External focused ultrasound treatment for neuropathic pain induced by common peroneal nerve injury
Tarun Prabhala, Abigail Hellman, Ian Walling, Teresa Maietta, Jiang Qian, Clif Burdette, Paul Neubauer, Miriam Shao, Amelia Stapleton, Juliette Thibodeau, Julie G. Pilitsis
Neuroscience Letters 2018, 684, 145-151 · 10.1016/j.neulet.2018.07.037
Abstract
Neuropathic pain caused by nerve injury or compressive lesions is a debilitating condition lacking effective, long-term treatments. Our objective was to assess the effects of external focused ultrasound on sensory thresholds utilizing a common peroneal injury rat model. CPNI was induced by ligating the CPN of the left hind paw. Neuropathic phenotype was confirmed using the Von Frey Fibers (VFF) with a 50% mechanical detection threshold below 4.0. The Place Escape Avoidance Paradigm (PEAP) was employed as a behavioral correlate. External FUS treatment was applied to the left L4,5 DRG at 8 W for 3-min. There were two treatment groups; one received a single FUS treatment, while the other received two. Control groups consisted of one sham CPNI group that received FUS treatment and a CPNI group that received sham FUS treatment. Behavioral tests were conducted pre-CPNI surgery, 1-week post-surgery, and for 1-week post-FUS treatment(s). CPNI surgery resulted in lower VFF mechanical thresholds in the left hind paw compared to baseline (p < 0.0001) and increased proportion of time spent on bright side compared to baseline values on PEAP (p = 0.0473), indicating neuropathic state. FUS treatment increased VFF thresholds after 24-hours (p < 0.0001), 48-h (p = 0.0079), and 72-h (p = 0.0164). VFF returned to baseline values from day 4-7. Following a second FUS treatment on day 8, increased mechanical thresholds were similarly observed after 24-h (p = 0.0021), 48-h (p < 0.0001), and 72-h (p = 0.0256). Control group analysis showed (1) CPNI rats experienced no change in mechanical thresholds following sham FUS treatment and (2) Sham CPNI rats receiving FUS did not experience significantly different mechanical thresholds compared to baseline and post-CPNI values. Post-FUS histological analysis demonstrated healthy ganglion cells without chromatolysis. Our results demonstrate changes in VFF and PEAP in rats who underwent CPNI. Single and multiple doses of external FUS increase mechanical thresholds without inducing histological damage. Based on our results, we have demonstrated the potential of FUS to serve as a non-pharmacological and non-ablative neuromodulatory approach for the treatment of allodynia and neuropathic pain.
Abstract via europepmc.
Exposures
Exposure 1: External FUS to the left L4,5 dorsal root ganglia (focused at L5 DRG), single and repeated treatments
Target: dorsal root ganglion — “left L4, 5 dorsal root ganglia (DRG), focused at the left L5 DRG”
Device: other named manufacturer · Acoustic MedSystems Inc. (AMC, Savoy, Illinois) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 11,000 | ✓✓✓ |
| Pulse duration (ms) | 13 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 38 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 49.4% | ⚑ |
| Sonication duration (s) | 180 | ✓✓✓ |
| 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 |
FUS was administered with a peak power of 8 W for 3 min, an ultrasonic frequency of 11 MHz pulsed at 38 Hz with a period of 90 ns, and a pulse width of 13 ms. No frequency modulation was utilized as the 11 MHz ultrasonic energy was pulsed in 13 ms intervals. FUS was administered using a pulse dosage to prevent irreversible conduction delays. Group 1 (n=10) received a single FUS treatment; Group 2 (n=6) received two FUS treatments separated by one week.
Flags from extraction
n_subjects— A third group (one sham-CPNI group receiving real FUS, n=8, described in Section 2.1) was also exposed to real ultrasound in addition to the two CPNI groups (n=10 single treatment, n=6 two treatments); no single stated total exists, so the three group sizes are listed.exposures[0].timing.duty_cycle_pct— Not explicitly stated; PRF (38 Hz, period 26.3 ms) and pulse width (13 ms) would imply a duty cycle of roughly 49%, but this was not computed per the no-arithmetic rule.sham_type— The mechanism of the 'sham FUS' control condition is not described in the text, so sham_type is recorded as 'other'.n_sessions_per_subject— Number of FUS sessions differed by group (one treatment for Group 1 and the sham-CPNI+FUS group; two treatments one week apart for Group 2), so no single value applies to all exposed subjects.