Focused ultrasound excites neurons via mechanosensitive calcium accumulation and ion channel amplification

Ultrasonic neuromodulation has the unique potential to provide non-invasive control of neural activity in deep brain regions with high spatial precision and without chemical or genetic modification. However, the biomolecular and cellular mechanisms by which focused ultrasound excites mammalian neurons have remained unclear, posing significant challenges for the use of this technology in research and potential clinical applications. Here, we show that focused ultrasound excites neurons through a primarily mechanical mechanism mediated by specific calcium-selective mechanosensitive ion channels. The activation of these channels results in a gradual build-up of calcium, which is amplified by calcium- and voltage-gated channels, generating a burst firing response. Cavitation, temperature changes, large-scale deformation, and synaptic transmission are not required for this excitation to occur. Pharmacological and genetic inhibition of specific ion channels leads to reduced responses to ultrasound, while over-expressing these channels results in stronger ultrasonic stimulation. These findings provide a critical missing explanation for the effect of ultrasound on neurons and facilitate the further development of ultrasonic neuromodulation and sonogenetics as unique tools for neuroscience research

Selective Ablation of Cancer Cells with Low Intensity Pulsed Ultrasound

Ultrasound can be focused into deep tissues with millimeter precision to perform noninvasive ablative therapy for diseases such as cancer. In most cases, this ablation uses high intensity ultrasound to deposit nonselective thermal or mechanical energy at the ultrasound focus, damaging both healthy bystander tissue and cancer cells. Here, we describe an alternative low intensity (I_(SPTA) 20 ms causes selective disruption of a panel of breast, colon, and leukemia cancer cell models in suspension without significantly damaging healthy immune or red blood cells. Mechanistic experiments reveal that the formation of acoustic standing waves and the emergence of cell-seeded cavitation lead to cytoskeletal disruption, expression of apoptotic markers, and cell death. The inherent selectivity of this low intensity pulsed ultrasound approach offers a potentially safer and thus more broadly applicable alternative to nonselective high intensity ultrasound ablation

Acoustically Detonated Biomolecules for Genetically Encodable Inertial Cavitation

Recent advances in molecular engineering and synthetic biology have made it possible for biomolecular and cell-based therapies to provide highly specific disease treatment. However, both the ability to spatially target the action of such therapies, and their range of effects on the target tissue remain limited. Here we show that biomolecules and cells can be engineered to deliver potent mechanical effects at specific locations inside the body under the direction of focused ultrasound. This capability is based on gas vesicles, a unique class of air-filled protein nanostructures derived from buoyant photosynthetic microbes. We show that low-frequency ultrasound can convert these nanoscale biomolecules into micron-scale cavitating bubbles, as demonstrated with acoustic measurements and ultrafast optical microscopy. This allows gas vesicles targeted to cell-surface receptors to serve as remotely detonated cell-killing agents. In addition, it allows cells genetically engineered to express gas vesicles to be triggered with ultrasound to lyse and release therapeutic payloads. We demonstrate these capabilities in vitro, in cellulo, and in vivo. This technology equips biomolecular and cellular therapeutics with unique capabilities for spatiotemporal control and mechanical action

drmittelstein/thermal_control v1.1

This repository includes scripts that allow the user to conduct thermal ultrasound experiments with closed loop control using a PID with anti-windup control system

drmittelstein/oncotripsy v1.1

This repository includes scripts that simulate cavitating bubbles' amplification of incident ultrasound pressure waves