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Dynamic changes in human brain connectivity following ultrasound neuromodulation.

Authors: Atkinson-Clement C, Alkhawashki M, Gatica M, Ross J, Kaiser M

Non-invasive neuromodulation represents a major opportunity for brain interventions, and transcranial focused ultrasound (FUS) is one of the most promising approaches. However, some challenges prevent the community from fully understanding its outcomes. We aimed to address one of them and unravel the temporal dynamics of FUS effects in humans. Twenty-two healthy volunteers participated in the study. Eleven received FUS in the right inferior frontal cortex while the other 11 were stimulated in the right thalamus. Using a temporal dynamic approach, we compared resting-state fMRI seed-based functional connectivity obtained before and after FUS. We also assessed behavioural changes as measured with a task of reactive motor inhibition. Our findings reveal that the effects of FUS are predominantly time-constrained and spatially distributed in brain regions functionally connected with the directly stimulated area. In addition, mediation analysis highlighted that FUS applied in the right inferior cortex was associated with behavioural alterations which was directly explained by the applied acoustic pressure and the brain functional connectivity change we observed. Our study underscored that the biological effects of FUS are indicative of behavioural changes observed more than an hour following stimulation and are directly related to the applied acoustic pressure.

Introduction

Purpose Transcranial ultrasound stimulation
Study Objective To characterize the temporal dynamics of FUS-induced changes in brain functional connectivity and motor inhibition in humans by comparing pre- and post-stimulation effects after targeting the right inferior frontal cortex versus the right thalamus.
Animal model / Human subject Human (Homo sapiens); strain: N/A; age: mean ~23.9 ± 5.7 years (IFC group: 25 ± 5.7 yrs; Thalamus group: 22.8 ± 5.7 yrs); sex: mixed, 12 F / 10 M; right-handed
Disease model Healthy
MRI or image guidance method MRI-based neuronavigation: individual T1-weighted MRI (inverse warp from MNI for target localization) plus ZTE skull imaging for skull extraction; trajectory optimization (lowest skull thickness) via custom code and acoustic simulations, with transducer placement implemented using Visor2™ neuronavigation (AntNeuro).
Targeted brain region(s) Thalamus
Target coordinates Right IFC (AP = 26, ML = 46, DV = 8; MNI), Right thalamus (AP = -18, ML = 11, DV = 7; MNI)

Outcomes and Safety

Summary of Outcomes Transcranial FUS produced time‑constrained, network‑specific changes in resting‑state functional connectivity: IFC‑FUS caused decreased connectivity between the right IFC and multiple connected regions (post‑central cortex, ACC, SFC, MTC, OFC, lingual) and led to faster GO reaction times without changing SSRT, while Thalamus‑FUS modulated the cerebello‑thalamo‑cortical network (decreased SMA, increased contralateral cerebellum Crus‑II and contralateral thalamus) with no behavioral effect. The observed behavioral speeding following IFC‑FUS was related to the applied peak acoustic pressure at the IFC (single ~80 s sonication) and mediated by the decreased IFC–post‑central connectivity, implicating peak pressure at the target as the effective parameter.
Duration of biological effect more than an hour
Safety-related matter Three participants reported transient side effects within one hour (dizziness, right eye‑corner muscle spasms and lack of coordination; small leg muscle twitches; and confusion by the MRI sound) that were no longer reported after that period. No serious or persistent adverse effects were reported, and the authors state further studies are needed to establish safety for clinical use.

Brain Region

Ultrasound Parameters

Ultrasound instrument NeuroFUS PRO TPO-203 with four-element CTX-500-4CH transducer (Sonic Concepts; Brainbox Ltd., Cardiff, United Kingdom). Transducer aperture/diameter: None
FUS Frequency 500 kHz
FUS Intensity I_SPPA = 54.51 W/cm^2; ISPTA (IFC group) = 83.3 ± 37.3 mW/cm^2 (0.0833 ± 0.0373 W/cm^2); ISPTA (Thalamus group) = 154.9 ± 69.2 mW/cm^2 (0.1549 ± 0.0692 W/cm^2)
FUS Pressure Peak pressure (means ± SD): IFC 0.1535 ± 0.0349 MPa; Thalamus 0.1348 ± 0.0267 MPa. Peak pressure in target (means ± SD): IFC 0.1249 ± 0.0574 MPa; Thalamus 0.1033 ± 0.0246 MPa. MI-derived peak negative pressure (p = MI * sqrt(f_MHz), f=0.5 MHz) (means ± SD): IFC 0.1584 ± 0.0431 MPa; Thalamus 0.2107 ± 0.0474 MPa.
FUS Mode pulsed
Pulse duration 20 ms
Duration of a single FUS session 80 s
Focal Characteristics Focal depth: right IFC = 31.1 ± 5 mm (range 24–42 mm); right thalamus = 73.8 ± 3.7 mm (range 69–82 mm). Focal length: None. Aperture size: None.
Treatment frequency Single session

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