Bidirectional and state-dependent modulation of brain activity by transcranial focused ultrasound in non-human primates

Pai-Feng Yang, M. Anthony Phipps, Sumeeth Jonathan, Allen T. Newton, Nellie Byun, John C. Gore, William A. Grissom, Charles F. Caskey, Li Min Chen

Brain Stimulation 2021, 14, 261-272 · 10.1016/j.brs.2021.01.006

nonhuman primatehealthyfmriother mri

Abstract

Transcranial focused ultrasound (FUS) stimulation under MRI guidance, coupled with functional MRI (fMRI) monitoring of effects, offers a precise, noninvasive technology to dissect functional brain circuits and to modulate altered brain functional networks in neurological and psychiatric disorders. Here we show that ultrasound at moderate intensities modulated neural activity bi-directionally. Concurrent sonication of somatosensory areas 3a/3b with 250 kHz FUS suppressed the fMRI signals produced there by peripheral tactile stimulation, while at the same time eliciting fMRI activation at inter-connected, off-target brain regions. Direct FUS stimulation of the cortex resulted in different degrees of BOLD signal changes across all five off-target regions, indicating that its modulatory effects on active and resting neurons differed. This is the first demonstration of the dual suppressive and excitative modulations of FUS on a specific functional circuit and of ability of concurrent FUS and MRI to evaluate causal interactions between functional circuits with neuron-class selectivity.

Abstract via europepmc.

Speciescynomolgus macaque (Macaca fascicularis)

Subjects2 animals

Sessions per subject3

Randomisednot reported

Blindingnot reported

Sham / controlnone

Auditory controlnot reported

Readout timingonline

Anaesthesiaanaesthetised

Readoutsfmri, other mri — BOLD fMRI of touch circuit (target and 5 off-target ROIs); MR-acoustic radiation force imaging (MR-ARFI) for FUS beam localisation

Direction of effectbidirectionalConcurrent med-FUS suppressed tactile-evoked BOLD activation at the target (area 3a/3b) and at all five off-target regions, while med-FUS alone (at rest, without tactile stimulation) directly excited neurons at the target and elicited BOLD activation in interconnected off-target regions; effects were state-dependent (active vs resting cortex).

Adverse eventsnot reported

Exposures

Exposure 1: Medium-amplitude FUS (med-FUS) to somatosensory areas 3a/3b

Target: primary somatosensory cortex — “areas 3a/3b of primary somatosensory cortex (S1)”
Device: Sonic Concepts · Sonic Concepts, Bothell, WA · H115 ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	250	✓✓✓
Pulse duration (ms)	0.252	✓✓✓⚑
Pulse repetition frequency (Hz)	2,000	✓✓✓
Duty cycle (%)	50pulse duration × PRF gives 50.4%	✓✓✓
Sonication duration (s)	0.3	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	425	✓✓✓
Free-field Isppa (W/cm²)	6	✓✓✓
Free-field Ispta (W/cm²)	0.0271	✓✓✓
In-situ estimate	deratingsingle value
In-situ pressure (kPa)	247	✓✓✓
In-situ Isppa (W/cm²)	2	✓✓✓
In-situ Ispta (W/cm²)	0.0091	✓✓✓

Protocol, in the paper’s words

During fMRI acquisition, FUS pulses were delivered in a block design of seven 30 s FUS on/off cycles matched to the tactile stimulation blocks. During an 'on' block, a 300 ms pulse was emitted at 0.333 Hz (i.e. one 300 ms pulse every 3 s), giving 10 FUS bursts per on block. Each 300 ms pulse itself consisted of 63-cycle tone bursts repeated at 2 kHz (50% duty cycle). Tactile alone, tactile+med-FUS, and med-FUS alone conditions were interleaved within each fMRI run.

Flags from extraction

exposures[0].timing.pulse_duration_ms — Pulse duration (0.252 ms) computed from the stated 63-cycle burst at 250 kHz (cycles ÷ fundamental frequency), as explicitly permitted for this synonym of pulse duration.
exposures[0].timing.protocol_description — The 0.333 Hz repetition rate of the 300 ms pulses within each 30 s on-block is a train-repetition interval, not the internal PRF field, and is described in protocol_description rather than the PRF field.
sham_type — No sham or inactive-FUS control condition is described; comparisons are between tactile-alone, med-FUS-alone and tactile+med-FUS conditions.