Focused ultrasound has been shown to be effective at stimulating neurons in many animal models, both in vivo and ex vivo. Ultrasonic neuromodulation is the only noninvasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. We imaged the isolated salamander retina of either sex during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements, consistent with radiation force, the nonlinear delivery of momentum by a propagating wave. We recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a broad range (0.5-43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative radiation force model can explain retinal responses and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo. Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the dominant physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina and propose that the control of standing waves is a new potential method to modulate these effects.

Imaging technologies that simultaneously provide anatomical, functional, and molecular information are emerging as an attractive choice for disease screening and management. Since the 1980s, transrectal ultrasound (TRUS) has been routinely used to visualize prostatic anatomy and guide needle biopsy, despite limited specificity. Photoacoustic imaging (PAI) provides functional and molecular information at ultrasonic resolution based on optical absorption. Combining the strengths of TRUS and PAI approaches, we report the development and bench-to-bedside translation of an integrated TRUS and photoacoustic (TRUSPA) device. TRUSPA uses a miniaturized capacitive micromachined ultrasonic transducer array for simultaneous imaging of anatomical and molecular optical contrasts [intrinsic: hemoglobin; extrinsic: intravenous indocyanine green (ICG)] of the human prostate. Hemoglobin absorption mapped vascularity of the prostate and surroundings, whereas ICG absorption enhanced the intraprostatic photoacoustic contrast. Future work using the TRUSPA device for biomarker-specific molecular imaging may enable a fundamentally new approach to prostate cancer diagnosis, prognostication, and therapeutic monitoring.

State-of-the-art 3-D medical ultrasound imaging requires transmitting and receiving ultrasound using a 2-D array of ultrasound transducers with hundreds or thousands of elements. A tight combination of the transducer array with integrated circuitry eliminates bulky cables connecting the elements of the transducer array to a separate system of electronics. Furthermore, preamplifiers located close to the array can lead to improved receive sensitivity. A combined IC and transducer array can lead to a portable, high-performance, and inexpensive 3-D ultrasound imaging system. This paper presents an IC flip-chip bonded to a 16 x 16-element capacitive micromachined ultrasonic transducer (CMUT) array for 3-D ultrasound imaging. The IC includes a transmit beamformer that generates 25-V unipolar pulses with programmable focusing delays to 224 of the 256 transducer elements. One-shot circuits allow adjustment of the pulse widths for different ultrasound transducer center frequencies. For receiving reflected ultrasound signals, the IC uses the 32-elements along the array diagonals. The IC provides each receiving element with a low-noise 25-MHz-bandwidth transimpedance amplifier. Using a field-programmable gate array (FPGA) clocked at 100 MHz to operate the IC, the IC generated properly timed transmit pulses with 5-ns accuracy. With the IC flip-chip bonded to a CMUT array, we show that the IC can produce steered and focused ultrasound beams. We present 2-D and 3-D images of a wire phantom and 2-D orthogonal cross-sectional images (Bscans) of a latex heart phantom.

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