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 techniques currently exist.

Background: GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease‐modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood–brain barrier (BBB). Microbubble‐mediated magnetic resonance–guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery.Methods: This open‐label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations.Results: BBB permeability was achieved and restored in all patients as quantified by dynamic contrast‐enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society–Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08.Conclusions: Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Computed tomography (CT)-based aberration corrections are employed in transcranial ultrasound both for therapy and imaging. In this study, analytical and numerical approaches for calculating aberration corrections based on CT data were compared, with a particular focus on their application to transcranial passive imaging. Two models were investigated: a three-dimensional full-wave numerical model (Connor and Hynynen 2004 IEEE Trans. Biomed. Eng . 51 1693–706) based on the Westervelt equation, and an analytical method (Clement and Hynynen 2002 Ultrasound Med. Biol . 28 617–24) similar to that currently employed by commercial brain therapy systems. Trans-skull time delay corrections calculated from each model were applied to data acquired by a sparse hemispherical (30 cm diameter) receiver array (128 piezoceramic discs: 2.5 mm diameter, 612 kHz center frequency) passively listening through ex vivo human skullcaps ( n = 4) to emissions from a narrow-band, fixed source emitter (1 mm diameter, 516 kHz center frequency). Measurements were taken at various locations within the cranial cavity by moving the source around the field using a three-axis positioning system. Images generated through passive beamforming using CT-based skull corrections were compared with those obtained through an invasive source-based approach, as well as images formed without skull corrections, using the main lobe volume, positional shift, peak sidelobe ratio, and image signal-to-noise ratio as metrics for image quality. For each CT-based model, corrections achieved by allowing for heterogeneous skull acoustical parameters in simulation outperformed the corresponding case where homogeneous parameters were assumed. Of the CT-based methods investigated, the full-wave model provided the best imaging results at the cost of computational complexity. These results highlight the importance of accurately modeling trans-skull propagation when calculating CT-based aberration corrections. Although presented in an imaging context, our results may also be applicable to the problem of transmit focusing through the skull.

Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson’s disease. The performance of the clinical MRgFUS system’s cavitation feedback controller for active power modulation throughout the exposures was examined. The putamen was targeted unilaterally by an ExAblate Neuro MRgFUS system operating at 220 kHz. Definity microbubbles were infused via a saline bag gravity drip at a rate of 4 µL/kg per 5 min. A cavitation emissions-based feedback controller was employed to modulate the acoustic power automatically according to prescribed target cavitation dose levels. BBB opening was measured by Gadolinium (Gd)-enhanced T1-weighted MR imaging, and the presence of potential micro-hemorrhages induced by the exposures was assessed via T2*-weighted MR imaging. A total of 12 treatment sessions were carried out across four patients, with target cavitation dose levels ranging from 0.20–0.40. BBB permeability in the targeted putamen was elevated successfully in all treatments, with a 14% ± 6% mean increase in Gd-enhanced T1-weighted MRI signal intensity relative to the untreated contralateral side. No indications of red blood cell extravasations were observed on MR imaging scans acquired one day following each treatment session. The cavitation emissions-based feedback controller was effective in modulating acoustic power levels to ensure BBB permeability enhancement while avoiding micro-hemorrhages, however, further technical advancements are warranted to improve its performance for use across a wide variety of brain diseases.

Transcranial magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) thermal ablation is under clinical investigation for non-invasive neurosurgery, though its use is restricted to central brain targets due primarily to skull heating effects. The combination of FUS and contrast agent microbubbles greatly reduces the ultrasound exposure levels needed to ablate brain tissue and may help facilitate the use of transcranial FUS ablation throughout the brain. However, sources of variability exist during microbubble-mediated FUS procedures that necessitate the continued development of systems and methods for online treatment monitoring and control, to ensure that excessive and/or off-target bioeffects are not induced from the exposures.