Brain edema and intracerebral necrosis caused by transcranial low-frequency 20-kHz ultrasound: a safety study in rats.

BACKGROUND AND PURPOSE Ultrasound-accelerated thrombolysis is a promising approach toward acute stroke treatment. In previous in vitro studies, we demonstrated enhanced thrombus destruction induced by 20-kHz ultrasound. However, little is known about biological interactions of low-frequency ultrasound with brain tissue. The aim of this in vivo MRI study was to assess safety aspects of transcranial low-frequency ultrasound in rats. METHODS The cranium of 33 male Wistar rats was sonificated for 20 minutes (20-kHz continuous wave). Power output was varied between 0 and 2.6 W/cm2. Tympanal and rectal temperature was monitored. Diffusion-weighted imaging and T2-weighted imaging was performed before and 4 hours, 24 hours, and 5 days after sonification. Apparent diffusion coefficients (ADCs) and T2 relaxation time (T2-RT) were measured in regions of interest in the cortex and the basal ganglia. The animals were euthanized for histological evaluation thereafter. RESULTS Tympanal temperature increased significantly during insonation with 1.1 and 2.6 W/cm2. ADCs decreased significantly at 0.5 and 1.1 W/cm2, indicating cytotoxic edema. T2-RT increased significantly in the 0.5 and 1.1 W/cm2 group, consistent with vasogenic edema. No changes were detectable in the low-power output group (0.2 W/cm2). After sonification with 2.6 W/cm2, a significant loss of neurons could be detected on histopathology. Furthermore, 3 animals developed circumscript cortical lesions that could be identified as parenchymal necrosis. CONCLUSIONS Low-frequency ultrasound caused vasogenic and cytotoxic brain edema and intracerebral necrosis in a dose-dependent fashion. This study indicates therapeutic low-frequency ultrasound as being potentially harmful and underlines the necessity of careful evaluation in further animal models.