Blood-cerebrospinal fluid barrier opening by modified single pulse transcranial focused shockwave

Abstract

Transcranial focused shockwave (FSW) is a novel noninvasive brain stimulation that can open blood-brain barriers (BBB) and blood-cerebrospinal fluid barriers (BCSFB) with a single low-energy (energy flux density 0.03 mJ/mm²) pulse and low-dose microbubbles (2 × 10⁶/kg). Similar to focused ultrasound, FSW deliver highly precise stimulation of discrete brain regions with adjustable focal lengths that essentially covers the whole brain. By opening the BCSFB, it allows for rapid widespread drug delivery to the whole brain by cerebrospinal fluid (CSF) circulation. Although no definite adverse effect or permeant injury was noted in our previous study, microscopic hemorrhage was infrequently observed. Safety concerns remain the major obstacle to further application of FSW in brain. To enhance its applicability, a modified single pulse FSW technique was established that present 100% opening rate but much less risk of adverse effect than previous methods. By moving the targeting area 2.5 mm more superficially on the left lateral ventricle as compared with the previous methods, the microscopic hemorrhage rate was reduced to zero. We systemically examine the safety profiles of the modified FSW-BCSFB opening regarding abnormal behavior and brain injury or hemorrhage 72 hr after 0, 1, and 10 pulses of FSW-treatment. Animal behavior, physiological monitor, and brain MRI were examined and recorded. Brain section histology was examined for hemorrhage, apoptosis, inflammation, oxidative stress related immunohistochemistry and biomarkers. The single pulse FSW group demonstrated no mortality or gross/microscopic hemorrhage (N = 30), and no observable changes in all examined outcomes, while 10 pulses of FSW was found to be associated with microscopic and temporary RBC extravasation (N = 6/30), and abnormal immunohistochemistry biomarkers which showed a trend of recovery at 72 hrs. The results suggest that single pulse low-energy FSW-BCSFB opening is effective, safe and poses minimal risk of injury to brain tissue (Sprague Dawley, SD rats).

Keywords:

• Safety
• shockwave
• blood-cerebrospinal fluid barrier
• CSF circulation
• brain

Acknowledgements

Thanks to the Ministry of Science and Technology (National Taiwan University) for the assistance in MRI experiments. We thank the Laboratory Animal Center at the National Taiwan University College of Medicine for technical support in this rat study and analysis.

Authors’ contributions

Y.K. developed and designed the FSW-BCSFB opening system and processed the major experiments. W.H.L. offered the biotechnological analysis information, C.H.W., M.T.L., M.Y.H. and W.S.C. guided the research. Y.K., W.S.C. and M.Y.H. wrote the manuscript.

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Consent for publication

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval and consent to participate

The study was permitted by the ethics committee of the Laboratory Animal Center at the National Taiwan University College of Medicine (approval No. 20190361).

Additional information

Funding

This work was funded by grant 109-53 from the Good Liver Foundation (Taiwan), by grants BN-108-PP-003 and BN-109-PP-03 from the National Health Research Institutes of the Republic of China (Taiwan), by grants 105-2923-B-002-001-MY3, 108-2314-B-002-164, 110-2314-B-002-065 and 110-2314-B-002-070 from the Ministry of Science and Technology (Taiwan), by grant 110-BIH009 from National Taiwan University Hospital (Hsin-Chu Branch), and by grants 107-M3989, 109-M4670 and 110-S5124 from National Taiwan University Hospital.