Background: Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system with integrated real-time 2-D microbubble cavitation mapping.

Objective: Passive acoustic mapping (PAM) provides the spatial information of acoustic energy emitted from microbubbles during focused ultrasound (FUS), which can be used for safety and efficacy monitoring of blood–brain barrier (BBB) opening. In our previous work with a neuronavigation-guided FUS system, only part of the cavitation signal could be monitored in real time due to the computational burden although full-burst analysis is required to detect transient and stochastic cavitation activity. In addition, the spatial resolution of PAM can be limited for a small-aperture receiving array transducer. For full-burst real-time PAM with enhanced resolution, we developed a parallel processing scheme for coherence-factor-based PAM (CF-PAM) and implemented it onto the neuronavigation-guided FUS system using a co-axial phased-array imaging transducer. Methods: Simulation and in-vitro human skull studies were conducted for the performance evaluation of the proposed method in terms of spatial resolution and processing speed. We also carried out real-time cavitation mapping during BBB opening in non-human primates (NHPs). Results: CF-PAM with the proposed processing scheme provided better resolution than that of traditional time-exposure-acoustics PAM with a higher processing speed than that of eigenspace-based robust Capon beamformer, which facilitated the full-burst PAM with the integration time of 10 ms at a rate of 2 Hz. In vivo feasibility of PAM with the co-axial imaging transducer was also demonstrated in two NHPs, showing the advantages of using real-time B-mode and full-burst PAM for accurate targeting and safe treatment monitoring. Significance: This full-burst PAM with enhanced resolution will facilitate the clinical translation of online cavitation monitoring for safe and efficient BBB opening.

Focused ultrasound (FUS)–mediated blood-brain barrier (BBB) opening with microbubbles is an emerging technology that enables drug delivery for central nervous system diseases. To date, most clinical trials assessing BBB opening in adults were designed to deliver US with a frequency of one treatment over several weeks. Little is known about the feasibility of shorter intervals of US delivery or whether this can be achieved in a pediatric population using a mobile device. Here, FUS and panobinostat were shown to have additive therapeutic effects in a syngeneic orthotopic model of diffuse midline glioma (DMG). We then conducted a single-arm first-in-pediatric trial to investigate the safety and feasibility of delivering neuronavigation-guided FUS treatment in combination with oral panobinostat in children with relapsed DMGs. We included an intrapatient escalation of FUS delivery to assess the feasibility of opening multiple sites in the brain. We demonstrated successful BBB opening using neuronavigation-guided FUS as frequently as every 2 days. Magnetic resonance imaging with contrast was used to identify the region of BBB opening. Three patients were accrued; 22 FUS procedures were delivered for 1 NOTS (number of tumor sites) treated, and four FUS procedures were delivered for 2 NOTS. All three patients received 1 NOTS, without serious adverse events, and two of the patients received 2 NOTS, all without sedation. For 2 NOTS, prolonged BBB opening and one grade 5 event, unlikely related to FUS, were observed. This study demonstrates feasibility of FUS for BBB opening and drug delivery without sedation in pediatric patients.

Plane wave imaging has been proven to provide transmit beams with a narrow and uniform beam width throughout the imaging depth. The transmit beam pattern, however, exhibits strong grating lobes that have to be suppressed by a tightly focused receive beam pattern. In this paper, we present the conditions of grating lobe occurrence by analyzing the synthetic transmit beam pattern. Based on the analysis, the threshold of the angle interval is presented to completely eliminate grating lobe problems when using uniformly distributed plane wave angles. However, this threshold requires a very small angle interval (or, equivalently, too many angles). We propose the use of non-uniform plane wave angles to disperse the grating lobes in the spatial domain. In this paper, we present an approach using two uniform angle sets with different intervals to generate a non-uniform angle set. The proposed methods were verified by continuous-wave transmit beam patterns and broad-band 2D point spread functions obtained by computer simulations.

Synthetic transmit focusing (STF) methods using unfocused waves or plane waves (PWs) have recently been investigated extensively. However, STF using PWs with a convex array (PWSTF-CA) has not been rigorously studied for high-resolution sector imaging. In this paper, the authors suggest an analytical model for accurate characterization of the spatial beam patterns of PWSTF-CA using a large range of either uniformly or non-uniformly distributed PW angles. On the basis of the model, a frame-based PWSTF-CA approach with non-uniform PW angles is suggested to achieve superior image quality at a higher frame rate than conventional transmit focusing (CTF). The analytical model can also be used for optimal selection of a set of PW angles to scan the entire sectorial field of view and its subsets employed for STF at each imaging point. The authors also investigate how to select transmit subarrays for each of the PWs to obtain the best spatial resolution. A theoretical analysis and simulations are conducted for the verification of the analytical model and the optimal utilization strategy of PWSTF-CA. The results indicate that the PWSTF-CA improves not only the frame rate but also the contrast, signal-to-noise ratio, and resolution compared with the CTF, as in the case of PWSTF with linear arrays.

Background: Focused ultrasound (FUS) is an emerging non-invasive technique for neuromodulation in the central nervous system (CNS). Functional ultrasound imaging (fUSI) leverages ultrafast Power Doppler Imaging (PDI) to detect changes in cerebral blood volume (CBV), which correlate well with neuronal activity and thus hold promise to monitor brain responses to FUS. Objective: Investigate the immediate and short-term effects of transcranial FUS neuromodulation in the brain with fUSI by characterizing hemodynamic responses. Methods: We designed a setup that aligns a FUS transducer with a linear array to allow immediate subsequent monitoring of the hemodynamic response with fUSI during and after FUS neuromodulation (FUS-fUSI) in lightly anesthetized mice. We investigated the effects of varying pressures and transducer positions on the hemodynamic responses. Results: We found that higher FUS pressures increase the size of the activated brain area, as well as the magnitude of change in CBV and could show that sham sonications did not produce hemodynamic responses. Unilateral sonications resulted in bilateral hemodynamic changes with a significantly stronger response on the ipsilateral side. FUS neuromodulation in mice with a cranial window showed distinct activation patterns that were frequency-dependent and different from the activation patterns observed in the transcranial model. Conclusion: fUSI is hereby shown capable of transcranially monitoring online and short-term hemodynamic effects in the brain during and following FUS neuromodulation