Transcranial Functional Ultrasound Imaging Detects Focused Ultrasound Neuromodulation Induced Hemodynamic Changes in Mouse and Nonhuman Primate Brains In Vivo.

Focused ultrasound (FUS) is an emerging noinvasive technique for neuromodulation in the central nervous system (CNS). To evaluate the effects of FUS-induced neuromodulation, many studies used behavioral changes, functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). However, behavioral readouts are often not easily mapped to specific brain activity, EEG has low spatial resolution limited to the surface of the brain and fMRI requires a large importable scanner that limits additional readouts and manipulations. In this context, functional ultrasound imaging (fUSI) holds promise to directly monitor the effects of FUS neuromodulation with high spatiotemporal resolution in a large field of view, with a comparatively simple and flexible setup. fUSI uses ultrafast Power Doppler Imaging (PDI) to measure changes in cerebral blood volume, which correlates well with neuronal activity and local field potentials. We designed a setup that aligns a FUS transducer with a linear array to allow immediate subsequent monitoring of the hemodynamic response with fUSI during and after FUS neuromodulation. We established a positive correlation between FUS pressure and the size of the activated area, as well as changes in cerebral blood volume (CBV) and found that unilateral sonications produce bilateral hemodynamic changes with ipsilateral accentuation in mice. We further demonstrated the ability to perform fully noninvasive, transcranial FUS-fUSI in nonhuman primates for the first time by using a lower-frequency transducer configuration.

Modulation of cardio-respiratory activity in mice via transcranial focused ultrasound.

OBJECTIVE: The objective of this study was to investigate the effect of FUS on autonomic nervous system activity, including heart and respiratory rates, and to separate the thermal modulation from combined thermal and mechanical FUS effects. METHODS: The thalamus and hypothalamus of wild-type mice were sonicated with a continuous-wave, 2 MHz FUS transducer at pressures of 425 and 850 kPa for 60 seconds. Cardiac and respiratory rates were monitored as signs of autonomic nervous activity. FUS-induced changes in autonomic activity were compared to FUS targeted to a spatially-distant motor region and to laser-induced heating. RESULTS: FUS delivered to the primary target over the thalamus and hypothalamus at 850 kPa reversibly increased the respiratory rate by 6.5±3.2 breaths per minute and decreased the heart rate by 3.2±1.8 beats per minute. No significant changes occurred in this region at 425 kPa or when targeting the motor regions at 850 kPa. Laser heating with the same temperature rise profile produced by 850 kPa sonication resulted in cardiorespiratory modulation similar to that of FUS. CONCLUSIONS: FUS is capable of reversibly and non-invasively modulating cardiorespiratory activity in mice. Localized changes in temperature may constitute the main cause for this activity, though further investigation is warranted into the distinct and complementary mechanisms of mechanically- and thermally-induced FUS neuromodulation. Close monitoring of vital signs during FUS neuromodulation may be warranted to monitor systemic responses to stimulation.

Interdependence of Tissue Temperature, Cavitation, and Displacement Imaging During Focused Ultrasound Nerve Sonication.

Focused ultrasound (FUS) peripheral neuromodulation has been linked to nerve displacement caused by the acoustic radiation force; however, the roles of cavitation and temperature accumulation on nerve modulation are less clear, as are the relationships between these three mechanisms of action. Temperature directly changes tissue stiffness and viscosity. Viscoelastic properties have been shown to affect cavitation thresholds in both theoretical and ex vivo models, but the direct effect of temperature on cavitation has not been investigated in vivo. Here, cavitation and tissue displacement were simultaneously mapped in response to baseline tissue temperatures of either 30 °C or 38 °C during sciatic nerve sonication in mice. In each mouse, the sciatic nerve was repeatedly sonicated at 1.1-MHz, 4-MPa peak-negative pressure, 5-ms pulse duration, and either 15- or 30-Hz pulse repetition frequency (PRF) for 10 s at each tissue temperature. Cavitation increased by 1.8-4.5 dB at a tissue temperature of 38 °C compared to 30 °C, as measured both by passive cavitation images and cavitation doses. Tissue displacement also increased by 1.3- [Formula: see text] at baseline temperatures of 38 °C compared to 30 °C. Histological findings indicated small increases in red blood cell extravasation in the 38 °C baseline temperature condition compared to 30 °C at both PRFs. A strong positive correlation was found between the inertial cavitation dose and displacement imaging noise, indicating the potential ability of displacement imaging to simultaneously detect inertial cavitation in vivo. Overall, tissue temperature was found to modulate both in vivo cavitation and tissue displacement, and thus, both tissue temperature and cavitation can be monitored during FUS to ensure both safety and efficiency.

Perspective on ultrasound bioeffects and possible implications for continuous post-dive monitoring safety.

Ultrasound monitoring, both in the form of Doppler and 2D echocardiography, has been used post-dive to detect decompression bubbles circulating in the bloodstream. With large variability in both bubble time course and loads, it has been hypothesised that shorter periods between imaging, or even continuous imaging, could provide more accurate post-dive assessments. However, while considering applications of ultrasound imaging post-decompression, it may also be prudent to consider the possibility of ultrasound-induced bioeffects. Clinical ultrasound studies using microbubble contrast agents have shown bioeffect generation with acoustic powers much lower than those used in post-dive monitoring. However, to date no studies have specifically investigated potential bioeffect generation from continuous post-dive echocardiography. This review discusses what can be drawn from the current ultrasound and diving literature on the safety of bubble sonication and highlights areas where more studies are needed. An overview of the ultrasound-bubble mechanisms that lead to bioeffects and analyses of ultrasound contrast agent studies on bioeffect generation in the pulmonary and cardiovascular systems are provided to illustrate how bubbles under ultrasound can cause damage within the body. Along with clinical ultrasound studies, studies investigating the effects of decompression bubbles under ultrasound are analysed and open questions regarding continuous post-dive monitoring safety are discussed.