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Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans

Siti N. Yaakub, Tristan A. White, Jamie Roberts, Eleanor Martin, Lennart Verhagen, Charlotte J. Stagg, Stephen Hall, Elsa F. Fouragnan

Nature Communications 2023, 14 · 10.1038/s41467-023-40998-0

human healthyhealthyother mrifmri

Abstract

Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive technique for focally modulating human brain function. The mechanisms and neurochemical substrates underlying TUS neuromodulation in humans and how these relate to excitation and inhibition are still poorly understood. In 24 healthy controls, we separately stimulated two deep cortical regions and investigated the effects of theta-burst TUS, a protocol shown to increase corticospinal excitability, on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and functional connectivity. We show that theta-burst TUS in humans selectively reduces GABA levels in the posterior cingulate, but not the dorsal anterior cingulate cortex. Functional connectivity increased following TUS in both regions. Our findings suggest that TUS changes overall excitability by reducing GABAergic inhibition and that changes in TUS-mediated neuroplasticity last at least 50 mins after stimulation. The difference in TUS effects on the posterior and anterior cingulate could suggest state- or location-dependency of the TUS effect-both mechanisms increasingly recognized to influence the brain's response to neuromodulation.

Abstract via europepmc.

Specieshuman
Subjects24 participants
Sessions per subject3
Randomisedyes
Blindingsingle
Sham / controlinactive transducer
Auditory controlmasking sound
Readout timingoffline
Anaesthesianot applicable
Readoutsother mri, fmri — Magnetic resonance spectroscopy (MEGA-PRESS; GABA+/water and Glx/water); resting-state fMRI functional connectivity (seed-based and independent components analysis)
Direction of effectexcitatoryTheta-burst TUS reduced GABA+ (disinhibition) selectively in the PCC (not dACC) at ~20-30 min post-stimulation, and increased resting-state functional connectivity of both the dACC and PCC with their associated networks, with larger effects at ~46 min than ~13 min post-TUS.
Adverse eventsobservedThree participants reported increased fatigue after TUS sessions; one reported a mild transient headache after dACC TUS; one reported a persistent headache/neck pain after the sham session (attributed to the MRI, not TUS); one reported a transient cool sensation near the transducer site after PCC TUS. No other symptoms were reported, and most participants could not distinguish TUS from sham.

Exposures

Exposure 1: Theta-burst TUS of left dorsal anterior cingulate cortex (dACC)

Target: dorsal anterior cingulate cortex — “left dorsal anterior cingulate cortex (dACC)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS TPO and CTX-500-4 ✓

Pulse timing
Waveformtheta burst
Fundamental frequency (kHz)500✓✓✓
Pulse duration (ms)20✓✓✓
Pulse repetition frequency (Hz)5✓✓✓⚑
Duty cycle (%)not reportedpulse duration × PRF gives 10%⚑
Sonication duration (s)80✓✓✓
Pressure and intensity, by domain
Free-field pressure (kPa)1,010✓✓✓
Free-field Isppa (W/cm²)33.8✓✓✓
Free-field Ispta (W/cm²)3.38✓✓✓
In-situ estimatesimulationmean or range across subjects
In-situ pressure (kPa)660✓✓✓⚑
In-situ Isppa (W/cm²)15.07✓✓✓
In-situ Ispta (W/cm²)1.51✓✓✓
Protocol, in the paper’s words

Theta-burst TUS protocol (previously shown to increase corticospinal excitability): 20 ms pulses delivered at a pulse repetition interval of 200 ms for a total duration of 80 s (400 pulses total), applied offline immediately before a series of MRI/MRS/rsfMRI scans acquired at approximately 13, 22-34, and 46 min post-TUS.

Exposure 2: Theta-burst TUS of left posterior cingulate cortex (PCC)

Target: posterior cingulate cortex — “left posterior cingulate cortex (PCC)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS TPO and CTX-500-4 ✓

Pulse timing
Waveformtheta burst
Fundamental frequency (kHz)500✓✓✓
Pulse duration (ms)20✓✓✓
Pulse repetition frequency (Hz)5✓✓✓
Duty cycle (%)not reportedpulse duration × PRF gives 10%⚑
Sonication duration (s)80✓✓✓
Pressure and intensity, by domain
Free-field pressure (kPa)1,010✓✓✓
Free-field Isppa (W/cm²)33.8✓✓✓
Free-field Ispta (W/cm²)3.38✓✓✓
In-situ estimatesimulationmean or range across subjects
In-situ pressure (kPa)650✓✓✓⚑
In-situ Isppa (W/cm²)14.47✓✓✓
In-situ Ispta (W/cm²)1.45✓✓✓
Protocol, in the paper’s words

Theta-burst TUS protocol: 20 ms pulses delivered at a pulse repetition interval of 200 ms for a total duration of 80 s (400 pulses total), applied offline immediately before a series of MRI/MRS/rsfMRI scans acquired at approximately 13, 22-34, and 46 min post-TUS.

Flags from extraction

  • exposures[0].timing.pulse_repetition_frequency_hz — Paper states pulse repetition interval (200 ms); converted to PRF (5 Hz) as a direct reciprocal unit conversion, not a computed/derived parameter.
  • exposures[0].timing.duty_cycle_pct — Duty cycle not explicitly stated as a percentage in the text (only pulse duration and PRI given); left not_reported rather than computed.
  • exposures[1].timing.duty_cycle_pct — Duty cycle not explicitly stated as a percentage in the text (only pulse duration and PRI given); left not_reported rather than computed.
  • exposures[0].in_situ.pressure_kpa — Value taken from Table 1 (mean +/- SD across participants from per-subject transcranial simulations); mean reported here, SD in quote.
  • exposures[1].in_situ.pressure_kpa — Value taken from Table 1 (mean +/- SD across participants from per-subject transcranial simulations); mean reported here, SD in quote.