Displacement Imaging for Focused Ultrasound Peripheral Nerve Neuromodulation
Stephen A. Lee, Hermes A. S. Kamimura, Mark T. Burgess, Elisa E. Konofagou
IEEE Transactions on Medical Imaging 2020, 39, 3391-3402 · 10.1109/tmi.2020.2992498
Abstract
Focused ultrasound (FUS) is an emerging technique for neuromodulation due to its noninvasive application and high depth penetration. Recent studies have reported success in modulation of brain circuits, peripheral nerves, ion channels, and organ structures. In particular, neuromodulation of peripheral nerves and the underlying mechanisms remain comparatively unexplored in vivo. Lack of methodologies for FUS targeting and monitoring impede further research in in vivo studies. Thus, we developed a method that non-invasively measures nerve engagement, via tissue displacement, during FUS neuromodulation of in vivo nerves using simultaneous high frame-rate ultrasound imaging. Using this system, we can validate, in real-time, FUS targeting of the nerve and characterize subsequent compound muscle action potentials (CMAPs) elicited from sciatic nerve activation in mice using 0.5 to 5 ms pulse durations and 22 - 28 MPa peak positive stimulus pressures at 4 MHz. Interestingly, successful motor excitation from FUS neuromodulation required a minimum interframe nerve displacement of 18 μm without any displacement incurred at the skin or muscle levels. Moreover, CMAPs detected in mice monotonically increased with interframe nerve displacements within the range of 18 to 300 μm . Thus, correlation between nerve displacement and motor activation constitutes strong evidence FUS neuromodulation is driven by a mechanical effect given that tissue deflection is a result of highly focused acoustic radiation force.
Abstract via europepmc.
Exposures
Exposure 1: Sciatic nerve FUS parameter sweep (pressure and pulse duration)
Target: sciatic nerve — “sciatic nerve”
Device: Sonic Concepts · Sonic Concepts Inc. · H-215 ✓
| Waveform | continuous | |
|---|---|---|
| Fundamental frequency (kHz) | 4,000 | ✓✓✓ |
| Pulse duration (ms) | not applicable | ⚑ |
| Pulse repetition frequency (Hz) | not applicable | |
| Duty cycle (%) | 100 | ✓? |
| Sonication duration (s) | 0.0005, 0.01swept | ✓✓✓ |
| 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) | 4,000, 30,000swept | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
The acoustic pressure was varied from 4 to 30 MPa in steps of 4 MPa and the pulse duration was varied from 0.5 to 10 ms in steps of 0.5 ms; single pulses were emitted at 0.03 Hz to mitigate cumulative bioeffects. A base parameter of 24 MPa and 1 ms was used for follow-up displacement/safety experiments. A separate histology safety experiment applied 100 pulses (22-30 MPa, 1 ms) at a stated PRF of 0.2 Hz in the Methods text but 0.3 Hz in the corresponding figure caption. Gait-analysis safety experiments used 10 sonications (24 MPa, 1 ms, 30 s inter-stimulus interval).
Flags from extraction
n_subjects— Paper reports separate animal counts for different sub-experiments (parameter-space mapping n=6; focal-depth displacement experiment n=4; histology safety n=6 nerves; gait analysis n=10, 5 sham/5 FUS) without a single combined total; a preliminary cavitation-mapping follow-up (147 sonications) does not state a distinct animal count and is not included in the list.sham_type— Sham sonications are mentioned (e.g., 'sham ultrasound', '5 sham' mice) but the paper never describes how the sham was delivered (transducer off, blocked, etc.).exposures[0].free_field.pressure_kpa— 6.5 MPa is a hydrophone beam-characterization value measured in free field water for FWHM mapping, distinct from the muscle-derated pressures (4-30 MPa) used to dose the sciatic nerve; both are reported here in their respective domains.exposures[0].in_situ.pressure_kpa— Appendix A states that 'All pressures reported in this study are derated for attenuation in muscle tissue', so the 4-30 MPa sweep values used throughout Methods/Results are treated as in_situ (muscle-derated), not free-field, values.exposures[0].timing.protocol_description— Text (Methods, section J) states the histology PRF was 0.2 Hz while the Figure 8 caption states 0.3 Hz for the same experiment; this text-vs-figure disagreement could not be resolved.exposures[0].timing.pulse_duration_ms— Individual ms-scale bursts (0.5-10 ms) have no internal pulsing and are repeated at a very low external rate (0.03-0.3 Hz); classified as waveform=continuous per the schema's tone-burst rule, with the burst length recorded as sonication_duration_s rather than pulse_duration_ms.