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Label free, capillary-scale blood flow mapping in vivo reveals that low-intensity focused ultrasound evokes persistent dilation in cortical microvasculature.

Authors: Shen YY, Jethe JV, Reid AP, Hehir J, Amaral MM, Ren C, Hao S, Zhou C, Fisher JAN

Non-invasive, low intensity focused ultrasound is an emerging neuromodulation technique that offers the potential for precision, personalized therapy. An increasing body of research has identified mechanosensitive ion channels that can be modulated by FUS and support acute electrical activity in neurons. However, neuromodulatory effects that persist from hours to days have also been reported. The brain's ability to provide blood flow to electrically active regions involves a multitude of non-neuronal cell types and signaling pathways in the cerebral vasculature; an open question is whether persistent effects can be attributed, at least partly, to vascular mechanisms. Using an in vivo optical approach, we found that microvasculature, and not larger vessels, exhibit significant persistent dilation following sonication without the use of microbubbles. This finding reveals a heretofore unseen aspect of the effects of FUS in vivo and indicates that concurrent changes in neurovascular function may partially underly persistent neuromodulatory effects.

Introduction

Purpose Transcranial ultrasound stimulation
Study Objective To determine whether low-intensity focused ultrasound produces persistent dilation in cortical microvasculature (capillary-scale) in vivo using label-free optical coherence tomography angiography.
Animal model / Human subject mouse, C57BL/6J, 4–6 months, male
Disease model healthy
MRI or image guidance method Optical image guidance: OCT-based alignment with co-localization of acoustic and optical foci using a thermochromic liquid-crystalline sheet (OCT beam 'crosshairs' used to correct FUS focus); animals positioned in a stereotaxic apparatus with a fixed headbar and a 3-axis transducer mount for fine positioning.
Targeted brain region(s) Primary Somatosensory Cortex (Forelimb Representation)
Target coordinates AP: 0 mm (at bregma), ML: ~2.5 mm lateral, DV: not specified

Outcomes and Safety

Summary of Outcomes Low-intensity FUS (510 kHz, 1–10 W/cm², 50% duty cycle, 20 s) produced significant persistent dilation of cortical capillaries and pre-capillary arterioles without BBB leakage or tissue damage; high-intensity sonication (>200 W/cm²) caused tissue damage and Evans blue extravasation.
Duration of biological effect not reported
Safety-related matter Low-intensity FUS (1–10 W/cm²) produced no BBB permeabilization or gross tissue disruption; high-intensity sonication (>200 W/cm²) caused clear tissue damage and Evans blue leakage extending >350 µm.

Brain Region

Ultrasound Parameters

Ultrasound instrument H-205B wide-aperture ring FUS transducer
FUS Frequency 510 kHz
FUS Intensity 1 W/cm²
FUS Pressure 0.124 MPa, 0.45 MPa
FUS Mode pulsed
Pulse duration 0.5 ms
Duration of a single FUS session 20 s
Treatment frequency Multiple

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