Optoacoustic brain stimulation at submillimeter spatial precision
Ying Jiang, Hyeon Jeong Lee, Lu Lan, Hua-an Tseng, Chen Yang, Heng-Ye Man, Xue Han, Ji-Xin Cheng
Nature Communications 2020, 11 · 10.1038/s41467-020-14706-1
Abstract
Low-intensity ultrasound is an emerging modality for neuromodulation. Yet, transcranial neuromodulation using low-frequency piezo-based transducers offers poor spatial confinement of excitation volume, often bigger than a few millimeters in diameter. In addition, the bulky size limits their implementation in a wearable setting and prevents integration with other experimental modalities. Here, we report spatially confined optoacoustic neural stimulation through a miniaturized Fiber-Optoacoustic Converter (FOC). The FOC has a diameter of 600 μm and generates omnidirectional ultrasound wave locally at the fiber tip through the optoacoustic effect. We show that the acoustic wave generated by FOC can directly activate individual cultured neurons and generate intracellular Ca 2+ transients. The FOC activates neurons within a radius of 500 μm around the fiber tip, delivering superior spatial resolution over conventional piezo-based low-frequency transducers. Finally, we demonstrate direct and spatially confined neural stimulation of mouse brain and modulation of motor activity in vivo.
Abstract via europepmc.
Exposures
Exposure 1: FOC stimulation of cultured cortical neurons (in vitro)
Target: cultured neurons — “cultured rat cortical neurons”
Device: custom-built · Fiber-Optoacoustic Converter (FOC)
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500, 5,000swept | ✓?⚑ |
| Pulse duration (ms) | 0.001 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 3,600 | ✓✓✓ |
| Duty cycle (%) | 0.36pulse duration × PRF gives 0.36% | ✓✓✓ |
| Sonication duration (s) | 0.02, 0.05, 0.1, 0.2swept | ✓✓✓ |
| Free-field pressure (kPa) | 480 | ✓✓✓⚑ |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not applicable | |
| In-situ pressure (kPa) | not applicable | |
| In-situ Isppa (W/cm²) | not applicable | |
| In-situ Ispta (W/cm²) | not applicable |
The FOC emits omnidirectional 1-us acoustic pulses at a 3.6 kHz laser repetition rate (duty cycle ~0.36%). Stimulation trains of 20, 50, 100 or 200 ms were delivered to cultured neurons to find an activation threshold (100 and 50 ms produced calcium transients, 20 ms did not); repeated reliability was also tested with eight 200-ms bursts at a 2-s inter-burst interval.
Exposure 2: FOC stimulation of mouse primary somatosensory cortex (S1), in vivo
Target: primary somatosensory cortex — “primary somatosensory cortex (S1)”
Device: custom-built · Fiber-Optoacoustic Converter (FOC)
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500, 5,000swept | ✓? |
| Pulse duration (ms) | 0.001 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 3,600 | ✓✓✓ |
| Duty cycle (%) | 0.36pulse duration × PRF gives 0.36% | ✓✓✓ |
| Sonication duration (s) | 0.05, 0.2swept | ✓✓✓ |
| Free-field pressure (kPa) | 480 | ✓✓✓ |
|---|---|---|
| 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 |
FOC placed in contact with the exposed brain surface (craniotomy, dura intact, saline-immersed); 200 ms and 50 ms laser pulse trains delivered while LFP was recorded from S1 with a tungsten electrode; separate trials tested ipsilateral A1 as an anatomical control and delivery without brain contact as a negative control.
Exposure 3: FOC stimulation of mouse primary motor cortex (M1), in vivo
Target: primary motor cortex — “motor cortex”
Device: custom-built · Fiber-Optoacoustic Converter (FOC)
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500, 5,000swept | ✓? |
| Pulse duration (ms) | 0.001 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 3,600 | ✓✓✓ |
| Duty cycle (%) | 0.36pulse duration × PRF gives 0.36% | ✓✓✓ |
| Sonication duration (s) | 0.2 | ✓✓✓ |
| Free-field pressure (kPa) | 480 | ✓✓✓ |
|---|---|---|
| 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 200 ms laser pulse train was delivered to the FOC placed on the motor cortex (stereotaxic coordinates) while EMG was recorded from the contralateral forelimb triceps brachii; the FOC was scanned over a 3x3 mm^2 grid (1 mm spacing) to map motor representation.
Flags from extraction
n_subjects— Paper never states a single total number of mice used across all in vivo experiments; group sizes stated per sub-experiment are 3 mice (S1/A1 LFP recordings), 3 mice (M1 EMG mapping), 2 mice (S1-to-forelimb EMG latency); these may partly overlap and are listed as reported rather than summed.exposures[0].fundamental_frequency_khz— The FOC is a broadband optoacoustic source (no discrete carrier/fundamental frequency); the stated 0.5-5 MHz range from the RF spectrum is recorded as the frequency range rather than a single value.exposures[0].free_field.pressure_kpa— 0.48 MPa is a general device characterization (measured underwater with a needle hydrophone at the fiber tip) rather than a value measured for each specific in vitro/in vivo experiment; applied to all three exposures as the only reported pressure figure.sham_type— Controls used were mechanistic (FOC lifted off contact / no acoustic coupling; uncoated fiber with laser only; FOC aimed at a different site (A1) for spatial-confinement testing) rather than a classic transducer-off sham; mapped to inactive_transducer/active_control_site/other.auditory_control— Paper tests for (and rules out) an indirect auditory/cochlear pathway by recording contralateral A1 responses, but does not implement a masking-sound or similar auditory control procedure; mapped to 'other'.