Non-invasive enhancement of intracortical solute clearance using transcranial focused ultrasound
Seung-Schik Yoo, Evgenii Kim, Kavin Kowsari, Jared Van Reet, Hyun-Chul Kim, Kyungho Yoon
Scientific Reports 2023, 13 · 10.1038/s41598-023-39640-2
Abstract
Transport of interstitial fluid and solutes plays a critical role in clearing metabolic waste from the brain. Transcranial application of focused ultrasound (FUS) has been shown to promote localized cerebrospinal fluid solute uptake into the brain parenchyma; however, its effects on the transport and clearance of interstitial solutes remain unknown. We demonstrate that pulsed application of low-intensity FUS to the rat brain enhances the transport of intracortically injected fluorescent tracers (ovalbumin and high molecular-weight dextran), yielding greater parenchymal tracer volume distribution compared to the unsonicated control group (ovalbumin by 40.1% and dextran by 34.6%). Furthermore, FUS promoted the drainage of injected interstitial ovalbumin to both superficial and deep cervical lymph nodes (cLNs) ipsilateral to sonication, with 78.3% higher drainage observed in the superficial cLNs compared to the non-sonicated hemisphere. The application of FUS increased the level of solute transport visible from the dorsal brain surface, with ~ 43% greater area and ~ 19% higher fluorescence intensity than the unsonicated group, especially in the pial surface ipsilateral to sonication. The sonication did not elicit tissue-level neuronal excitation, measured by an electroencephalogram, nor did it alter the molecular weight of the tracers. These findings suggest that nonthermal transcranial FUS can enhance advective transport of interstitial solutes and their subsequent removal in a completely non-invasive fashion, offering its potential non-pharmacological utility in facilitating clearance of waste from the brain.
Abstract via europepmc.
Exposures
Exposure 1: Pulsed FUS to intracortical tracer injection site
Target: cerebral cortex — “rat cerebral cortex at the intracortical tracer injection site (3 mm lateral, 1 mm caudal to bregma, 2 mm deep)”
Device: Ultran · Ultran Group ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 200 | ✓✓✓ |
| Pulse duration (ms) | 100 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 1 | ✓✓✓ |
| Duty cycle (%) | 10pulse duration × PRF gives 10% | ✓✓✓ |
| Sonication duration (s) | 1,800, 3,600swept | ✓✓✓⚑ |
| Free-field pressure (kPa) | 770 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | 5 | ✓✓✓ |
| Free-field Ispta (W/cm²) | 0.5 | ✓✓✓ |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | 679.6 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 4.4 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported | ⚑ |
FUS was delivered stereotactically to the intracortical tracer injection site 30 min after needle withdrawal, for 30 min in the tracer-transport experiment (ovalbumin and FITC-dextran, n=7/group FUS+ and FUS-) or for 60 min in the lymphatic-clearance experiment (ovalbumin only, n=8/group FUS+ and FUS-).
Consistency checks: intensity pressure inconsistent free field; intensity pressure inconsistent in situ.
Flags from extraction
n_sessions_per_subject— Each rat appears to undergo a single acute, terminal sonication session, but the paper never explicitly states a number of sessions per animal.exposures[0].timing.sonication_duration_s— 30 min (1800 s) was used in the tracer-transport experiment and 60 min (3600 s) in the lymphatic-clearance experiment; both are recorded as a list for this single target/frequency exposure.exposures[0].in_situ.ispta_w_cm2— Numerical simulation reports in-situ ISPPA and peak-to-peak pressure at the injection site but not an in-situ ISPTA value.sham_type— The exact mechanism of the FUS- control condition (e.g., whether the transducer was positioned but left inactive) is not explicitly described; inactive_transducer is inferred from 'the same procedure without receiving sonication'.