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Focused ultrasound (FUS) offers an attractive tool for non-invasive neuromodulation, addressing a clinical need to develop more minimally invasive approaches that are safer, more tolerable and versatile. In combination with a cavitation agent, the effects of ultrasound can be amplified and localized for therapy. Using c-Fos expression mapping, we show how ultrasound-sensitive nanodroplets can be used to induce either neurosuppression or neurostimulation, without disrupting the blood-brain barrier in rats. By repurposing a commercial ultrasound contrast agent, Definity, lipid-shell decafluorobutane-core nanodroplets of 212.5 ± 2.0 nm were fabricated and loaded with or without pentobarbital. FUS was delivered with an atlas-based targeting system at 1.66 MHz to the motor cortex of rats, using a feedback-controller to detect successful nanodroplet vaporization and drug release. Neuromodulation was quantified through changes in sensorimotor function and c-Fos expression. Following FUS-triggered delivery, sham nanodroplets induced a 22.6 ± 21% increase in local c-Fos expression, whereas pentobarbital-loaded nanodroplets induced a 21.7 ± 13% decrease (n = 6). Nanodroplets, combined with FUS, offer an adaptable tool for neuromodulation, through local delivery of small molecule anesthetics or targeted mechanical effects.

Focused ultrasound (FUS) is an emerging modality for performing incisionless neurosurgical procedures including thermoablation and blood-brain barrier (BBB) modulation. Emerging evidence suggests that low intensity FUS can also be used for neuromodulation with several benefits, including high spatial precision and the possibility of targeting deep brain regions. Here we review the existing data regarding the biological mechanisms of FUS neuromodulation, the characteristics of neuronal activity altered by FUS, emerging indications for FUS neuromodulation, as well as the strengths and limitations of this approach.

The blood-brain barrier, while fundamental in maintaining homeostasis in the central nervous system, is a bottleneck to achieving efficacy for numerous therapeutics. Improved brain penetration is also desirable for reduced dose, cost, and systemic side effects. Transient disruption of the blood-brain barrier with focused ultrasound (FUS) can facilitate drug delivery noninvasively with precise spatial and temporal specificity. FUS technology is transcranial and effective without further drug modifications, key advantages that will accelerate adoption and translation of existing therapeutic pipelines. In this review, we performed a comprehensive literature search to build a database and provide a synthesis of ultrasound parameters and drug characteristics that influence the safety and efficacy profile of FUS to enhance drug delivery.

New strategies are required to enhance the penetration and tumor-wide distribution of cancer therapeutics, including viruses, antibodies, and oligonucleotides. We have shown previously that increasing the density of a nanoparticle can enhance its ultrasound-mediated transport, particularly when exposed to microstreaming. The current study investigates how the physical characteristics and dynamics of different cavitation nucleation agents affect the cavitation-mediated transport of therapeutics not directly bound to the gas nuclei. SonoVue (Bracco, Milan, Italy) microbubble contrast agent (with 3 μm mean initial bubble diameter) and polymeric gas-entrapping nanoparticles (with 260 nm mean initial bubble diameter) were first compared in terms of inertial cavitation threshold and cavitation persistence. Under the same ultrasound exposure conditions (centre frequencies of either 0.5 MHz or 1.6 MHz, and peak negative pressures from 0.2 MPa to 3.5 MPa) their respective cavitation emissions were found to differ ...

Rate-adaptive pacemakers make use of sensors in order to automatically adjust the pacing rate according to the metabolic needs of the patient, thus overcoming the limitation of fixed-rate pacemakers that cannot ensure an adequate heart beat in cases of varying physical, mental or emotional activity. This feature significantly improves the quality of life of patients with chronotropic incompetence, i.e. Whose heart is unable to increase its rate as the activity increases. We develop a formal model of a rate-adaptive pacemaker based on hybrid automata that explicitly includes sensors for rate control. In particular, we model the VVIR pacemaker with a QT interval sensor, a highly specific metabolic sensor that can sense the exercise activity level, based on the fact that physical (and mental) stresses shorten the QT interval, in turn requiring an increased heart rate. We implement the QT interval sensor through a runtime ECG detection algorithm and validate our model with patient data, showing that the simulated VVIR pacemaker is able to successfully regulate a bradycardia ECG signal and produce a correctly paced heart. The validated rate-adaptive pacemaker is plugged into the model-based framework introduced in Chen et al. (2014), which enables rigorous and quantitative verification of closed-loop patient-device systems described as hybrid automata, and supports multiple heart and pacemaker models in a modular way. We demonstrate the usefulness of the framework by performing in silico experiments to demonstrate the correct functioning of rate modulation under different activity levels. Our framework has the potential to reduce the need for exercise testing with real patients.

A significant barrier to successful drug delivery in cancer therapy is the limited penetration of nanoscale therapeutics deep into tumors. Ultrasound mediated cavitation has been shown to promote nanoparticle transport, but achieving tumor wide distribution still represents a considerable challenge. The current study investigates the way in which nanoparticle drug-carriers may be designed to enhance penetration under ultrasound exposure. A computational model has been developed to predict the transport of a nanoparticle in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming, and microstreaming. Experimental investigations were also performed in a tissue-mimicking phantom to study the transport of different types of particle, in the presence or absence of a microbubble ultrasound contrast agent, at ultrasound frequencies of 0.5 MHz and 1.6 MHz with peak pressures in the range of 0–2.0 MPa. Micro- and nanoparticles with contrasting density cores ranging from 1.0 g/cm3 to 19.3 g/cm3 were used for the study. Both the theoretical and experimental results showed that the denser particles exhibit significantly greater ultrasound-mediated transport than their lower density counterparts, indicating that this is a key consideration in the design of nanoscale therapeutics.