Noninvasive Low-Intensity Focused Ultrasound Mediates Tissue Protection following Ischemic Stroke
Alexandra M. Kaloss, Lauren N. Arnold, Eman Soliman, Maya Langman, Nathalie Groot, Eli Vlaisavljevich, Michelle H. Theus
BME Frontiers 2022 · 10.34133/2022/9864910
Abstract
Objective and Impact Statement . This study examined the efficacy and safety of pulsed, low-intensity focused ultrasound (LIFU) and determined its ability to provide neuroprotection in a murine permanent middle cerebral artery occlusion (pMCAO) model. Introduction . Focused ultrasound (FUS) has emerged as a new therapeutic strategy for the treatment of ischemic stroke; however, its nonthrombolytic properties remain ill-defined. Therefore, we examined how LIFU influenced neuroprotection and vascular changes following stroke. Due to the critical role of leptomeningeal anastomoses or pial collateral vessels, in cerebral blood flow restoration and tissue protection following ischemic stroke, we also investigated their growth and remodeling. Methods . Mice were exposed to transcranial LIFU (fundamental frequency: 1.1 MHz, sonication duration: 300 ms, interstimulus interval: 3 s, pulse repetition frequency: 1 kHz, duty cycle per pulse: 50%, and peak negative pressure: -2.0 MPa) for 30 minutes following induction of pMCAO and then evaluated for infarct volume, blood-brain barrier (BBB) disruption, and pial collateral remodeling at 24 hrs post-pMCAO. Results . We found significant neuroprotection in mice exposed to LIFU compared to mock treatment. These findings correlated with a reduced area of IgG deposition in the cerebral cortex, suggesting attenuation of BBB breakdown under LIFU conditions. We also observed increased diameter of CD31-postive microvessels in the ischemic cortex. We observed no significant difference in pial collateral vessel size between FUS and mock treatment at 24 hrs post-pMCAO. Conclusion . Our data suggests that therapeutic use of LIFU may induce protection through microvascular remodeling that is not related to its thrombolytic activity.
Abstract via europepmc.
Exposures
Exposure 1: LIFU after pMCAO, 1.1 MHz, 30 min
Target: cerebral cortex — “cerebral vasculature, including the MCA-ACA pial collateral niche (left parietal bone 4 mm rostral of bregma and 2 mm lateral of midline)”
Device: Sonic Concepts · Sonic Concepts · H-101 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 1,100 | ✓✓✓ |
| Pulse duration (ms) | 0.5 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1,000 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓✓✓ |
| Sonication duration (s) | 0.3 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Pressure, domain unspecified (kPa) | 1,800, 2,000, 3,500swept | ✓✓✓⚑ |
Pulsed LIFU: sonication duration 300 ms delivered every 3 s (ISI = 3 s) for 600 stimulations, a total of 30 min, starting immediately after pMCAO.
Flags from extraction
n_subjects— Only fourteen (safety pilot) and 23 (final study) mice stated; not all were sonicated (some untreated or mock), so the number exposed is not stated as a total.exposures[0].unspecified_domain.pressure_kpa— Peak negative pressures 1.8, 2.0 and 3.5 MPa; focal pressures measured by hydrophone before experiments but the paper does not say water or through skull, so placed in unspecified domain.exposures[0].timing.pulse_duration_ms— Tone-burst duration 0.5 ms stated; consistent with 50% DC at 1 kHz PRF (burst rule resolved by stated TBD).exposures[0].target.terms— Transducer placed over parietal bone; target is cerebral vasculature/MCA territory, term chosen loosely.