Focused Ultrasound Stimulation of the Anterior Ethmoidal Nerve: Design and Experimental Validation of a Noninvasive Transducer for the Treatment of Dry Eye Disease in Rabbits
Yulin Chen, Yiting Sun, Xirenayi Zhuoruo, Chujun Ni, Xiuming Jin, Ji Fu
Ultrasound in Medicine & Biology 2026 · 10.1016/j.ultrasmedbio.2026.05.020
Abstract
Objective Dry eye disease (DED) is a prevalent condition that significantly impacts quality of life. While neurostimulation of the anterior ethmoidal nerve (AEN) shows clinical potential, current methods are limited by invasiveness and discomfort, leading to poor patient compliance. Low-intensity focused ultrasound (LIPUS) has emerged as a promising noninvasive alternative, offering precise neuromodulation and high parameter tunability to optimize patient tolerance. Methods This study employed an in vivo rabbit model to deliver standardized LIPUS stimulation targeting the AEN. The primary objectives were to evaluate the efficacy of LIPUS in promoting tear secretion and to assess its safety profile during the procedure. Results The results demonstrated that LIPUS intervention significantly enhanced tear production. Furthermore, the procedure exhibited a favorable safety profile, with no significant tissue damage observed following stimulation. Conclusion This study provides the first validation of ultrasound-mediated AEN stimulation as a novel, noninvasive therapeutic strategy for DED. By establishing a rigorous nonpharmaceutical intervention model and highlighting the potential for parameter optimization, this research offers a promising new solution for dry eye treatment.
Abstract via europepmc.
Exposures
Exposure 1: 4 MHz focused US over the lateral nasal region targeting the anterior ethmoidal nerve
Target: peripheral nerve — “anterior ethmoidal nerve (AEN)”
Device: custom-built · custom-designed single-element spherical focused transducer, 12 mm aperture
| Waveform | pulsed, continuous | |
|---|---|---|
| Fundamental frequency (kHz) | 4,000 | ✓✓✓ |
| Pulse duration (ms) | 0.5, 0.75swept | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1,000 | ✓✓✓ |
| Duty cycle (%) | 50, 75, 100swept | ✓✓✓ |
| Sonication duration (s) | 30 | ✓✓✓ |
| 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 |
PW at PRI 1 ms with 50 % or 75 % DC (0.5 or 0.75 ms pulses), or CW; three amplifier gain levels (26, 28, 30 dB) at 0.9 Vpp input; one 30-s stimulation per animal-condition followed by Schirmer test 5 min later.
Flags from extraction
n_subjects— 30 rabbits total: 27 experimental (subgroups of about 6) and 3 sham; only the 27 were sonicated.exposures[0].free_field— Hydrophone calibration was done but no pressure or intensity values are stated in the text; pressure levels are given only as amplifier gain (26, 28, 30 dB).auditory_control— Sham kept the power amplifier on 'to maintain consistent environmental noise'; no auditory control for the ultrasound itself described.anaesthesia— Only topical ocular anaesthesia was applied; recorded as awake.conditions— No dry eye model is described; the animals appear to be normal rabbits with DED named as the clinical target.exposures[0].timing.pulse_duration_ms— Pulse widths 0.5 and 0.75 ms stated for the PW modes; CW has none.