The ability of ultrasound to be focused into a small region of interest through the intact skull within the brain has led researchers to investigate its potential therapeutic uses for functional neurosurgery and tumor ablation. Studies have used high-intensity focused ultrasound to ablate tissue in localised brain regions for movement disorders and chronic pain while sparing the overlying and surrounding tissue. More recently, low-intensity focused ultrasound (LIFU) that induces reversible biological effects has been emerged as an alternative neuromodulation modality due to its bi-modal (i.e. excitation and suppression) capability with exquisite spatial specificity and depth penetration. Many compelling evidences of LIFU-mediated neuromodulatory effects including behavioral responses, electrophysiological recordings and functional imaging data have been found in the last decades. LIFU, therefore, has the enormous potential to improve the clinical outcomes as well as to replace the currently available neuromodulation techniques such as deep brain stimulation (DBS), transcranial magnetic stimulation and transcranial current stimulation. In this paper, we aim to provide a summary of pioneering studies in the field of ultrasonic neuromodulation including its underlying mechanisms that were published in the last 60 years. In closing, some of potential clinical applications of ultrasonic brain stimulation will be discussed.

The aim of boiling histotripsy is to mechanically fractionate tissue as an alternative to thermal ablation for therapeutic applications. In general, the shape of a lesion produced by boiling histotripsy is tadpole like, consisting of a head and a tail. Although many studies have demonstrated the efficacy of boiling histotripsy for fractionating solid tumors, the exact mechanisms underpinning this phenomenon are not yet well understood, particularly the interaction of a boiling vapor bubble with incoming incident shockwaves. To investigate the mechanisms involved in boiling histotripsy, a high-speed camera with a passive cavitation detection system was used to observe the dynamics of bubbles produced in optically transparent tissue-mimicking gel phantoms exposed to the field of a 2.0-MHz high-intensity focused ultrasound (HIFU) transducer. We observed that boiling bubbles were generated in a localized heated region and cavitation clouds were subsequently induced ahead of the expanding bubble. This process was repeated with HIFU pulses and eventually resulted in a tadpole-shaped lesion. A simplified numerical model describing the scattering of the incident ultrasound wave by a vapor bubble was developed to help interpret the experimental observations. Together with the numerical results, these observations suggest that the overall size of a lesion induced by boiling histotripsy is dependent on the sizes of (i) the heated region at the HIFU focus and (ii) the backscattered acoustic field by the original vapor bubble.

In boiling histotripsy, the presence of a boiling vapour bubble and understanding of its dynamic behaviour are crucially important for the initiation of the tissue fractionation process and for the control of the size of a lesion produced. Whilst many in vivo studies have shown the feasibility of using boiling histotripsy in mechanical fractionation of solid tumours, not much is known about the evolution of a boiling vapour bubble in soft tissue induced by boiling histotripsy. The main objective of this present study is therefore to investigate the formation and dynamic behaviour of a boiling vapour bubble which occurs under boiling histotripsy insonation. Numerical and experimental studies on the bubble dynamics induced in optically transparent tissue-mimicking gel phantoms exposed to the field of a 2.0 MHz High Intensity Focused Ultrasound (HIFU) transducer were performed with a high speed camera. The Gilmore-Zener bubble model coupled with the Khokhlov-Zabolotskaya-Kuznetsov and the Bio-heat Transfer equations was used to simulate bubble dynamics driven by boiling histotripsy waveforms (nonlinear-shocked wave excitation) in a viscoelastic medium as functions of surrounding temperature and of tissue elasticity variations. In vivo animal experiments were also conducted to examine cellular structures around a freshly created lesion in the liver resulting from boiling histotripsy. To the best of our knowledge, this is the first study reporting the numerical and experimental evidence of the appearance of rectified bubble growth in a viscoelastic medium. Accounting for tissue phantom elasticity adds a mechanical constraint on vapour bubble growth, which improves the agreement between the simulation and the experimental results. In addition the numerical calculations showed that the asymmetry in a shockwave and water vapour transport can result in rectified bubble growth which could be responsible for HIFU-induced tissue decellularisation. Strain on liver tissue induced by this radial motion can damage liver tissue while preserving blood vessels.

Boiling histotripsy is a promising non-invasive High-Intensity Focused Ultrasound (HIFU) technique that employs HIFU mechanical effects to fractionate solid tumours without causing any significant thermal damage. It has been suggested that boiling histotripsy may induce a strong immune response due to the absence of denatured antigenic protein at the HIFU focus. The underlying immunological mechanisms of this technique are, however, poorly understood. In this study, we demonstrated the feasibility of using boiling histotripsy to mechanically fractionate human breast adenocarcinoma cells (MDA-MB-231) and the potential immunological effects induced by boiling histotripsy, for the first time. Our results showed that mechanical stresses produced by boiling histotripsy promote immunogenic cell death of cancer cells via TNF-induced necrosis signaling pathway. This immunogenic cell death significantly increases secretions of damage-associated molecular patterns (CRT, HSP70, HMGB-1), pro-inflammatory cytokines (IFN-γ, IL-1α, IL-1β, IL-18) and chemokines (IL-8) which are related to M1 macrophage activation. Furthermore, the levels of these signaling proteins increase with the degree of mechanical damage induced by boiling histotripsy. Together, the results presented can suggest that boiling histotripsy could be a potential therapeutic approach for not only mechanically destroying solid tumours (e.g., breast cancer) but also promoting immunogenic cell death via TNF-induced necrosis to trigger antitumour immunity.

A phenomenological implementation of Classical Nucleation Theory (CNT) is employed to investigate the connection between high intensity focused ultrasound (HIFU) pressure and temperature fields with the energetic requirements of bubble nucleation. As a case study, boiling histotripsy in tissue-mimicking phantoms is modelled. The physics of key components in the implementation of CNT in HIFU conditions such as the derivation of nucleation pressure thresholds and approximations regarding the surface tension of the liquid are reviewed and discussed. Simulations show that the acoustic pressure is the ultimate trigger for millisecond bubble nucleation in boiling histotripsy, however, HIFU heat deposition facilitates nucleation by lowering nucleation pressure thresholds. Nucleation thus occurs preferentially at the regions of highest heat deposition within the HIFU field. This implies that bubble nucleation subsequent to millisecond HIFU heat deposition can take place at temperatures below 100 °C as long as the focal HIFU peak negative pressure exceeds the temperature-dependent nucleation threshold. It is also found that the magnitude of nucleation pressure thresholds decreases with decreasing frequencies. Overall, results indicate that it is not possible to separate thermal and mechanical effects of HIFU in the nucleation of bubbles for timescales of a few milliseconds. This