Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism
Tomokazu Sato, Mikhail G. Shapiro, Doris Y. Tsao
Neuron 2018, 98, 1031-1041.e5 · 10.1016/j.neuron.2018.05.009
Abstract
Ultrasound has received widespread attention as an emerging technology for targeted, non-invasive neuromodulation based on its ability to evoke electrophysiological and motor responses in animals. However, little is known about the spatiotemporal pattern of ultrasound-induced brain activity that could drive these responses. Here, we address this question by combining focused ultrasound with wide-field optical imaging of calcium signals in transgenic mice. Surprisingly, we find cortical activity patterns consistent with indirect activation of auditory pathways rather than direct neuromodulation at the ultrasound focus. Ultrasound-induced activity is similar to that evoked by audible sound. Furthermore, both ultrasound and audible sound elicit motor responses consistent with a startle reflex, with both responses reduced by chemical deafening. These findings reveal an indirect auditory mechanism for ultrasound-induced cortical activity and movement requiring careful consideration in future development of ultrasonic neuromodulation as a tool in neuroscience research.
Abstract via europepmc.
Exposures
Exposure 1: Focused ultrasound to posterior visual cortex, 5 intensities
Target: visual cortex — “posterior portion of the visual cortex”
Device: Blatek · Blatek · AT24020 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 0.2 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1,500 | ✓✓✓ |
| Duty cycle (%) | 30pulse duration × PRF gives 30% | ✓✓✓ |
| 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 | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Ispta, domain unspecified (W/cm²) | 4.2, 1.3, 0.38, 0.11, 0.034swept | ✓✓✓⚑ |
All ultrasound stimuli were of 500 kHz acoustic frequency, 100 cycles/pulse, 1.5 kHz pulse repetition frequency, and 120 pulses, yielding a duty cycle of 30% and a stimulus duration of approximately 80 ms. Each imaging block presented one trial each of 5 ultrasound intensities, 4 sound intensities, and a light flash in random order (200 blocks per imaging session); EMG sessions used 25 trials per stimulus type (sound, ultrasound, air puff, light) with a 10 s inter-trial interval, in two blocks 30 and 150 min after final injection.
Flags from extraction
exposures[0].timing.pulse_duration_ms— Text states pulse duration of 200 ms, but 100 cycles/pulse at 500 kHz and a duty cycle of 30% at a PRF of 1500 Hz arithmetically imply a pulse duration of ~0.2 ms (200 microseconds); recorded as stated in the text.exposures[0].unspecified_domain.ispta_w_cm2— Methods list the ultrasound intensity series as 4.2, 1.3, 0.38, 0.11, 0.034 W/cm2, but the Figure 4C legend gives the second-highest value as 1.4 W/cm2; recorded the Methods values.exposures[0].unspecified_domain— Paper labels these values I_SPTA in a figure legend but does not state whether intensities used for stimulation were measured in free field (water tank) or at the target through the (thinned) skull; placed in unspecified_domain.n_subjects— No single total N is stated; recorded as the four distinct group sizes reported across the imaging cohort (n=10) and the three EMG deafening-experiment cohorts (deafened n=8, saline n=7, no-gel n=5).sham_type— No sham/inactive-ultrasound arm was used; the comparisons are across stimulus modalities (ultrasound, sound, light, air puff), so sham_type is recorded as none.