J. Shimizu 1, J. Kubota 1, T. Fukuda 2, A. Sasaki 3, T. Azuma 3, K. Sasaki 4, K. Shimizu 5, T. Oishi 6, S. Umemura 7, H. Furuhata 1
1 Medical Engineering Laboratory,
2 Division of Neuropathology, The Jikei University School of Medicine – Tokyo, Japan
3 Faculty of Engineering, The University of Tokyo – Tokyo, Japan
4 Department of Veterinary Medicine, Tokyo University of Agriculture and Technology – Tokyo, Japan
5 Department of Zoology, Faculty of Science, Okayama University of Science – Okayama, Japan
6 Department of Cellular and Molecular Biology, Primate Research Institute, Kyoto University – Inuyama, Japan
7 Graduate School of Biomedical Engineering, Tohoku University – Sendai, Japan
Objective: We are developing mid-frequency sonothrombolysis, however, hemorrhagic complication in TRUMBI trial is a fence at these frequency. We evaluated safety in primate with a developed 490 kHz continuous waveform (CW)-US probe and investigated 400 kHz burst waveform (BW)-US emission for rabbit.
Material and Methods: 1.We applied a developed probe to Macaca monkey brain via sonication of the MCA through a temporal window. Each three cynomolgus monkeys were maintained for 1 day and 7 days after sonication. And more two elder rhesus monkeys were sonicated under the alteplase (0.9 mg/kg) i.v., and maintained for 7 days. An automatic switching circuit operated a therapeutic US (T-beam) generator for thrombolysis (490 kHz; CW-US, Ispta 0.72 W/cm2) and diagnostic TC-CFI (D-beam; 2.5 MHz; Ispta 0.20 W/cm2). A 15-min protocol, comprising 4 repeats of a sequence of 120-s T-beam followed by 30-s D-beam and then 5-min T-beam deactivation monitoring with D-beam, was repeated 4 times. 2. The three male rabbits were made a 2.5 cm of craniotomy window. 10days after surgery, they received the 15-min of transcutaneous BW-US (400 kHz, DC 20%, Ispta 0.70 W/cm2) from the craniotomy window. All animal brains were estimated histologically.
Results: 1.None of the monkeys showed neuropathological damage after sonication. 2. In rabbit, amyloid precursor protein positive axons in white matter and alpha-B crystallin positive astrocytes in cortex were observed which was similar to a diffuse axonal injury.
Discussion: One of the hemorrhagic causes in the TRUMBI trial is high effective mechanical index (eMI) over 2.0. There was no brain damage in monkey brain by developed probe at eMI=0.42. According to McDannold, the eMI threshold of the disruption in rabbit BBB by BW-US is 1.38. In our rabbit study, the similar traumatic change appeared at the eMI=1.56 by BW-US. It suggests that high eMI at brain induce traumatic damage.
Key words: mechanical index, neuropathology, safety, sonothrombolysis.