Clearance of intracranial debris by ultrasound reduces inflammation and improves outcomes in hemorrhagic stroke models
Matine M. Azadian, Sepideh Kiani Shabestari, Arjun Rajan, Payton J. Martinez, Nicholas Macedo, Eric Markarian, Yun Xiang, Brenda J. Yu, Paul M. George, Ryann M. Fame, Raag D. Airan
Nature Biotechnology 2026 · 10.1038/s41587-025-02866-8
Abstract
Impaired clearance of neurotoxic debris in the brain exacerbates neurologic disease and presents a promising therapeutic target. Pharmacologic therapies can enhance meningeal lymphatic clearance in preclinical models but may be limited by systemic toxicities or invasive administration. Here we report a low-intensity, focused ultrasound protocol that noninvasively clears pathogenic substances from the cerebrospinal fluid and brain interstitium in mice. Using two models of hemorrhagic stroke, we demonstrate that this protocol clears the cerebrospinal fluid and interstitium of blood cells, which accumulate in the deep cervical lymph nodes via meningeal lymphatics. The protocol directly modulates molecular processes, including mechanosensitive channels, to shift microglial phenotypes and astrocytic aquaporin localization to reduce neuroinflammation and neurocytotoxicity. In the intracerebral hemorrhage model, it improves behavioral outcomes and increases survival with greater efficacy than a pharmacologic benchmark. The protocol satisfies Food and Drug Administration safety guidelines, supporting clinical translatability. If demonstrated effective clinically, it may provide therapeutic benefit not only in hemorrhagic stroke but also in other neurologic disorders that involve impaired debris clearance.
Abstract via europepmc.
Exposures
Exposure 1: UDC 250 kHz pulsed FUS, whole brain, SAH and ICH mouse models
Target: whole brain or unfocused — “applied transcranially throughout the brain”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 250 | ✓✓✓ |
| Pulse duration (ms) | 50 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓⚑ |
| Duty cycle (%) | 25pulse duration × PRF gives 25% | ✓✓✓ |
| Sonication duration (s) | 600 | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationsingle value | |
| In-situ pressure (kPa) | 450 | ✓✓✓ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Pulsed protocol, 50-ms pulse width, 250 ms pulse cycle time, 10 min per session, three sessions 24-48 h apart; sham was ultrasound power off. An earlier 650 kHz continuous protocol is mentioned only as prior work.
Flags from extraction
exposures[0].in_situ.method— Pressure is called 'peak in situ negative pressure' and 'estimated'; k-Wave simulation of the skull profile is shown but the paper does not say whether the 0.45 MPa value was simulated, derated or measured.exposures[0].timing.pulse_repetition_frequency_hz— PRF of 5 Hz stated only in an Extended Data figure legend; main text gives 250 ms pulse cycle time.n_sessions_per_subject— Three sessions stated only in a figure panel text for the SAH/ICH experiments.n_subjects— Group sizes vary by experiment (n=4, 6, 8 and others); no total stated.exposures[0].device.family— Transducer maker not named (250 kHz, 70- or 100-mm aperture, f=1.0).exposures[0].timing.sonication_duration_s— 10 min per session converted to 600 s.