Differential dose responses of transcranial focused ultrasound at brain regions indicate causal interactions
Pai-Feng Yang, M. Anthony Phipps, Allen T. Newton, Sumeeth Jonathan, Thomas J. Manuel, John C. Gore, William A. Grissom, Charles F. Caskey, Li Min Chen
Brain Stimulation 2022, 15, 1552-1564 · 10.1016/j.brs.2022.12.003
Abstract
We have previously shown that focused ultrasound (FUS) pulses in low pressure range exerted bidirectional and brain state-dependent neuromodulation in the nonhuman primate somatosensory cortices by fMRI. Here we aim to gain insights about the proposed neuron selective modulation of FUS and probe feedforward versus feedback interactions by simultaneously quantifying the stimulus (FUS pressures: 925, 425, 250 kPa) and response (% BOLD fMRI changes) function at the targeted area 3a/3b and off-target cortical areas at 7T. In resting-state, lowered intensities of FUS resulted in decreased fMRI signal changes at the target area 3a/3b and off-target area 1/2, S2, MCC, insula and auditory cortex, and no signal difference in thalamic VPL and MD nuclei. In activated states, concurrent high-intensity FUS significantly enhanced touch-evoked signals in area 1/2. Medium- and low-intensity FUS significantly suppressed touch-evoked BOLD signals in all areas except in the auditory cortex, VPL and MD thalamic nuclei. Distinct state dependent and dose-response curves led us to hypothesize that FUS's neuromodulatory effects may be mediated through preferential activation of different populations of neurons. Area 3a/3b may have distinct causal feedforward and feedback interactions with Area 1/2, S2, MCC, insula, and VPL. FUS offers a noninvasive neural stimulation tool for dissecting brain circuits and probing causal functional connections.
Abstract via europepmc.
Exposures
Exposure 1: FUS neuromodulation of area 3a/3b at 250 kHz (high/medium/low pressure)
Target: primary somatosensory cortex — “area 3a/3b (primary somatosensory cortex, hand region)”
Device: Sonic Concepts · Sonic Concepts · H115 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 0.25 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 2,000 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 0.3 | ✓✓✓ |
| Free-field pressure (kPa) | 925, 425, 200swept | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | 1.24, 5.6, 26.6swept | ✓✓✓⚑ |
| Free-field Ispta (W/cm²) | 0.062, 0.28, 1.33swept | ✓✓✓ |
| In-situ estimate | deratingsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 0.4, 1.9, 8.9swept | ✓✓✓⚑ |
| In-situ Ispta (W/cm²) | 0.0209, 0.094, 0.446swept | ✓✓✓ |
FUS pulses were delivered in a block-based scheme identical to the tactile stimuli. During an 'on' block, a 250 kHz, 300 ms pulse was emitted with a 3-s intersonication interval; a single 300 ms pulse consisted of 63-cycle bursts repeated at 2 kHz (50% duty cycle). Stimulation blocks were 30 s total, resulting in 10 FUS bursts per 'on' block.
Exposure 2: MR-ARFI beam localization sonication at third harmonic (non-neuromodulatory)
Target: primary somatosensory cortex — “area 3a/3b (primary somatosensory cortex, hand region)”
Device: Sonic Concepts · Sonic Concepts · H115 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 802 | ✓✓✓⚑ |
| Pulse duration (ms) | 4.5 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | not reported | |
| Duty cycle (%) | 0.23 | ✓✓✓ |
| Sonication duration (s) | not reported |
| Free-field pressure (kPa) | 2,810 | ✓✓✓ |
|---|---|---|
| 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 |
For beam localization (not neuromodulation), sonications were performed at the third harmonic of the transducer (802 kHz) for 4.5 ms (3609 cycles) with a maximum free-field pressure of 2.81 MPa and a duty cycle of 0.23%, to generate detectable MR-ARFI tissue displacement.
Flags from extraction
exposures[0].free_field.isppa_w_cm2— As stated in the text, the un-derated intensity and mechanical index values (1.24-26.6 W/cm2 and MI 0.9-1.9) appear in an order that decreases with increasing pressure (925->200 kPa gives MI 0.9->1.9), which is the inverse of the expected relationship (intensity/MI should rise with pressure); recorded exactly as ordered in the source text.exposures[0].in_situ.isppa_w_cm2— Same apparent high/medium/low pressure vs. intensity ordering inversion as in the free-field values; recorded as stated.exposures[1].fundamental_frequency_khz— 802 kHz is the third harmonic of the H115 transducer's 250 kHz fundamental, used only for MR-ARFI beam localization, not for neuromodulation.exposures[1].timing.pulse_duration_ms— The paper gives total sonication length (4.5 ms, 3609 cycles) and duty cycle (0.23%) for the MR-ARFI sonication but not a pulse repetition frequency, so the individual pulse duration/PRF (the burst-rule split) cannot be resolved and are left not_reported.randomised— The paper does not describe randomisation of stimulation condition order or session assignment.