Neuronavigated Repetitive Transcranial Ultrasound Stimulation Induces Long-Lasting and Reversible Effects on Oculomotor Performance in Non-human Primates.

Authors: Pouget P, Frey S, Ahnine H, Attali D, Claron J, Constans C, Aubry JF, Arcizet F

Since the late 2010s, Transcranial Ultrasound Stimulation (TUS) has been used experimentally to carryout safe, non-invasive stimulation of the brain with better spatial resolution than Transcranial Magnetic Stimulation (TMS). This innovative stimulation method has emerged as a novel and valuable device for studying brain function in humans and animals. In particular, single pulses of TUS directed to oculomotor regions have been shown to modulate visuomotor behavior of non-human primates during 100 ms ultrasound pulses. In the present study, a sustained effect was induced by applying 20-s trains of neuronavigated repetitive Transcranial Ultrasound Stimulation (rTUS) to oculomotor regions of the frontal cortex in three non-human primates performing an antisaccade task. With the help of MRI imaging and a frame-less stereotactic neuronavigation system (SNS), we were able to demonstrate that neuronavigated TUS (outside of the MRI scanner) is an efficient tool to carry out neuromodulation procedures in non-human primates. We found that, following neuronavigated rTUS, saccades were significantly modified, resulting in shorter latencies compared to no-rTUS trials. This behavioral modulation was maintained for up to 20 min. Oculomotor behavior returned to baseline after 18-31 min and could not be significantly distinguished from the no-rTUS condition. This study is the first to show that neuronavigated rTUS can have a persistent effect on monkey behavior with a quantified return-time to baseline. The specificity of the effects could not be explained by auditory confounds.

Introduction

Purpose Transcranial ultrasound stimulation

Study Objective To determine whether neuronavigated repetitive transcranial ultrasound stimulation (rTUS) applied to frontal oculomotor regions in macaque monkeys produces a sustained, location-specific modulation of antisaccade saccade latencies and to quantify the duration and return-to-baseline of that effect.

Animal model / Human subject Non-human primates (monkeys); strain: Macaca fascicularis; age: None; sex: male

Disease model Healthy

MRI or image guidance method MRI imaging and a frame-less stereotactic neuronavigation system (neuronavigated)

Targeted brain region(s) Frontal Eye Field; Supplementary Eye Field

Outcomes and Safety

Summary of Outcomes Neuronavigated rTUS produced a significant, reversible reduction in ipsilateral antisaccade latencies lasting approx. 18-31 min, with no comparable effects at control regions.

Duration of biological effect 20 min

Safety-related matter No adverse effects or discomfort were reported: no muscle twitching, no noise or mechanical vibration, and rTUS did not disturb general performance although very small increases in error rates were observed in some animals. The authors caution that safety needs further investigation prior to clinical translation, noting potential thermal rise at higher frequencies and referencing histological safety assessments in rodents, pigs, sheep, and monkeys.

Brain Region

Ultrasound Parameters

Ultrasound instrument Single element focused ultrasound transducer (H115, Sonice Concept, Bothell, WA, US)

FUS Frequency 0.32 MHz

FUS Intensity ISPTA: 1.9 W/cm2; ISPPA: 6.5 W/cm2

FUS Pressure 0.44 Mpa

FUS Mode pulsed

Pulse duration 30 ms

Duration of a single FUS session 20 s

Focal Characteristics Focal depth: 45 mm; Focal length: 63.2 mm; Aperture size: 64 mm

Treatment frequency single

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