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

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.

Introduction

Purpose Transcranial ultrasound stimulation

Study Objective To determine whether theta-burst transcranial ultrasound stimulation induces offline changes in GABA levels and functional connectivity in the dorsal anterior cingulate and posterior cingulate cortices in healthy humans.

Animal model / Human subject Human (Homo sapiens); strain: N/A; age: 22-53 years (mean 33.8 ± 9.7); sex: 14 female, 10 male

Disease model Healthy

MRI or image guidance method Neuronavigation using Brainsight on each participant’s high-resolution T1-weighted MRI co-registered to MNI space; targets set from MNI coordinates then adjusted to individual anatomical landmarks (dACC/PCC) with focal depth adjusted per participant. Transcranial acoustic simulations used participant-specific pseudo-CT (from T1) for skull modelling.

Targeted brain region(s) Dorsal Anterior Cingulate Cortex (Dacc) And Posterior Cingulate Cortex (Pcc)

Target coordinates dACC (MNI x,y,z): -5, 24, 30; PCC (MNI x,y,z): -5, -35, 35

Outcomes and Safety

Summary of Outcomes Eighty-second theta-burst transcranial ultrasound stimulation (TUS) produced a region-specific neuromodulatory effect: PCC-targeted theta-burst TUS reduced local GABA levels and increased PCC and default-mode network functional connectivity, while dACC-targeted theta-burst TUS increased salience-network functional connectivity but did not alter GABA. The tested parameter was an 80-s offline theta-burst TUS applied to left PCC or left dACC (vs. sham), with PCC-targeted theta-burst TUS showing the GABA decrease and robust network connectivity increases.

Duration of biological effect At least 50 minutes

Safety-related matter Acoustic simulations showed in situ intensities and mechanical index below US FDA limits and simulated skull heating <2°C; no serious adverse events were observed. A few minor, transient effects were reported (three participants felt more fatigued, one had a mild headache after dACC TUS that resolved within a day, one had persistent headache/neck pain attributed to the MRI after a sham session, and one reported a brief cool sensation at the transducer site), and most participants reported no symptoms or could not distinguish TUS from sham.

Brain Region

Ultrasound Parameters

Ultrasound instrument NeuroFUS TPO and CTX-500-4 transducer (Brainbox Ltd., Cardiff, UK); four-element ultrasound transducer, 64 mm diameter

FUS Frequency 500 kHz

FUS Intensity 33.8 W/cm2

FUS Mode pulsed

Pulse duration 20 ms

Duration of a single FUS session 80 s

Focal Characteristics Focal depth: 60 mm and 69 mm; Focal length: None; Aperture size: 64 mm diameter

Treatment frequency multiple sessions

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