Focused ultrasound-induced inhibition of peripheral nerve fibers in an animal model of acute pain
Thomas Anthony Anderson, Cholawat Pacharinsak, Jose Vilches-Moure, Husniye Kantarci, J Bradley Zuchero, Kim Butts-Pauly, David Yeomans
Regional Anesthesia & Pain Medicine 2023 · 10.1136/rapm-2022-104060
Abstract
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 via europepmc.
Exposures
Exposure 1: FUS applied directly to exposed rat sciatic nerve, two 8 s pulse trains 2 min apart
Target: sciatic nerve — “rat sciatic nerve”
Device: custom-built · custom built in-house ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,470 | ✓✓✓ |
| Pulse duration (ms) | 25 | ✓✓✓ |
| Pulse repetition frequency (Hz) | not reported | ⚑ |
| Duty cycle (%) | 50 | ✓✓✓ |
| Sonication duration (s) | 8 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Pressure, domain unspecified (kPa) | 1,860, 1,970swept | ✓✓✓⚑ |
| Isppa, domain unspecified (W/cm²) | 110.4, 123.8swept | ✓✓✓ |
FUS was applied in a pulse train, where each 25 ms pulse was followed by 25 ms off, for a duty cycle of 50%. Applied once as two 8 s trains 2 min apart at 1.86 then 1.97 MPa peak-to-peak.
Flags from extraction
exposures[0].unspecified_domain.pressure_kpa— Peak-to-peak pressures (1.86 and 1.97 MPa); focal pressures were determined previously with a hydrophone but the paper does not say water or in situ, so recorded as unspecified.exposures[0].timing.pulse_repetition_frequency_hz— PRF not stated; only 25 ms on / 25 ms off given, left not_reported.n_subjects— 12 FUS rats in the behavioural study; a separate histology cohort (n=2 nerves per arm) also received FUS but its size is not stated.blinding— Testers were blinded 'when possible'; no blinding possible for animals without incision.exposures[0].timing.sonication_duration_s— Two 8 s trains separated by 2 min; recorded per-train duration.