Noninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration
Gengxi Lu, Chen Gong, Yizhe Sun, Xuejun Qian, Deepthi S. Rajendran Nair, Runze Li, Yushun Zeng, Jie Ji, Junhang Zhang, Haochen Kang, Laiming Jiang, Jiawen Chen, Chi-Feng Chang, Biju B. Thomas, Mark S. Humayun, Qifa Zhou
Nature Communications 2024, 15 · 10.1038/s41467-024-48683-6
Abstract
Retinal degeneration, a leading cause of irreversible low vision and blindness globally, can be partially addressed by retina prostheses which stimulate remaining neurons in the retina. However, existing electrode-based treatments are invasive, posing substantial risks to patients and healthcare providers. Here, we introduce a completely noninvasive ultrasonic retina prosthesis, featuring a customized ultrasound two-dimensional array which allows for simultaneous imaging and stimulation. With synchronous three-dimensional imaging guidance and auto-alignment technology, ultrasonic retina prosthesis can generate programmed ultrasound waves to dynamically and precisely form arbitrary wave patterns on the retina. Neuron responses in the brain's visual center mirrored these patterns, evidencing successful artificial vision creation, which was further corroborated in behavior experiments. Quantitative analysis of the spatial-temporal resolution and field of view demonstrated advanced performance of ultrasonic retina prosthesis and elucidated the biophysical mechanism of retinal stimulation. As a noninvasive blindness prosthesis, ultrasonic retina prosthesis could lead to a more effective, widely acceptable treatment for blind patients. Its real-time imaging-guided stimulation strategy with a single ultrasound array, could also benefit ultrasound neurostimulation in other diseases.
Abstract via europepmc.
Exposures
Exposure 1: Retina stimulation for electrophysiology and behavior (4.5 MHz default protocol)
Target: retina — “retina”
Device: custom-built · custom single-channel and 16x16 2D ultrasound array transducers (4.4-4.5 MHz)
| Waveform | continuous | |
|---|---|---|
| Fundamental frequency (kHz) | 4,500 | ✓✓✓ |
| Pulse duration (ms) | not applicable | |
| Pulse repetition frequency (Hz) | not applicable | |
| Duty cycle (%) | 100 | ✓✓✓ |
| Sonication duration (s) | 0.01, 0.02swept | ✓✓✓ |
| 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 | |
| Pressure, domain unspecified (kPa) | 2,830, 2,900swept | ✓✓✓ |
Unless otherwise specified, the default US sequences used in this study were 10-ms pulse with 100% duty cycle. The frame interval was at least 6 seconds to ensure the stimulated neurons fully recovered after each stimulation. Initial validation used focused ultrasound stimuli (4.5 MHz, 10 ms, 2.83 MPa); the figure legend for the same experiment instead states 4.4 MHz, 10 ms, 3 MPa. Water-licking training and testing used 4.5 MHz, 20 ms, 2.9 MPa.
Exposure 2: Long-term safety exposure (3, 4.5, 20 MHz)
Target: retina — “retina”
Device: custom-built · custom single-channel ultrasound transducers (3, 4.5, 20 MHz) ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 3,000, 4,500, 20,000swept | ✓✓✓ |
| Pulse duration (ms) | 10 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | not reportedpulse duration × PRF gives 5% | |
| Sonication duration (s) | 10,800 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | 5,800, 4,300, 1,700, 3,500swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
We subjected three healthy rats, each with one eye under ultrasound stimulation at frequencies of 3, 4.5, and 20 MHz. The pulses had a duration of 10 ms and a repetition frequency of 5 Hz, with pressure amplitudes surpassing the threshold by 50% (derated pressures were 5.8 MPa, 4.3 MPa, and 1.7 MPa). In the positive control group, the 20-MHz ultrasound were applied for three hours with a pressure 100% higher than the safe intensity (3.5 MPa vs 1.7 MPa, 10-ms pulse duration, and a repetition frequency of 5 Hz). Each rat underwent stimulation for 3 hours triweekly for two weeks (Day 1 to Day 13).
Flags from extraction
exposures[0].free_field.pressure_kpa— Main text states 4.5 MHz/2.83 MPa for the initial validation experiment, but the Figure 1 legend states 4.4 MHz/3 MPa for the same experiment; both values are recorded.n_subjects— Paper describes many partially-overlapping animal subsets for different sub-experiments (e.g., 3+3, 8, 8+8, 2+2, 3, 1) without ever stating a single overall total; not summed here.n_sessions_per_subject— Session counts differ by sub-experiment (single acute sessions vs 8-day behavioral training vs triweekly safety sessions over 2 weeks) with no single value applicable to all subjects.exposures[1].in_situ.pressure_kpa— The 3.5 MPa positive-control value applies specifically to the 20 MHz condition, not to all three frequencies; list combines values from different sub-conditions.anaesthesia— Electrophysiology and safety experiments used anesthetized rats, while water-licking behavioral sessions were performed in awake, head-fixed rats.