Restoration of Glymphatic Influx After Photothrombotic Stroke Using Low-Intensity Focused Ultrasound.

This study aimed to investigate the regional modulation effect of low-intensity focused ultrasound (LIFU) on cerebrospinal fluid (CSF) influx dynamics, focusing on the differential changes between hemispheres in a mouse model of unilateral ischemic stroke. LIFU was administered with a commercial transducer at the unilateral M1 cortex of mice using specific parameters (0.5 MHz center frequency, 250 kHz pulse repetition frequency, 300 ms burst duration, 2 ms pulse length, 50% intraburst duty factor, 2 s interstimulation interval, spatial peak temporal average intensities of 0.5 W/cm<sup>2</sup>, and a total sonication duration of 10 min). The regional CSF influx was observed through in vivo macroscopy and brain section imaging in a photothrombotic stroke model, both with and without LIFU. Localized LIFU stimulation at the M1 region triggered a rapid CSF influx, peaking 20-30 min poststimulation. Following photothrombotic stroke, a marked reduction in CSF influx was observed in both ipsilesional and contralesional MCA regions, most notably on Days 1 and 3, with a return to baseline by Day 7. However, daily contralesional LIFU stimulation for 7 days effectively restored CSF influx on both sides. Daily contralesional LIFU stimulation restores impaired CSF influx bilaterally after stroke, suggesting potential therapeutic implications for stroke-related pathophysiology.

Introduction

Purpose Transcranial ultrasound stimulation

Study Objective To investigate whether low‑intensity focused ultrasound (LIFU) can modulate and restore cerebrospinal fluid (CSF) influx dynamics, including hemispheric differences, in a mouse model of unilateral ischemic stroke.

Animal model / Human subject Mouse, C57BL/6, age not specified (body weight 20–25 g), male

Disease model Unilateral ischemic stroke (photothrombotic stroke model in mice)

MRI or image guidance method Stereotactic placement using skull landmarks

Targeted brain region(s) M1 Cortex (Primary Motor Cortex)

Target coordinates AP: -1 mm (1 mm posterior to bregma), ML: 3.5 mm (lateral to bregma), DV: not specified

Cargo name and characteristics not reported

Route of administration Intracisternal injection into the cisterna magna

Outcomes and Safety

Summary of Outcomes Localized low-intensity focused ultrasound (LIFU) at M1 rapidly enhances CSF influx in mice, and daily contralesional LIFU over 7 days restores bilateral CSF influx that is acutely reduced after photothrombotic stroke.

Duration of biological effect 20–30 minutes

Safety-related matter The authors note that the intermittent LIFU parameters used have been shown in previous studies to cause no damage, and that contralesional targeting may carry less risk and minimize systemic adverse effects compared with pharmacologic approaches.

Brain Region

Ultrasound Parameters

Ultrasound instrument Focused ultrasound transducer H-104 (Sonic Concepts, USA)

FUS Frequency 0.5 MHz

FUS Intensity 0.5 W/cm2

FUS Pressure Not reported

FUS Mode pulsed

Pulse duration 2 ms

Duration of a single FUS session 10 min

Focal Characteristics Not specified

Treatment frequency Multiple sessions (daily LIFU for 7 days); single-session immediate effects were also tested

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