Frequency Dependence of Ultrasound Neurostimulation in the Mouse Brain
Patrick Peiyong Ye, Julian R. Brown, Kim Butts Pauly
Ultrasound in Medicine & Biology 2016, 42, 1512-1530 · 10.1016/j.ultrasmedbio.2016.02.012
Abstract
Ultrasound neuromodulation holds promise as a non-invasive technique for neuromodulation of the central nervous system. However, much remains to be determined about how the technique can be transformed into a useful technology, including the effect of ultrasound frequency. Previous studies have demonstrated neuromodulation in vivo using frequencies <1 MHz, with a trend toward improved efficacy with lower frequency. However, using higher frequencies could offer improved ultrasound spatial resolution. We investigate the ultrasound neuromodulation effects in mice at various frequencies both below and above 1 MHz. We find that frequencies up to 2.9 MHz can still be effective for generating motor responses, but we also confirm that as frequency increases, sonications require significantly more intensity to achieve equivalent efficacy. We argue that our results provide evidence that favors either a particle displacement or a cavitation-based mechanism for the phenomenon of ultrasound neuromodulation.
Abstract via europepmc.
Exposures
Exposure 1: Frequency sweep (0.3-2.9 MHz) ultrasound stimulation of mouse motor cortex
Target: motor cortex — “motor cortex (forelimb representation)”
Device: Olympus / Panametrics · Olympus ✓
| Waveform | continuous | |
|---|---|---|
| Fundamental frequency (kHz) | 300, 400, 500, 600, 1,000, 1,400, 1,900, 2,400, 2,900swept | ✓✓✓⚑ |
| Pulse duration (ms) | not applicable | |
| Pulse repetition frequency (Hz) | not applicable | |
| Duty cycle (%) | not applicable | |
| Sonication duration (s) | 0.08 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | deratingmean or range across subjects | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 0.02, 127swept | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | not reported |
Five sets of experiments (A-E) tested continuous-wave sonications at frequencies from 0.3 to 2.9 MHz. Experiment A compared 0.3-0.6 MHz using both a constant 40,000-cycle duration and a constant 80 ms duration; experiments B-E used a fixed 80 ms CW pulse duration throughout (0.6-1.4 MHz in B, 1.4-2.9 MHz in C, 0.3-0.6 MHz with a different focused transducer in D, and 1.4 vs 2.9 MHz mapped across multiple brain sites in E). Within each block, sonications of different intensities plus one sham (transducer output off) were delivered in random order, with at least a 2 s delay between sonications.
Flags from extraction
n_subjects— Group sizes are given per sub-experiment (A-D: n=5 mice each, E: n=6 mice); the paper never states a combined total, and some mice/experiments were later excluded (see Methods), so group sizes are listed rather than summed.exposures[0].target.terms— Target is the mouse motor cortex region controlling forelimb (triceps) contraction, identified via EMG; not a more specific sub-region such as primary motor cortex.exposures[0].fundamental_frequency_khz— Frequencies pooled from Table 1 across five sub-experiments (A-E) that used different transducers/geometries; treated as one exposure per the frequency-response-curve exception since target and general timing (80 ms CW pulses) were held constant across the sweep.exposures[0].device.model— Four different Olympus transducers (0.5 MHz planar 1 in.; 1 MHz focused 0.75 in., 1.90 in. PTF; 2.25 MHz focused 0.75 in., 1 in. PTF used for both experiments C and E) were used across the frequency sweep; see paper Table 1 for exact geometry per experiment.exposures[0].in_situ.isppa_w_cm2— Value is an approximate overall range ('about 1' to 'more than 100 W/cm2') stated in the Results text for threshold intensities across the full 0.3-2.9 MHz sweep; per-frequency/per-experiment ranges differ substantially and are given only in Table 1 and Figs. 5a-d, which could not be captured by a single verbatim quote.exposures[0].in_situ.isppa_w_cm2— Domain classified as in_situ because intensities are described in figure captions (e.g., Fig. 5) as 'spatial peak intensity after accounting for skull attenuation', i.e. derated for measured mouse-skull insertion loss.