Ryan M. Jones

Three-Dimensional Transcranial Ultrasound Imaging of Microbubble Clouds Using a Sparse Hemispherical Array

There is an increasing interest in bubble-mediated focused ultrasound (FUS) interventions in the brain. However, current technology lacks the ability to spatially monitor the interaction of the microbubbles with the applied acoustic field, something which is critical for safe clinical translation of these treatments. Passive acoustic mapping could offer a means for spatially monitoring microbubble emissions that relate to bubble activity and associated bioeffects. In this study, a hemispherical receiver array was integrated within an existing transcranial therapy array to create a device capable of both delivering therapy and monitoring the process via passive imaging of bubble clouds. A 128-element receiver array was constructed and characterized for varying bubble concentrations and source spacings. Initial in vivo feasibility testing was performed. The system was found to be capable of monitoring bubble emissions down to single bubble events through an ex vivo human skull. The lateral resolution of the system was found to be between 1.25 and 2 mm and the axial resolution between 2 and 3.5 mm, comparable to the resolution of MRI-based temperature monitoring during thermal FUS treatments in the brain. The results of initial in vivo experiments show that bubble activity can be mapped starting at pressure levels below the threshold for blood-brain barrier disruption. This study presents a feasible solution for imaging bubble activity during cavitation-mediated FUS treatments in the brain.

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

Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimers 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 used are clinically relevant and indicate safety for clinical translation. Further study is warranted to determine if FUS has positive effects on naturally occurring amyloid pathology.

Simulations of transcranial passive acoustic mapping with hemispherical sparse arrays using computed tomography-based aberration corrections

Passive acoustic mapping (PAM) is receiving increasing interest as a method for monitoring focused ultrasound (FUS) therapy. PAM would be beneficial during transcranial cavitation-enhanced FUS treatments, particularly non-thermal, cavitation-mediated applications such as FUS-induced blood–brain barrier disruption or sonothrombolysis, for which no real-time monitoring technique currently exists. However, the use of PAM in the brain is complicated by the presence of the skull bone. If not properly accounted for, skull-induced aberrations of propagating cavitation emissions will lead to image distortion and artifacts upon reconstruction. Through the use of numerical simulations, this study investigated the feasibility of transcranial PAM via hemispherical sparse hydrophone arrays. A multi-layered ray acoustic transcranial ultrasound propagation model based on computed tomography-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm [Norton and Won, IEEE Trans. Geosci. Remote Sens. 38, 1337–1343 (2000)], simulated acoustic source fields were spatially mapped through digitized human skulls. The effects of array sparsity and receiver element configuration on the formation of passive acoustic maps were examined. Multiple source locations were simulated to determine the imageable volume within the skull cavity. Finally, the reconstruction algorithms sensitivity to noise was explored.

Three-dimensional transcranial microbubble imaging for guiding volumetric ultrasound-mediated blood-brain barrier opening

Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening recently entered clinical testing for targeted drug delivery to the brain. Sources of variability exist in the current procedures, motivating the development of real-time monitoring and control techniques to improve treatment safety and efficacy. Here we used three-dimensional (3D) transcranial microbubble imaging to calibrate FUS exposure levels for volumetric BBB opening. Methods: Using a sparse hemispherical transmit/receive ultrasound phased array, pulsed ultrasound was focused transcranially into the thalamus of rabbits during microbubble infusion and multi-channel 3D beamforming was performed online with receiver signals captured at the subharmonic frequency. Pressures were increased pulse-by-pulse until subharmonic activity was detected on acoustic imaging (psub), and tissue volumes surrounding the calibration point were exposed at 50-100%psub via rapid electronic beam steering. Results: Spatially-coherent subharmonic microbubble activity was successfully reconstructed transcranially in vivo during calibration sonications. Multi-point exposures induced volumetric regions of elevated BBB permeability assessed via contrast-enhanced magnetic resonance imaging (MRI). At exposure levels ≥75%psub, MRI and histological examination occasionally revealed tissue damage, whereas sonications at 50%psub were performed safely. Substantial intra-grid variability of FUS-induced bioeffects was observed via MRI, prompting future development of multi-point calibration schemes for improved treatment consistency. Receiver array sparsity and sensor configuration had substantial impacts on subharmonic detection sensitivity, and are factors that should be considered when designing next-generation clinical FUS brain therapy systems. Conclusion: Our findings suggest that 3D subharmonic imaging can be used to calibrate exposure levels for safe FUS-induced volumetric BBB opening, and should be explored further as a method for cavitation-mediated treatment guidance.

Passive mapping of acoustic sources within the human skull cavity with a hemispherical sparse array using computed tomography-based aberration corrections

Traditionally, the use of ultrasound (US) in the brain has been limited by the skull bone, which presents unique challenges for both transcranial therapy and imaging due to its attenuating and aberrating effects, which become more prevalent at higher US frequencies. On transmit, these skull-induced aberrations can be overcome through the use of large-aperture phased array transducers with appropriate driving frequencies, combined with computed tomography (CT)-based bone morphology and numerical models to derive element driving signals which minimize the distortions. Recently, we have demonstrated in silico that an analogous approach can be performed during beamforming on receive, to allow for passive acoustic imaging over a large region within the skull cavity [Jones et al., Phys. Med. Biol. 58, 4981–5005 (2013)]. We will present preliminary results obtained from applying this technique experimentally with a hemispherical (30 cm diam.) sparse receiver array (128 piezo-ceramic elements, 2.5 mm diam., and 6...

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...

Applications of an ultra low‐drag towed array deployed from a glider

We have deployed a Webb Research Slocum glider towing a 21‐meter 16‐element line array in two experiments, the Makai experiment off of Kauai, and the PLUSNet experimient in Monterey Bay. A glider platform provides some unique capabilities. It is very quiet, by virtue of its buoyancy‐driven propulsion, and it visits or samples most of the water column on a regular basis, following its sawtooth dive profile. We have collected data in several configurations, including a stop‐and‐drift mode, in which the array assumes a vertical posture, recording narrowband and broadband controlled sources and ambient noise. We will present the results of processing these datasets, and discuss their implications for surveillance, seabed mapping, and ambient noise measurements.

Advances in controlled transcranial bubble-mediated drug delivery and opportunities for transvertebral therapy

The treatment of central nervous system (CNS) disorders is hindered by the presence of specialized barriers that maintain the privileged CNS environment and in doing so restrict the transport of molecules from the vascular compartment to the parenchyma. The ability of ultrasound in combination with intravenously administered microbubbles to transiently open the Blood-Brain Barrier (BBB) to permit the delivery of therapeutic agents is well established in preclinical models and has reached the stage of clinical investigations. Although the methods are not yet as developed as those for BBB opening, ultrasound can also modify the Blood-Spinal Cord Barrier (BSCB) to facilitate drug delivery. Both treatments have immense potential to revolutionize the treatment of CNS disorders, but their widespread clinical adoption hinges on the establishment of robust methods to deliver, monitor and control the exposures to ensure safe and effective treatments in these sensitive tissues. This talk will present recent advances in methods for brain therapy, including three-dimensional transcranial microbubble mapping for treatment control, and will also present new preclinical findings in BSCB opening and approaches for controlled transvertebral focusing at clinical scale.The treatment of central nervous system (CNS) disorders is hindered by the presence of specialized barriers that maintain the privileged CNS environment and in doing so restrict the transport of molecules from the vascular compartment to the parenchyma. The ability of ultrasound in combination with intravenously administered microbubbles to transiently open the Blood-Brain Barrier (BBB) to permit the delivery of therapeutic agents is well established in preclinical models and has reached the stage of clinical investigations. Although the methods are not yet as developed as those for BBB opening, ultrasound can also modify the Blood-Spinal Cord Barrier (BSCB) to facilitate drug delivery. Both treatments have immense potential to revolutionize the treatment of CNS disorders, but their widespread clinical adoption hinges on the establishment of robust methods to deliver, monitor and control the exposures to ensure safe and effective treatments in these sensitive tissues. This talk will present recent advance...

Treatment monitoring for sonothrombolysis in deep vein thrombosis: Receiver array design

The current treatment standard for deep vein thrombosis (DVT) is anticoagulation therapy, which does little to address long term morbidity compared to clot removal approaches. High intensity ultrasound can resolve clots by generating bubble clouds that erode thrombi. However, lack of appropriate treatment monitoring is a limiting factor in its widespread adoption. Passive cavitation imaging is capable of high frame rate, volumetric imaging, the combination of which has been shown to be important for monitoring the onset and development of bubble clouds inducing clot erosion (Acconcia et al. 2017). The results from our previous work motivated development of a device tailored to DVT with a relevant geometry (e.g., semi-cylindrical). Transmit simulations for such a device were conducted in a human thigh model (Smirnov and Hynynen 2017) with a design based on the modular transducer technology developed in our lab (Ellens et al. 2015). Here, we examine the integration of a sparse, randomly distributed receiver array within a semi-cylindrical arrangement of transmit modules for acoustic-based monitoring. Using a multi-layered propagation model, cavitation sources were localized to the femoral vessel, the accuracy of which depended on the inclusion of phase corrections. The receiver size was shown to be an important consideration with implicit trade-offs between directivity and channel SNR. Volumetric rates of ~1 MHz should be achievable with a modest number of receivers (128) in the presence of experimentally derived noise conditions.

Non-auditory, electrophysiological potentials preceding dolphin biosonar click production

The auditory brainstem response to a dolphin’s own emitted biosonar click can be measured by averaging epochs of the instantaneous electroencephalogram (EEG) that are time-locked to the emitted click. In this study, averaged EEGs were measured using surface electrodes placed on the head in six different configurations while dolphins performed an echolocation task. Simultaneously, biosonar click emissions were measured using contact hydrophones on the melon and a hydrophone in the farfield. The averaged EEGs revealed an electrophysiological potential (the pre-auditory wave, PAW) that preceded the production of each biosonar click. The largest PAW amplitudes occurred with the non-inverting electrode just right of the midline—the apparent side of biosonar click generation—and posterior of the blowhole. Although the source of the PAW is unknown, the temporal and spatial properties rule out an auditory source. The PAW may be a neural or myogenic potential associated with click production; however, it is not known if muscles within the dolphin nasal system can be actuated at the high rates reported for dolphin click production, or if sufficiently coordinated and fast motor endplates of nasal muscles exist to produce a PAW detectable with surface electrodes.