The feasibility of transcranial passive acoustic mapping with hemispherical sparse arrays (30 cm diameter, 16 to 1372 elements, 2.48 mm receiver diameter) using CT-based aberration corrections was investigated via numerical simulations. A multi-layered ray acoustic transcranial ultrasound propagation model based on CT-derived skull morphology was developed. By incorporating skull-specific aberration corrections into a conventional passive beamforming algorithm (Norton and Won 2000 IEEE Trans. Geosci. Remote Sens. 38 1337–43), simulated acoustic source fields representing the emissions from acoustically-stimulated microbubbles were spatially mapped through three digitized human skulls, with the transskull reconstructions closely matching the water-path control images. Image quality was quantified based on main lobe beamwidths, peak sidelobe ratio, and image signal-to-noise ratio. The effects on the resulting image quality of the source’s emission frequency and location within the skull cavity, the array sparsity and element configuration, the receiver element sensitivity, and the specific skull morphology were all investigated. The system’s resolution capabilities were also estimated for various degrees of array sparsity. Passive imaging of acoustic sources through an intact skull was shown possible with sparse hemispherical imaging arrays. This technique may be useful for the monitoring and control of transcranial focused ultrasound (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.

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 1.25-2 mm and the axial resolution between 2-3.5 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.

OBJECTIVETranscranial MR-guided focused ultrasound (MRgFUS) is a minimally invasive treatment for movement disorders. Considerable interpatient variability in skull transmission efficiency exists with the current clinical devices, which is thought to be dependent on each patient’s specific skull morphology. Lower skull density ratio (SDR) values are thought to impede acoustic energy transmission across the skull, attenuating or preventing the therapeutic benefits of MRgFUS. Patients with SDR values below 0.4 have traditionally been deemed poor candidates for MRgFUS. Although considerable anecdotal evidence has suggested that SDR is a reliable determinant of procedural and clinical success, relationships between SDR and clinical outcomes have yet to be formally investigated. Moreover, as transcranial MRgFUS is becoming an increasingly widespread procedure, knowledge of SDR distribution in the general population may enable improved preoperative counseling and preparedness.METHODSA total of 98 patients who underwent MRgFUS thalamotomy at the authors’ institutions between 2012 and 2018 were analyzed (cohort 1). The authors retrospectively assessed the relationships between SDR and various clinical outcomes, including tremor improvement and adverse effects, as well as procedural factors such as sonication parameters. An SDR was also prospectively obtained in 163 random emergency department patients who required a head CT scan for various clinical indications (cohort 2). Patients’ age and sex were used to explore relationships with SDR.RESULTSIn the MRgFUS treatment group, 17 patients with a thalamotomy lesion had an SDR below 0.4. Patients with lower SDRs required more sonication energy; however, their low SDR did not influence their clinical outcomes. In the emergency department patient group, about one-third of the patients had a low SDR (< 0.4). SDR did not correlate with age or sex.CONCLUSIONSAlthough lower SDR values correlated with higher energy requirements during MRgFUS thalamotomy, within the range of this study population, the SDR did not appreciably impact or provide the ability to predict the resulting clinical outcomes. Sampling of the general population suggests that age and sex have no relationship with SDR. Other variables, such as local variances in bone density, should also be carefully reviewed to build a comprehensive appraisal of a patient’s suitability for MRgFUS treatment.

Purpose: Experimentally verify a previously described technique for performing passive acoustic imaging through an intact human skull using noninvasive, computed tomography (CT)-based aberration corrections Jones et al. [Phys. Med. Biol. 58, 4981-5005 (2013)]. Methods: A sparse hemispherical receiver array (30 cm diameter) consisting of 128 piezoceramic discs (2.5 mm diameter, 612 kHz center frequency) was used to passively listen through ex vivo human skullcaps (n = 4) to acoustic emissions from a narrow-band fixed source (1 mm diameter, 516 kHz center frequency) and from ultrasound-stimulated (5 cycle bursts, 1 Hz pulse repetition frequency, estimated in situ peak negative pressure 0.11-0.33 MPa, 306 kHz driving frequency) Definity™ microbubbles flowing through a thin-walled tube phantom. Initial in vivo feasibility testing of the method was performed. The performance of the method was assessed through comparisons to images generated without skull corrections, with invasive source-based corrections, and with water-path control images. Results: For source locations at least 25 mm from the inner skull surface, the modified reconstruction algorithm successfully restored a single focus within the skull cavity at a location within 1.25 mm from the true position of the narrow-band source. The results obtained from imaging single bubbles are in good agreement with numerical simulations of point source emitters and the authors' previous experimental measurements using source-based skull corrections O'Reilly et al. [IEEE Trans. Biomed. Eng. 61, 1285-1294]. In a rat model, microbubble activity was mapped through an intact human skull at pressure levels below and above the threshold for focused ultrasound-induced blood-brain barrier opening. During bursts that led to coherent bubble activity, the location of maximum intensity in images generated with CT-based skull corrections was found to deviate by less than 1 mm, on average, from the position obtained using source-based corrections. Conclusions: Taken together, these results demonstrate the feasibility of using the method to guide bubble-mediated ultrasound therapies in the brain. The technique may also have application in ultrasound-based cerebral angiography. C 2015 American Association of Physicists in Medicine.

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.

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 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.

Focused ultrasound (FUS) phased arrays show promise for non-invasive brain therapy. However, the majority of them are limited to a single transmit/receive frequency and therefore lack the versatility to expose and monitor the treatment volume. Multi-frequency arrays could offer variable transmit focal sizes under a fixed aperture, and detect different spectral content on receive for imaging purposes. Here, a three-frequency (306, 612 and 1224 kHz) sparse hemispherical ultrasound phased array (31.8 cm aperture; 128 transducer modules) was constructed and evaluated for microbubble-mediated transcranial therapy and simultaneous cavitation mapping. The array is able to perform effective electronic beam steering over a volume spanning [−40, 40] and [−30, 50] mm in the lateral and axial directions, respectively. The focal size at the geometric center is approximately 0.9 (2.1) mm, 1.7 (3.9) mm, and 3.1 (6.5) mm in lateral (axial) pressure full width at half maximum (FWHM) at 1224, 612, and 306 kHz, respectively. The array was also found capable of dual-frequency excitation and simultaneous multi–foci sonication, which enables the future exploration of more complex exposure strategies. Passive acoustic mapping of dilute microbubble clouds demonstrated that the point spread function of the receive array has a lateral (axial) intensity FWHM between 0.8-3.5 mm (1.7-11.7 mm) over a volume spanning [−25, 25] mm in both the lateral and axial directions, depending on the transmit/receive frequency combination and the imaging location. The device enabled both half and second harmonic imaging through the intact skull, which may be useful for improving the contrast-to-tissue ratio or imaging resolution, respectively. Preliminary in-vivo experiments demonstrated the system's ability to induce blood-brain barrier opening and simultaneously spatially map microbubble cavitation activity in a rat model. This work presents a tool to investigate optimal strategies for non-thermal FUS brain therapy and concurrent microbubble cavitation monitoring through the availability of multiple frequencies.

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