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Background Moderate-to-severe acute pain is prevalent in many healthcare settings and associated with adverse outcomes. Peripheral nerve blockade using traditional needle-based and local anesthetic-based techniques improves pain outcomes for some patient populations but has shortcomings limiting use. These limitations include its invasiveness, potential for local anesthetic systemic toxicity, risk of infection with an indwelling catheter, and relatively short duration of blockade compared with the period of pain after major injuries. Focused ultrasound is capable of inhibiting the peripheral nervous system and has potential as a pain management tool. However, investigations of its effect on peripheral nerve nociceptive fibers in animal models of acute pain are lacking. In an in vivo acute pain model, we investigated focused ultrasound's effects on behavior and peripheral nerve structure. Methods Focused ultrasound was applied directly to the sciatic nerve of rats just prior to a hindpaw incision; three control groups (focused ultrasound sham only, hindpaw incision only, focused ultrasound sham+hindpaw incision) were also included. For all four groups (intervention and controls), behavioral testing (thermal and mechanical hyperalgesia, hindpaw extension and flexion) took place for 4 weeks. Structural changes to peripheral nerves of non-focused ultrasound controls and after focused ultrasound application were assessed on days 0 and 14 using light microscopy and transmission electron microscopy. Results Compared with controls, after focused ultrasound application, animals had (1) increased mechanical nociceptive thresholds for 2 weeks; (2) sustained increase in thermal nociceptive thresholds for =4 weeks; (3) a decrease in hindpaw motor response for 0.5 weeks; and (4) a decrease in hindpaw plantar sensation for 2 weeks. At 14 days after focused ultrasound application, alterations to myelin sheaths and nerve fiber ultrastructure were observed both by light and electron microscopy. Discussion Focused ultrasound, using a distinct parameter set, reversibly inhibits A-delta peripheral nerve nociceptive, motor, and non-nociceptive sensory fiber-mediated behaviors, has a prolonged effect on C nociceptive fiber-mediated behavior, and alters nerve structure. Focused ultrasound may have potential as a peripheral nerve blockade technique for acute pain management. However, further investigation is required to determine C fiber inhibition duration and the significance of nerve structural changes. [ABSTRACT FROM AUTHOR]

Transcranial ultrasonic stimulation (TUS) is rapidly gaining traction for non-invasive human neuromodulation, with a pressing need to establish protocols that maximise neuromodulatory efficacy. In this review, we aggregate and examine empirical evidence for the relationship between tunable TUS parameters and in vitro and in vivo outcomes. Based on this multiscale approach, TUS researchers can make better informed decisions about optimal parameter settings. Importantly, we also discuss the challenges involved in extrapolating results from prior empirical work to future interventions, including the translation of protocols between models and the complex interaction between TUS protocols and the brain. A synthesis of the empirical evidence suggests that larger effects will be observed at lower frequencies within the sub-MHz range, higher intensities and pressures than commonly administered thus far, and longer pulses and pulse train durations. Nevertheless, we emphasise the need for cautious interpretation of empirical data from different experimental paradigms when basing protocols on prior work as we advance towards refined TUS parameters for human neuromodulation., Competing Interests: Declarations of interest: KBP has no competing interests related to the reported work. Unrelated to the reported work, KBP has a relationship with MR Instruments, having received equipment on loan, and with Attune Neurosciences as a consultant. LV has no competing interests related to the reported work. Unrelated to the reported work, LV has a relationship with Brainbox Initiative as a member of the scientific committee, with Nudge LLC, having received consulting fees, with Sonic Concepts Ltd, having received equipment on loan, and with Image Guided Therapy, having received equipment on loan.