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High-Intensity Ultrasound Treatment for Vincristine-Induced Neuropathic Pain

Youngwon Youn, Abigail Hellman, Ian Walling, Lucy Gee, Jiang Qian, Clif Burdette, Lance Frith, Julie G Pilitsis

Neurosurgery 2018 · 10.1093/neuros/nyx488

rodentchronic painbehaviourhistology molecular

Abstract

Background Vincristine is a commonly used chemotherapeutic agent that results in debilitating untreatable peripheral neuropathy. Objective To determine the effects of pulsed high-intensity focused ultrasound (HIFU) on sensory thresholds in a validated vincristine-induced neuropathy (VIN) rodent model. Methods VIN was induced and mechanical allodynia was confirmed by nociceptive testing. von Frey fibers and Randall-Sellito test were used as measures of innocuous and noxious mechanical thresholds, respectively, and the hot plate test for thermal thresholds. Tests were performed before VIN, after 2 wk of vincristine, at 24, 48, 72, and 120 h after HIFU applied to the left L5 dorsal root ganglia at 3 Watts for 3 min. Comparisons were made between a VIN cohort who underwent HIFU, a VIN cohort who underwent sham HIFU, and naïve rodents who underwent HIFU. Results VIN HIFU rats had significantly increased mechanical thresholds at 24 h (P Conclusion Our data suggest that HIFU increases mechanical and thermal thresholds in VIN rodents. Whether HIFU can preclude the development of reduced thresholds in the VIN model warrants further study.

Abstract via europepmc.

Speciesrat (Sprague-Dawley)
Subjects7, 5swept animals
Sessions per subject1
Randomisednot reported
Blindingnot reported
Sham / controlother
Auditory controlnot reported
Readout timingoffline
Anaesthesiaanaesthetised
Readoutsbehaviour, histology molecular — von Frey fibres; Randall-Selitto test; hot plate test; H&E histology of L5 DRG
Direction of effectinhibitoryHIFU to the L5 DRG raised mechanical and thermal thresholds in vincristine-induced neuropathy rats at 24 and 48 h versus sham; thresholds were unchanged in naive rats.
Adverse eventsobservedHistology showed transient cellular swelling that largely resolved by 24-48 h and intact ganglion cells at 5 d; no obvious motor dysfunction for 7 d.

Exposures

Exposure 1: Pulsed HIFU to left L5 DRG

Target: dorsal root ganglion — “left L5 dorsal root ganglia”
Device: other named manufacturer · Acoustic MedSystems Inc · interstitial HIFU device ✓

Pulse timing
Waveformpulsed
Fundamental frequency (kHz)not reported⚑
Pulse duration (ms)0.09✓✓✓⚑
Pulse repetition frequency (Hz)38✓✓✓⚑
Duty cycle (%)not reportedpulse duration × PRF gives 0.342%
Sonication duration (s)180✓✓✓
Pressure and intensity, by domain
Free-field pressure (kPa)not reported
Free-field Isppa (W/cm²)not reported
Free-field Ispta (W/cm²)not reported
In-situ estimatenot reported
In-situ pressure (kPa)not reported
In-situ Isppa (W/cm²)not reported
In-situ Ispta (W/cm²)not reported
Protocol, in the paper’s words

Pulsed HIFU delivered with the probe touching the DRG, 'frequency of 38 Hz, pulse width of 90 us, and amplitude of 3 W for 3 min'; acoustic output power of 3 W stated to produce a power density of 2.05 W/cm2. A 2 min dose was ineffective in a preliminary experiment.

Flags from extraction

  • exposures[0].fundamental_frequency_khz — The paper gives only 'a frequency of 38 Hz'; the acoustic carrier frequency is never stated
  • exposures[0].timing.pulse_repetition_frequency_hz — 38 Hz is called the frequency of administration; interpreted as PRF but the paper does not say so
  • exposures[0].timing.pulse_duration_ms — Text reads 'pulse width of 90 us' with OCR 'μss'; 90 us converted to 0.09 ms
  • exposures[0].unspecified_domain — Power density of 2.05 W/cm2 is stated for 3 W output without saying which intensity metric or domain; not placed in a field
  • n_subjects — 23 rats compared includes 7 sham and 4 VIN-only; HIFU-exposed groups listed as [7, 5]; a further 8 VIN HIFU rats were used in the preliminary 2 min experiment
  • sham_type — Sham rats underwent DRG exposure surgery without HIFU; mechanism not in the vocabulary, recorded as other
  • conditions — Vincristine-induced neuropathic pain model mapped to chronic_pain