Noninvasive Ultrasound Retinal Stimulation for Vision Restoration at High Spatiotemporal Resolution
Xuejun Qian, Gengxi Lu, Biju B. Thomas, Runze Li, Xiaoyang Chen, K. Kirk Shung, Mark Humayun, Qifa Zhou
BME Frontiers 2022, 2022 · 10.34133/2022/9829316
Abstract
Objective . Retinal degeneration involving progressive deterioration and loss of function of photoreceptors is a major cause of permanent vision loss worldwide. Strategies to treat these incurable conditions incorporate retinal prostheses via electrically stimulating surviving retinal neurons with implanted devices in the eye, optogenetic therapy, and sonogenetic therapy. Existing challenges of these strategies include invasive manner, complex implantation surgeries, and risky gene therapy. Methods and Results . Here, we show that direct ultrasound stimulation on the retina can evoke neuron activities from the visual centers including the superior colliculus and the primary visual cortex (V1), in either normal-sighted or retinal degenerated blind rats in vivo . The neuron activities induced by the customized spherically focused 3.1 MHz ultrasound transducer have shown both good spatial resolution of 250 μ m and temporal resolution of 5 Hz in the rat visual centers. An additional customized 4.4 MHz helical transducer was further implemented to generate a static stimulation pattern of letter forms. Conclusion . Our findings demonstrate that ultrasound stimulation of the retina in vivo is a safe and effective approach with high spatiotemporal resolution, indicating a promising future of ultrasound stimulation as a novel and noninvasive visual prosthesis for translational applications in blind patients.
Abstract via europepmc.
Exposures
Exposure 1: Retinal US stimulation, 3.1 MHz spherically focused transducer (parametric study)
Target: retina — “retina”
Device: custom-built · custom (USC Dept. of Biomedical Engineering) · custom 3.1 MHz spherically focused single-element transducer (DL-47 piezo, Del-Piezo Specialties) ✓
| Waveform | continuous, pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 3,100 | ✓✓✓ |
| Pulse duration (ms) | not reported | |
| Pulse repetition frequency (Hz) | not reported | ⚑ |
| Duty cycle (%) | 100, 30, 50, 70swept | ✓✓✓ |
| Sonication duration (s) | 0.001, 0.2swept | ✓✓✓⚑ |
| Free-field pressure (kPa) | 1,290, 3,370swept | ✓✓✓ |
|---|---|---|
| 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 |
The default US sequence was a continuous wave at 100% duty cycle with a 6-second frame interval between stimulations to allow full neuronal recovery. Driving voltage (hence free-field NPP, 1.29-3.37 MPa) and US duration (stated as 1-200 ms in Results, 50-200 ms in Methods) were each swept to assess their effect on evoked SC/VC responses; pulsed-mode sequences with 30%, 50%, or 70% duty cycle were also compared against the continuous mode at matched time-averaged energy. Temporal resolution was assessed with 10-ms, 2.83 MPa NPP stimuli delivered at frame rates of 1, 2, 5, and 10 Hz over 20-second trains. Prior to each stimulation series, the beam was directed away from the eye as an off-target control.
Exposure 2: Static letter-pattern generation, 4.4 MHz helical transducer
Target: retina — “retina (letter-pattern generation)”
Device: custom-built · custom (USC Dept. of Biomedical Engineering) · custom 4.4 MHz helical transducer (1-3 composite DL-48, Del-Piezo Specialties) ✓
| Waveform | not reported | |
|---|---|---|
| Fundamental frequency (kHz) | 4,400 | ✓✓✓ |
| Pulse duration (ms) | not reported | |
| Pulse repetition frequency (Hz) | not reported | |
| Duty cycle (%) | 100 | ✓✓✓ |
| Sonication duration (s) | not reported |
| 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 |
A single-element helical transducer (4.4 MHz, 4 mm outer/2 mm inner diameter, 10 mm focal length, 1.2 mm vertical separation) was used to generate a static acoustic beam pattern in the shape of the letter 'C' on the retina, matched to the hydrophone-measured water-condition field pattern, and MEA recordings in SC confirmed a corresponding response pattern.
Flags from extraction
exposures[0].timing.sonication_duration_s— Results text states US duration was explored 'from 1 ms to 200 ms', while the Methods section states 'a test ranging from 50 ms to 200 ms with an interval of 50 ms'; the Results range was recorded here and the discrepancy is flagged.exposures[0].timing.waveform— Default sequence was continuous wave (100% duty cycle), but the study also compared pulsed sequences at 30/50/70% duty cycle without stating pulse duration or PRF for these; recorded as a list of waveform types.exposures[0].timing.pulse_repetition_frequency_hz— PRF was not stated numerically for the pulsed-mode duty-cycle comparison conditions.n_subjects— 26 rats were investigated in total across all sub-experiments; not all were necessarily exposed to identical parameters (see Supplementary Table 1 for the breakdown, not available in the extracted text).