Low Intensity Focused Ultrasound Increases Duration of Anti-Nociceptive Responses in Female Common Peroneal Nerve Injury Rats

Andrea Liss, Abigail Hellman, Vraj J. Patel, Teresa Maietta, Kanakaharini Byraju, Rachel Trowbridge, Jenica Acheta, Drishti Panse, Adithya Srikanthan, Paul Neubauer, Clif Burdette, Goutam Ghoshal, Emery Williams, Jiang Qian, Julie G. Pilitsis

Neuromodulation: Technology at the Neural Interface 2022 · 10.1111/ner.13531

rodentchronic painbehaviouremg mephistology molecular

Abstract

Objective Chronic pain affects 7%-10% of Americans, occurs more frequently and severely in females, and available treatments have been shown to have less efficacy in female patients. Preclinical models addressing sex-specific treatment differences in the treatment of chronic pain have been limited. Here we examine the sex-specific effects of low intensity focused ultrasound (liFUS) in a modified sciatic nerve injury (SNI) model. Materials and methods A modified SNI performed by ligating the common peroneal nerve (CPN) was used to measure sensory, behavioral pain responses, and nerve conduction studies in female and male rats, following liFUS of the L5 dorsal root ganglion. Results Using the same dose of liFUS in females and males of the same weight, CPN latency immediately after treatment was increased for 50 min in females compared to 25 min in males (p Conclusions Neuromodulation with liFUS has a greater effect in female rats on CPN latency, mechanical allodynia duration, and depression-like behavior. In order to customize neuromodulatory techniques for different patient phenotypes, it is essential to understand how they may alter sex-specific pathophysiologies.

Abstract via europepmc.

Speciesrat (Sprague-Dawley)

Subjects8, 11swept animals

Sessions per subject1

Randomisednot reported

Blindingnot reported

Sham / controlundescribed

Auditory controlnot reported

Readout timingboth

Anaesthesiaanaesthetised

Readoutsbehaviour, emg mep, histology molecular — Von Frey filament mechanical threshold testing, hot plate test, open field test, elevated plus maze, forced swim test; sensory nerve action potential (SNAP) nerve conduction velocity/latency; H&E and fluoro-jade histology of the DRG

Direction of effectinhibitoryliFUS to the L5 DRG increased mechanical pain thresholds (anti-nociceptive), reduced immobility in the forced swim test (anti-depressant-like), and increased sensory nerve conduction latency, consistent with the authors' proposed mechanism of K2P/Na channel activation causing long-term hyperpolarization of DRG neurons; effects lasted longer in females (7 days) than males (3 days).

Adverse eventsnone observedAt the 8 W/3 min dose used, liFUS produced no fluoro-jade or H&E evidence of pyknosis or cellular edema in the DRG at 1 day or 1 week post-treatment, and no locomotor damage (open field testing) was observed; a higher 10 W dose used in prior work had produced edema.

Exposures

Exposure 1: liFUS of the L5 dorsal root ganglion in CPN-injury rats

Target: dorsal root ganglion — “L5 dorsal root ganglion (DRG)”
Device: other named manufacturer · Acoustic MedSystems, Savoy, IL · Volumetric Focused Ultrasound (VFUS), multi-channel array with four internal transducers ✓

Pulse timing
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	✓✓✓

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 estimate	not 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

liFUS was delivered transcutaneously to the L5 DRG for 3 min at 8 W (a dose-response curve from 4-8 W was also tested), described as pulsed at 38 Hz; the text gives two different short-duration values for this pulsing that could not be reconciled: 'a pulse modulation at 38 Hz for 90 microseconds' in one place, and '38 Hz with a period of 90 microseconds, and pulse width of 13 msec' in another. Power (Watts) is reported rather than a spatial-average pressure or intensity, so no kPa or W/cm2 value could be extracted.

Flags from extraction

exposures[0].timing.pulse_duration_ms — Two different short-duration values are given for the 38 Hz pulsing: 'a pulse modulation at 38 Hz for 90 microseconds' (Methods, dose-response sentence) and 'pulse width of 13 msec' (Methods, main dosing sentence), and it is unclear which (if either) is the true per-pulse duration versus a nested sub-cycle period; left not_reported per the burst-duration ambiguity rule.
exposures[0].free_field.pressure_kpa — Dose is reported only as electrical drive power (4-8 W), never as a spatial-average pressure (kPa) or intensity (W/cm2), so no value could be placed in any domain.
sham_type — The paper refers to 'sham liFUS' cohorts but does not describe in this text how the sham condition was produced (e.g. inactive transducer vs detuned); classified as undescribed.
n_subjects — No single total N is stated; the two largest reported group sizes (female and male baseline VFF cohorts) are given as a list. Downstream dose-response and electrophysiology sub-experiments use smaller, non-overlapping subsets of these animals.