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Dynamical and individualised approach of transcranial ultrasound neuromodulation effects in non-human primates.

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

Low-frequency transcranial ultrasound stimulation (TUS) allows to alter brain functioning with a high spatial resolution and to reach deep targets. However, the time-course of TUS effects remains largely unknown. We applied TUS on three brain targets for three different monkeys: the anterior medial prefrontal cortex, the supplementary motor area and the perigenual anterior cingulate cortex. For each, one resting-state fMRI was acquired between 30 and 150 min after TUS as well as one without stimulation (control). We captured seed-based brain connectivity changes dynamically and on an individual basis. We also assessed between individuals and between targets homogeneity and brain features that predicted TUS changes. We found that TUS prompts heterogenous functional connectivity alterations yet retain certain consistent changes; we identified 6 time-courses of changes including transient and long duration alterations; with a notable degree of accuracy we found that brain alterations could partially be predicted. Altogether, our results highlight that TUS induces heterogeneous functional connectivity alterations. On a more technical point, we also emphasize the need to consider brain changes over-time rather than just observed during a snapshot; to consider inter-individual variability since changes could be highly different from one individual to another.

Introduction

Purpose Transcranial ultrasound stimulation
Study Objective To characterize how low-frequency transcranial ultrasound stimulation (TUS) alters whole-brain functional connectivity over time across different targets and individuals, and whether baseline brain features can predict these changes.
Animal model / Human subject Rhesus macaque (Macaca mulatta); strain: not specified; age: average 6.35 years; sex: male
Disease model Healthy
MRI or image guidance method Frameless stereotaxic neuronavigation (Rogue Research) using registration of the animal's T1-weighted MRI to the head with continuous infrared tracking of the ultrasound transducer and the head
Targeted brain region(s) Anterior Medial Prefrontal Cortex; Supplementary Motor Area; Perigenual Anterior Cingulate Cortex
Target coordinates amPFC (AP=24, ML=-0.7, DV=11); SMA (AP=2, ML=0.1, DV=19); pACC (AP=15, ML=0, DV=6)
Route of administration Inhalational (isoflurane); intramuscular injection (ketamine, xylazine, midazolam, atropine); intravenous injection (meloxicam, ranitidine)

Outcomes and Safety

Summary of Outcomes Low-frequency transcranial ultrasound stimulation produced heterogeneous, target-dependent alterations in resting-state functional connectivity with both transient and long-lasting network effects
Duration of biological effect >2 h
Safety-related matter The paper does not report any adverse effects or safety issues related to transcranial ultrasound stimulation; no injuries, adverse events, or safety concerns were mentioned.

Brain Region

Ultrasound Parameters

Ultrasound instrument Single-element ultrasound transducer H115-MR (Sonic Concept); diameter 64 mm; focal depth 51.74 mm
FUS Frequency 250 kHz
FUS Intensity 31.7 W/cm2 (ISSPA, amPFC); 24.1 W/cm2 (ISSPA, SMA); 18.8 W/cm2 (ISSPA, pACC); 9.5 W/cm2 (ISPTA, amPFC); 7.2 W/cm2 (ISPTA, SMA); 5.63 W/cm2 (ISPTA, pACC)
FUS Pressure 1.01 MPa; 0.88 MPa; 0.78 MPa
FUS Mode pulsed
Pulse duration 30 ms
Duration of a single FUS session 40 s
Focal Characteristics Focal depth: 51.74 mm; Focal length: None; Aperture size: 64 mm
Treatment frequency multiple

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