histologic analysis was performed to determine the extent of damage to the tissue. Statistical analysis was performed by using Student t tests. RESULTS For sonications resulting in BBB disruption, the mean peak pressure was 0.28 MPa ± 0.05 (standard deviation) (range, 0.18-0.40 MPa). By using the control algorithm, a linear relationship was found between the scaling level and the mean enhancement on T1-weighted MR images after contrast agent injection. At a 50% scaling level, mean enhancement of 19.6% ± 1.7 (standard error of the mean) was achieved without inducing damage. At higher scaling levels, histologic analysis revealed gross tissue damage, while at a 50% scaling level, no damage was observed at high-field-strength MR imaging or histologic examination 8 days after treatment. CONCLUSION This study demonstrates that acoustic emissions can be used to actively control focused ultrasound exposures for the safe induction of BBB disruption.

Focused-Ultrasound Disruption of the Blood-Brain Barrier Using Closely-Timed Short Pulses: Influence of Sonication Parameters and Injection Rate

Blood-brain barrier disruption (BBBD) shows promise for drug delivery in the brain; however, optimal parameters for disruption have yet to be firmly established. Previous work has shown that BBBD can be achieved using bursts comprised of microsecond-length pulses at 50% duty cycle to eliminate standing waves and variability. The capabilities and limitations of this sort of pulse sequence comprising short bursts were examined. Ultrasound-induced BBBD was performed in 28 rats using Definity contrast agent. The spacing between 3-μs pulses at 1.18 MHz was either 6 μs, 60 μs, 300 μs or 600 μs during a 10-ms pulse, or 1 s for a single-pulse burst. The rate of infusion of the microbubbles was also examined, as well as the burst pulse repetition frequency (PRF) under infusion conditions. A semi-log relationship between enhancement mean and the number of cycles in a burst was discovered, with a one-pulse burst (i.e., a 3-μs burst at 1 Hz) still capable of disrupting the BBB. No increased efficacy or safety benefit over bursts containing more cycles was found, however. Microbubble infusions showed no improvement in T1w enhancement, but did improve consistency. Increased burst PRF combined with infusion improved T1w enhancement but without statistical significance, whereas a decrease in burst PRF showed a statistically significant decrease in enhancement.

Ultrasound enhanced drug delivery to the brain and central nervous system.

There is an increasing interest in the use of ultrasound to enhance drug delivery to the brain and central nervous system. Disorders of the brain and CNS historically have had poor response to drug therapy due to the presence of the blood–brain barrier (BBB). Techniques for circumventing the BBB are typically highly invasive or involve disrupting large portions of the BBB, exposing the brain to pathogens. Ultrasound can be non-invasively delivered to the brain through the intact skull. When combined with preformed microbubbles, ultrasound can safely induce transient, localised and reversible disruption of the BBB, allowing therapeutics to be delivered. Investigations to date have shown positive response to ultrasound BBB disruption combined with therapeutic agent delivery in rodent models of primary and metastatic brain cancer and Alzheimers disease. Recent work in non-human primates has demonstrated that the technique is feasible for use in humans. This review examines the current status of drug delivery to the brain and CNS both by disruption of the BBB, and by ultrasound enhancement of drug delivery through the already compromised BBB. Cellular and physical mechanisms of disruption are discussed, as well as treatment technique, safety and monitoring.

Ultrasound insertion loss of rat parietal bone appears to be proportional to animal mass at submegahertz frequencies.

Transcranial ultrasound therapy is an increasing area of research for noninvasive treatments in the brain including targeted drug delivery. Measurements of ultrasound transmission through rat parietal bone at five frequencies (0.268 MHz, 0.841 MHz, 1.409 MHz, 1.972 MHz and 2.53 MHz) were performed at 88 locations in 22 ex vivo rat skullcaps (Wistar) using a fiber-optic hydrophone system. At submegahertz frequencies, the skull insertion loss was found to be proportional to animal mass, while at higher frequencies this trend was lost. Maps of the transverse pressure profile of the transducer before and after skull insertion showed increased distortion effects at higher frequencies. Parietal bone thickness was measured and was found to increase with increasing body mass. Additional measurements were made through mouse and rabbit skulls at 2.53 MHz. At this frequency, aberration effects through mouse skull were negligible, while large distortions were observed through rat and rabbit skull. Preclinical transcranial ultrasound studies in rats may be improved by scaling applied powers according to body mass to produce more consistent in situ pressures.

Comparison of Computed Tomography Based Parametric and Patient-specific Finite Element Models of the Healthy and Metastatic Spine Using a Mesh-morphing Algorithm

Study Design. A comparative analysis of parametric and patient-specific finite element (FE) modeling of spinal motion segments. Objectives. To develop patient-specific FE models of spinal motion segments using mesh-morphing methods applied to a parametric FE model. To compare strain and displacement patterns in parametric and morphed models for both healthy and metastatically involved vertebrae. Summary of Background Data. Parametric FE models may be limited in their ability to fully represent patient-specific geometries and material property distributions. Generation of multiple patient-specific FE models has been limited because of computational expense. Morphing methods have been successfully used to generate multiple specimen-specific FE models of caudal rat vertebrae. Methods. FE models of a healthy and a metastatic T6–T8 spinal motion segment were analyzed with and without patient-specific material properties. Parametric and morphed models were compared using a landmark-based morphing algorithm. Results. Morphing of the parametric FE model and including patient-specific material properties both had a strong impact on magnitudes and patterns of vertebral strain and displacement. Conclusion. Small but important geometric differences can be represented through morphing of parametric FE models. The mesh-morphing algorithm developed provides a rapid method for generating patient-specific FE models of spinal motion segments.

Emerging non-cancer applications of therapeutic ultrasound

Abstract Ultrasound therapy has been investigated for over half a century. Ultrasound can act on tissue through a variety of mechanisms, including thermal, shockwave and cavitation mechanisms, and through these can elicit different responses. Ultrasound therapy can provide a non-invasive or minimally invasive treatment option, and ultrasound technology has advanced to the point where devices can be developed to investigate a wide range of applications. This review focuses on non-cancer clinical applications of therapeutic ultrasound, with an emphasis on treatments that have recently reached clinical investigations, and preclinical research programmes that have great potential to impact patient care.

A non-surgical model of cervical spinal cord injury induced with focused ultrasound and microbubbles.

BACKGROUND The most commonly used animal models of spinal cord injury (SCI) involve surgical exposure of the dorsal spinal cord followed by transection, contusion or compression. This high level of invasiveness often requires significant post-operative care and can limit post-operative imaging, as the surgical incision site can interfere with coil placement for magnetic resonance imaging (MRI) during the acute phase of SCI. While these models are considered to be similar to human SCI, they do not occur in a closed vertebral system as do the majority of human injuries. NEW METHOD Here we describe a novel, non-surgical model of SCI in the rat using MR-guided focused ultrasound (FUS) in combination with intravenous injection of microbubbles, applied to the cervical spinal cord. RESULTS The injury was well-tolerated and resulted in cervical spinal cord damage in 60% of the animals. The area of Gd-enhancement immediately post-FUS and area of signal abnormality at 24h were correlated with the degree of injury. The extent of injury was easily visualized with T2-weighted MRI and was confirmed using histology. COMPARISON WITH EXISTING METHOD(S) Pathology was similar to that seen in other rat models of direct spinal cord contusion and compression. Unlike these methods, FUS is non-surgical and has lower mortality than seen in other models of cervical SCI. CONCLUSIONS We developed a novel model of SCI which was non-surgical, well-tolerated, localized, and replicated the pathology seen in other models of SCI.

Transcranial bubble activity mapping for therapy and imaging

Bubble-mediated ultrasound therapies in the brain, such as targeted disruption of the blood-brain barrier (BBB) or cavitation-enhanced stroke treatments, are being increasingly investigated due to their potential to revolutionize the treatment of brain disorders. Due to the fact that they are non-thermal in nature, these therapies must be monitored by acoustic means to ensure efficacy and safety. A sparse, 128-element hemispherical receiver array (612 kHz) was integrated within a 306 kHz therapy array. The receiver arrangement was optimized through numerical simulations. The array was characterized on the benchtop to map the activity of bubbles in a tube phantom through an ex vivo human skullcap. In vivo the array was used to map bubble activity in small animal models during microbubble-mediated BBB disruption. The array was investigated as well for diagnostic purposes, imaging transcranial structures filled with very dilute concentrations of microbubbles. A spiral tube phantom with tube diameter of 255 µ...

Standing Waves in Small Animal Models Investigating Ultrasound Disruption of the Blood‐Brain Barrier

Ultrasound disruption of the blood‐brain barrier (BBB) has potential to treat a range of diseases, and important preclinical work is being conducted in small‐animal models, where the potential for standing waves is high. To ensure work is clinically translatable, the effects of standing waves in preclinical models must be examined. The effects of standing waves under different sonication parameters were examined in ex vivo rat skulls using a fiber‐optic hydrophone and a scanning laser vibrometer. Pressure profiles measured in the skulls were consistent with standing waves and were highly variable based on location in the skull. A modified pulse consisting of single excitation cycles delivered to the transducer at closely timed intervals was successful in eliminating standing waves. The modified pulse was used to disrupt the BBB in rats, demonstrating that neither standing wave conditions or continuous wave excitation are required to induce blood‐brain barrier disruption.

Feasibility of a PVDF Receiver for Monitoring of Transcranial Therapy

An MRI compatible PVDF receiver was designed and manufactured for integration into a transcranial therapy array. 4.8 mm diameter, 110 μm thick PVDF film was air‐backed by clamping it across brass tubing. A preamplifier was enclosed within the tubing to improve SNR and drive the long coaxial cables required to reach outside the MRI. The receiver was mounted inside a ring element from an existing array. The receiver performance was compared with a commercial needle hydrophone and tested for MRI compatibility. The PVDF receiver displayed a higher sensitivity than the needle hydrophone and a better capability to reject electrical coupling with the transmit element. MRI image artifacts created by the device were small, and diagnostic ultrasound was possible with the device while simultaneously obtaining an MRI image. Microbubble contrast agent was sonicated both directly, and through a fragment of human skull. The transmit/receive pair was successful in sonicating the microbubbles transcranially and detecting ...