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Objective . Focused ultrasound spinal cord neuromodulation has been demonstrated in small animals. However, most of the tested neuromodulatory exposures are similar in intensity and exposure duration to the reported small animal threshold for possible spinal cord damage. All efforts must be made to minimize the risk and assure the safety of potential human studies, while maximizing potential treatment efficacy. This requires an understanding of ultrasound propagation and heat deposition within the human spine. Approach . Combined acoustic and thermal modelling was used to assess the pressure and heat distributions produced by a 500 kHz source focused to the C5/C6 level via two approaches (a) the posterior acoustic window between vertebral posterior arches, and (b) the lateral intervertebral foramen from which the C6 spinal nerve exits. Pulse trains of fifty 0.1 s pulses (pulse repetition frequency: 0.33 Hz, free-field spatial peak pulse-averaged intensity: 10 W cm -2 ) were simulated for four subjects and for ±10 mm translational and ±10 ∘ rotational source positioning errors. Main results. Target pressures ranged between 20%-70% of free-field spatial peak pressures with the posterior approach, and 20%-100% with the lateral approach. When the posterior source was optimally positioned, peak spine heating values were below 1  ∘ C, but source mispositioning resulted in bone heating up to 4  ∘ C. Heating with the lateral approach did not exceed 2  ∘ C within the mispositioning range. There were substantial inter-subject differences in target pressures and peak heating values. Target pressure varied three to four-fold between subjects, depending on approach, while peak heating varied approximately two-fold between subjects. This results in a nearly ten-fold range between subjects in the target pressure achieved per degree of maximum heating. Significance . This study highlights the utility of trans-spine ultrasound simulation software and need for precise source-anatomy positioning to assure the subject-specific safety and efficacy of focused ultrasound spinal cord therapies., (Creative Commons Attribution license.)

New focused ultrasound spinal cord applications have emerged, particularly those improving therapeutic agent delivery to the spinal cord via blood-spinal cord barrier opening and the neuromodulation of spinal cord tracts. One hurdle in the development of these applications is safety. It may be possible to use safety trends from seminal and subsequent works in focused ultrasound to guide the development of safety guidelines for spinal cord applications. We collated data from decades of pre-clinical studies and illustrate a clear relationship between damage, time-averaged spatial peak intensity and exposure duration. This relationship suggests a thermal mechanism underlies ultrasound-induced spinal cord damage. We developed minimum and mean thresholds for damage from these pre-clinical studies. When these thresholds were plotted against the parameters used in recent pre-clinical ultrasonic spinal cord neuromodulation studies, the majority of the neuromodulation studies were near or above the minimum threshold. This suggests that a thermal neuromodulatory effect may exist for ultrasonic spinal cord neuromodulation, and that the thermal dose must be carefully controlled to avoid damage to the spinal cord. By contrast, the intensity-exposure duration threshold had no predictive value when applied to blood-spinal cord barrier opening studies that employed injected contrast agents. Most blood-spinal cord barrier opening studies observed slight to severe damage, except for small animal studies that employed an active feedback control method to limit pressures based on measured bubble oscillation behavior. The development of new focused ultrasound spinal cord applications perhaps reflects the recent success in the development of focused ultrasound brain applications, and recent work has begun on the translation of these technologies from brain to spinal cord. However, a great deal of work remains to be done, particularly with respect to developing and accepting safety standards for these applications., Competing Interests: Conflict of interest The authors declare no competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Abstract: Ultrasound is known to produce a range of nonlethal responses in cells and tissues. Frequencies in the kilohertz ultrasound range have been shown to produce relaxation in large arteries. The present work explores the effects of insonation at MHz frequencies, representative of those used diagnostically and therapeutically, in an in vitro preparation of the carotid artery. Fresh 12.7 mm wide rings of equine common carotid artery obtained from the abattoir were mounted in a purpose-made myograph. They were immersed in a bath of Krebs-Ringer buffer at 37 °C and were positioned at the focus of an ultrasound beam from a weakly focused 3.2 MHz source. Continuous wave insonation produced contraction. The tension increased rapidly over the first 2 min, followed by a slower increase for the duration of the exposure up to 15 min. At a power of 145 mW a maximum contractile stress of 0.04 ± 0.03 mN/mm2 (mean ± SD, n = 77) was measured, which was approximately 4% of the maximum wall stress generated by noradrenaline (0.1 mM). The magnitude of the response was weakly dependent on power in the range 72–145 mW and was not significantly different for pulsed and continuous wave stimulation where time averaged power was constant. The response was unaffected by mechanical removal of the endothelium. The ultrasound beam generated insufficient radiation force to produce a measurable effect and streaming at the vessel surface was very small compared with flow rates known to produce physiologic effects. The temperature rise at the beam focus was approximately 0.3 °C and we hypothesise that this contributes to the observed response, probably through changes in ion channel activity in smooth muscle cell membranes. (E-mail: e.martin@exeter.ac.uk) [Copyright &y& Elsevier]