In this animal study, rapid short-pulse sequences deliver drugs uniformly to the brain by disrupting the blood-brain barrier permeability for less than 10 minutes and with a low level of blood albu... BackgroundPrevious work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this seque...

Purpose: Brain tumors, particularly glioblastoma multiforme (GBM), present significant prognostic challenges despite multimodal therapies, including surgical resection, chemotherapy, and radiotherapy. One major obstacle is the limited drug delivery across the blood–brain barrier (BBB). Focused ultrasound (FUS) combined with systemically administered microbubbles has emerged as a non-invasive, targeted, and reversible approach to transiently open the BBB, thus enhancing drug delivery. This review examines clinical trials employing BBB opening techniques to optimise pharmacotherapy for brain tumors, evaluates current challenges, and proposes directions for further research. Methods: A systematic literature search was conducted in PubMed and ClinicalTrials.gov up to November 2023, searching for “ultrasound” AND “brain tumor”. The search yielded 1446 results. After screening by title and abstract, followed by full-text screening (n = 48), 35 studies were included in the analysis. Results: Our analysis includes data from 11 published studies and 24 ongoing trials. The predominant focus of these studies is on glioma, including GMB and astrocytoma. One paper investigated brain metastasis from breast cancer. Evidence indicates that FUS facilitates BBB opening and enhances drug uptake following sonication. Exploration of FUS in the pediatric population is limited, with no published studies and only three ongoing trials dedicated to this demographic. Conclusion: FUS is a promising strategy to safely disrupt the BBB, enabling precise and non-invasive lesion targeting, and enhance drug delivery. However, pharmacokinetic studies are required to quantitatively assess improvements in drug uptake. Most studies are phase I clinical trials, and long-term follow-up investigating patient outcomes is essential to evaluate the clinical benefit of this treatment approach. Further studies involving diverse populations and pathologies will be beneficial.

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2 – 0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

Transcranial focused ultrasound (FUS) in conjunction with circulating microbubbles injection is the sole non-invasive technique that temporally and locally opens the blood-brain barrier (BBB), allowing targeted drug delivery into the central nervous system (CNS). However, single-element FUS technologies do not allow the simultaneous targeting of several brain structures with high-resolution, and multi-element devices are required to compensate the aberrations introduced by the skull. In this work, we present the first preclinical application of acoustic holograms to perform a bilateral BBB opening in two mirrored regions in mice. The system consisted of a single-element focused transducer working at 1.68 MHz, coupled to a 3D-printed acoustic hologram designed to produce two symmetric foci in anesthetized mice in vivo and, simultaneously, compensate the aberrations of the wavefront caused by the skull bones. T1-weighed MR images showed gadolinium extravasation at two symmetric quasi-spherical focal spots. By encoding time-reversed fields, holograms are capable of focusing acoustic energy with a resolution near the diffraction limit at multiple spots inside the skull of small preclinical animals. This work demonstrates the feasibility of hologram-assisted BBB opening for low-cost and highly-localized targeted drug delivery in the CNS in symmetric regions of separate hemispheres.

Despite the promise of microbubble-mediated focused ultrasound therapies, in vivo findings have revealed over-treated and under-treated regions distributed throughout the focal volume. This poor distribution cannot be improved by conventional pulse shapes and sequences, due to their limited ability to control acoustic cavitation dynamics within the ultrasonic focus. This paper describes the design of a rapid short-pulse (RaSP) sequence which is comprised of short pulses separated by μs off-time intervals. Improved acoustic cavitation distribution was based on the hypothesis that microbubbles can freely move during the pulse off-times. Flowing SonoVue® microbubbles (flow velocity: 10 mm/s) were sonicated with a 0.5 MHz focused ultrasound transducer using RaSP sequences (peak-rarefactional pressures: 146–900 kPa, pulse repetition frequency: 1.25 kHz, and pulse lengths: 5–50 cycles). The distribution of cavitation activity was evaluated using passive acoustic mapping. RaSP sequences generated uniform distributions within the focus in contrast to long pulses (50 000 cycles) that produced non-uniform distributions. Fast microbubble destruction occurred for long pulses, whereas microbubble activity was sustained for longer durations for shorter pulses. High-speed microscopy revealed increased mobility in the direction of flow during RaSP sonication. In conclusion, RaSP sequences produced spatiotemporally uniform cavitation distributions and could result in efficient therapies by spreading cavitation throughout the treatment area.

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.