There has been increasing interest in wireless, miniaturized implantable medical devices for in vivo and in situ physiological monitoring. Here, we present such an implant that uses a conventional ultrasound imager for wireless powering and data communication and acts as a probe for real-time temperature sensing, including the monitoring of body temperature and temperature changes resulting from therapeutic application of ultrasound. The sub–0.1-mm3, sub–1-nW device, referred to as a mote, achieves aggressive miniaturization through the monolithic integration of a custom low-power temperature sensor chip with a microscale piezoelectric transducer fabricated on top of the chip. The small displaced volume of these motes allows them to be implanted or injected using minimally invasive techniques with improved biocompatibility. We demonstrate their sensing functionality in vivo for an ultrasound neurostimulation procedure in mice. Our motes have the potential to be adapted to the distributed and localized sensing of other clinically relevant physiological parameters.

Significance Modulation of peripheral nervous system (PNS) activity has shown promise in treating a wide range of diseases, from epilepsy to rheumatoid arthritis. Clinically, stimulation of nerves is most commonly delivered through invasive and risk-laden surgical electrode placement. Noninvasive technologies for PNS modulation can both increase safety and expand modulation application to various disease stages. Recent studies have revealed the therapeutic potential of noninvasive neuromodulation of brain circuits with ultrasound. This study identifies reliable protocols and molecular mechanisms for stimulating action potentials from individual peripheral neurons in the mammalian nervous system. These findings reveal the translational potential of ultrasound to effectively modulate the PNS through intrinsic neuronal mechanisms.

Focused ultrasound (FUS) is an emerging technique for neuromodulation due to its noninvasive application and high depth penetration. Recent studies have reported success in modulation of brain circuits, peripheral nerves, ion channels, and organ structures. In particular, neuromodulation of peripheral nerves and the underlying mechanisms remain comparatively unexplored in vivo. Lack of methodologies for FUS targeting and monitoring impede further research in in vivo studies. Thus, we developed a method that non-invasively measures nerve engagement, via tissue displacement, during FUS neuromodulation of in vivo nerves using simultaneous high frame-rate ultrasound imaging. Using this system, we can validate, in real-time, FUS targeting of the nerve and characterize subsequent compound muscle action potentials (CMAPs) elicited from sciatic nerve activation in mice using 0.5 to 5 ms pulse durations and 22-28 MPa peak positive stimulus pressures at 4 MHz. Interestingly, successful motor excitation from FUS neuromodulation required a minimum interframe nerve displacement of 18 µm without any displacement incurred at the skin or muscle levels. Moreover, CMAPs detected in mice monotonically increased with interframe nerve displacements within the range of 18 to 300 µm. Thus, correlation between nerve displacement and motor activation constitutes strong evidence FUS neuromodulation is driven by a mechanical effect given that tissue deflection is a result of highly focused acoustic radiation force.

Objective. Focused ultrasound (FUS) has recently been demonstrated capable of exciting motor neuronal activity. However, comprehensive understanding of elucidated excitatory and inhibitory effects is required to better assess FUS-mediated modulation. In this study, we demonstrate that image-guided FUS can selectively modulate motor neuron activity in the mouse sciatic nerve in vivo and attribute motor responses to thermal effects. Approach. FUS was applied on the sciatic nerve of anesthetized mice in vivo through the intact skin and muscle using ultrasound imaging for targeting. Both excitatory and inhibitory effects were recorded using electromyography (EMG) along with muscle response of the hind limb. The effects of FUS modulation versus heating by invasive alternative heating source (AHS) on electrically evoked EMG responses in the sciatic nerve in vivo were also investigated. The safety and reversibility of the technique were validated using histology and EMG recovery. Main results. The FUS was capable of eliciting motor neuronal activity comparable to electrical stimulation ES, and facilitating motor neuronal response on electrically evoked potentials with temperature elevation up to 11.5 °C  ±  0.3 °C (PRF  ⩽  40 Hz). On the other hand, FUS-induced temperature elevations above 15.1 °C  ±  1.6 °C (PRF  ⩾  100 Hz) resulted in the suppression of electrically-evoked motor neuronal activity along with a decrease in EMG latency and area under the curve (AUC), which was validated against the invasive AHS with temperature elevation of 18.1 °C  ±  8.5 °C. Histological findings along with EMG responses after FUS modulation demonstrated a reversible or irreversible modulation. Significance. The findings reported herein indicate that image-guided FUS (PRF  ⩽  100 Hz) induces safe and controllable modulation of involuntarily evoked motor neuron activity in vivo.

Measuring temperature during focused ultrasound (FUS) procedures is critical for characterization, calibration, and monitoring to ultimately ensure safety and efficacy. Despite the low cost and the high spatial and temporal resolutions of temperature measurements using thermocouples, the viscous heating (VH) artifact at the thermocouple-tissue interface requires reading corrections for correct thermometric analysis. In this study, a simulation pipeline is proposed to correct the VH artifact arising from temperature measurements using thermocouples in FUS fields. The numerical model consists of simulating a primary source of heating due to ultrasound absorption and a secondary source of heating from viscous forces generated by the thermocouple in the FUS field. Our numerical validation found that up to 90% of the measured temperature rise was due to VH effects. Experimental temperature measurements were performed using thermocouples embedded in fresh chicken breast samples. Temperature corrections were demonstrated for single high-intensity FUS pulses at 3.1 MHz and for multiple pulses (3.1 MHz, 100 Hz, and 500 Hz pulse repetition frequency). The VH accumulated during sonications and produced a temperature increase of 3.1 C and 15.3 C for the single and multiple pulse sequences, respectively. The methodology presented here enables the decoupling of the temperature increase generated by absorption and VH. Thus, more reliable temperature measurements can be extracted from thermocouple measurements by correcting for VH.