Low-intensity ultrasound can stimulate excitable cells in a noninvasive and targeted manner, but which parameters are effective has remained elusive. This question has been difficult to answer because differences in transducers and parameters-frequency in particular-lead to profound differences in the stimulated tissue volumes. The objective of this study is to control for these differences and evaluate which ultrasound parameters are effective in stimulating excitable cells. Methods: Here, we stimulated the human peripheral nervous system using a single transducer operating in a range of frequencies, and matched the stimulated volumes with an acoustic aperture. Results: We found that low frequencies (300 kHz) are substantially more effective in generating tactile and nociceptive responses in humans compared to high frequencies (900 kHz). The strong effect of ultrasound frequency was observed for all pressures tested, for continuous and pulsed stimuli, and for tactile and nociceptive responses. Conclusion: This prominent effect may be explained by a mechanical force associated with ultrasound. The effect is not due to heating, which would be weaker at the low frequency. Significance: This controlled study reveals that ultrasonic stimulation of excitable cells is stronger at lower frequencies, which guides the choice of transducer hardware for effective ultrasonic stimulation of the peripheral nervous system in humans.

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Transcranial ultrasound is emerging as a noninvasive tool for targeted treatments of brain disorders. Transcranial ultrasound has been used for remotely mediated surgeries, transient opening of the blood-brain barrier, local drug delivery, and neuromodulation. However, all applications have been limited by the severe attenuation and phase distortion of ultrasound by the skull. Here, we characterized the dependence of the aberrations on specific anatomical segments of the skull. In particular, we measured ultrasound propagation properties throughout the perimeter of intact human skulls at 500 kHz. We found that the parietal bone provides substantially higher transmission (average pressure transmission 31±7%) and smaller phase distortion (242±44 degrees) than frontal (13±2%, 425±47 degrees) and occipital bone regions (16±4%, 416±35 degrees). In addition, we found that across skull regions, transmission strongly anti-correlated (R = −0.79) and phase distortion correlated (R = 0.85) with skull thickness. This information guides the design, positioning, and skull correction functionality of next-generation devices for effective, safe, and reproducible transcranial focused ultrasound therapies.

ObjectiveLow-intensity ultrasound can stimulate excitable cells in a noninvasive and targeted manner, but which parameters are effective has remained elusive. This question has been difficult to answer because differences in transducers and parameters—frequency in particular—lead to profound differences in the stimulated tissue volumes. The objective of this study is to control for these differences and evaluate which ultrasound parameters are effective in stimulating excitable cells.MethodsHere, we stimulated the human peripheral nervous system using a single transducer operating in a range of frequencies, and matched the stimulated volumes with an acoustic aperture.ResultsWe found that low frequencies (300 kHz) are substantially more effective in generating tactile and nociceptive responses in humans compared to high frequencies (900 kHz). The strong effect of ultrasound frequency was observed for all pressures tested, for continuous and pulsed stimuli, and for tactile and nociceptive responses.ConclusionThis prominent effect may be explained by a mechanical force associated with ultrasound. The effect is not due to heating, which would be weaker at the low frequency.SignificanceThis controlled study reveals that ultrasonic stimulation of excitable cells is stronger at lower frequencies, which guides the choice of transducer hardware for effective ultrasonic stimulation of the peripheral nervous system in humans.

Systems that emit electromagnetic or sonic waves for diagnostic or interventional applications often have constraints on the size of their aperture, and thus produce an elongated focus in the axial dimension. This extended depth of focus limits imaging resolution and spatial specificity of the delivered energy. Here, we have developed a method that substantially minimizes the depth of focus. The method superimposes beams of distinct frequencies in space and time to create constructive interference at target and amplify deconstructive interference everywhere else, thus sharpening the focus. The method does not require labeling of targets or other manipulations of the medium. Using simulations, we found that the method tightens the depth of focus even for systems with a narrow bandwidth. Moreover, we implemented the method in ultrasonic hardware and found that a 46.1% frequency fractional bandwidth provides an average 7.4-fold reduction in the focal volume of the resulting beams. This method can be readily applied to sharpen the focus of interventional systems and is expected to also improve the axial resolution of existing imaging systems.