Transcranial focused ultrasound remotely modulates extrastriate visual cortex by stimulating frontal eye field with subregion specificity

Kai Yu, Samantha Schmitt, Yunruo Ni, Emily C Crane, Matthew A Smith, Bin He

Journal of Neural Engineering 2024, 21, 066018 · 10.1088/1741-2552/ad9406

nonhuman primatehealthyinvasive electrophysiology

Abstract

Objective. Low-intensity transcranial focused ultrasound (tFUS) has emerged as a powerful neuromodulation tool characterized by its deep penetration and precise spatial targeting to influence neural activity. Our study directed low-intensity tFUS stimulation onto a region of prefrontal cortex (the frontal eye field, or FEF) of a rhesus macaque to examine its impact on a remote site, the extrastriate visual cortex (area V4) through this top-down modulatory circuit that has been studied extensively with electrical microstimulation. Approach. To measure the impact of tFUS stimulation, we recorded local field potentials and multi-unit spiking activities from a multi-electrode array implanted in the visual cortex. To deliver tFUS stimulation, we leveraged a customized 128-element random array ultrasound transducer with precise spatial targeting. Main results. We observed that tFUS stimulation in FEF produced modulation of V4 neuronal activity, either through enhancement or suppression, dependent on the pulse repetition frequency of the tFUS stimulation. Electronically steering the transcranial ultrasound focus through the targeted FEF cortical region produced changes in the level of modulation, indicating that the tFUS stimulation was spatially targeted within FEF. Modulation of V4 activity was confined to specific frequency bands, and this modulation was dependent on the presence or absence of a visual stimulus during tFUS stimulation. A control study targeting the insula produced no effect, emphasizing the region-specific nature of tFUS neuromodulation. Significance. Our findings shed light on the capacity of tFUS to modulate specific neural pathways and provide a comprehensive understanding of its potential applications for neuromodulation within brain networks.

Abstract via europepmc.

Speciesrhesus macaque (Macaca mulatta)

Subjects1 animals

Sessions per subjectnot reported

Randomisedyes

Blindingnot reported

Sham / controlinactive transducer, active control site

Auditory controlnot reported

Readout timingboth

Anaesthesiaawake

Readoutsinvasive electrophysiology — Local field potentials (LFP) and multi-unit spiking activity recorded from a 96-channel Utah array in area V4; peri-stimulus time histograms (PSTH)

Direction of effectbidirectionaltFUS at FEF produced pulse-repetition-frequency-dependent bidirectional remote modulation of V4 activity: 100 Hz PRF produced an inhibitory effect (reduced LFP/spiking) while 200 Hz, 1-4 kHz PRF produced excitatory effects (increased LFP amplitude/spiking); higher duty cycle produced a broader excitatory impact; effects were spatially confined to FEF sub-regions and absent when targeting insula or using decoupled sham.

Adverse eventsnone observedStimulations were observed to be safe, based on tFUS safety monitoring described in the paper's Supplementary Note 2.

Exposures

Exposure 1: tFUS to frontal eye field (FEF)

Target: frontal eye field — “frontal eye field (FEF)”
Device: Sonic Concepts · Sonic Concepts, Inc. · H275 ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	700	✓✓✓
Pulse duration (ms)	5, 2.5, 0.5, 0.25, 0.126, 0.0629, 0.2swept	✓?⚑
Pulse repetition frequency (Hz)	100, 200, 1,000, 2,000, 4,000, 3,000swept	✓✓✓
Duty cycle (%)	50, 25, 60swept	✓✓✓
Sonication duration (s)	0.3, 0.4swept	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	2,700	✓✓✓
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	not reported
In-situ estimate	measurementsingle value
In-situ pressure (kPa)	952.8, 1,160swept	✓✓✓⚑
In-situ Isppa (W/cm²)	10.4	✓✓✓
In-situ Ispta (W/cm²)	5.2, 2.6, 6.2swept	✓✓✓

Protocol, in the paper’s words

tFUS delivered to FEF at varying pulse repetition frequencies (100 Hz-4 kHz) and duty cycles (25-60%) with 300 ms sonication duration (400 ms for fixation-only trials without visual stimulus), while electronically steering the ultrasound focus through the depth of FEF (superficial to deep in the arcuate sulcus) to test subregional specificity; e.g. 100 Hz PRF used a tone burst duration of 5 ms (3500 cycles per pulse, 30 pulses per sonication, rectangular ramp shape); a decoupled sham condition (transducer physically disconnected from scalp) and an active control targeting the insula were also tested.

Flags from extraction

n_sessions_per_subject — Multiple recording sessions with 120-240 trials each were conducted across different PRF/duty-cycle/steering conditions, but no total session count is stated
exposures[0].in_situ.pressure_kpa — Two in-situ pressure figures are given for the FEF target: 952.8 kPa from direct hydrophone measurement through an excised skull sample, and 1.16 MPa from full subject-specific skull/brain simulation; both are listed
exposures[0].timing.pulse_duration_ms — Most pulse durations were computed from stated cycles-per-pulse divided by the 700 kHz fundamental frequency (an explicitly permitted conversion), except the 5 ms value for the 100 Hz PRF condition which was stated directly
exposures[0].timing — Many PRF/duty-cycle/duration combinations were tested at one target and frequency (FEF, 700 kHz); values are listed rather than split into separate exposures, so pairing between specific PRF and duty-cycle/duration values is not preserved in these lists