Low-Power 2-MHz Pulsed-Wave Transcranial Ultrasound Reduces Ischemic Brain Damage in Rats

Abstract

It is largely unknown whether prolonged insonation with ultrasound impacts the ischemic brain tissue by itself. Our goal was to evaluate safety and the effect of high-frequency ultrasound on infarct volume in rats. Thirty-two Long-Evans rats with permanent middle cerebral and carotid artery occlusions received either 2-MHz ultrasound at two levels of insonation power (128 or 10 mW) or no ultrasound (controls). We measured cerebral hemorrhage, indirect and direct infarct volume as well as edema volume at 24 h. No cerebral hemorrhages were detected in all animals. Exposure to low-power (10 mW) ultrasound resulted in a significantly decreased indirect infarct volume (p = 0.0039), direct infarct volume (p = 0.0031), and brain edema volume (p = 0.01) compared with controls. High-power (128 mW) ultrasound had no significant effects. An additional experiment with India ink showed a greater intravascular penetration of dye into ischemic tissues exposed to low-power ultrasound. Insonation with high-frequency, low-power ultrasound reduces ischemic brain damage in rat. Its effect on edema reduction and possible promotion of microcirculation could be used to facilitate drug and nutrient delivery to ischemic areas.

Outcomes following Sonothrombolysis in Severe Acute Ischemic Stroke: Subgroup Analysis of the CLOTBUST Trial

“…The rationale why we decided to analyze patients with severe stroke severity is based on the fact that these patients most commonly (>80%) have an underlying proximal major occlusion (3,4), and hence, only modest benefits with IV tPA therapy (5). Also, even though the continuous exposure of cerebral ischemic tissues to ultrasound seems to have additional effects (21), it benefits patients mostly by improving early recanalization of a large thrombo-embolic occlusion. Rapid arterial recanalization and restoration of perfusion belong to the most important independent predictors of good functional outcome after AIS (22,23).…”

Towards use of MRI-guided ultrasound for treating cerebral vasospasm

“…We know of only two publications relevant to the cerebral vasculature. In rats, Alexandrov and colleagues [ 65 ] reported significant reductions in the volume of edematous and ischemic brain with application of a commercially available TCD with a 2.0-MHz carrier frequency, 10-mW acoustic power, and 5-KHz pulse repetition frequency. They observed significant reductions in the volume of ischemic and edematous brain (75 vs. 22.5 mm 3 ; 12.7 vs. 1.56 mm 3 , respectively) [ 65 ].…”

“…In rats, Alexandrov and colleagues [ 65 ] reported significant reductions in the volume of edematous and ischemic brain with application of a commercially available TCD with a 2.0-MHz carrier frequency, 10-mW acoustic power, and 5-KHz pulse repetition frequency. They observed significant reductions in the volume of ischemic and edematous brain (75 vs. 22.5 mm 3 ; 12.7 vs. 1.56 mm 3 , respectively) [ 65 ]. Given the unlikely occurrence of cavitation in the brain with these parameters [ 63 , 64 ], we hypothesize this may have occurred through US-mediated enhancement of collateral flow in the volume of tissue surrounding the region of ischemic damage, due to local US-induced vasodilation of collateral blood vessels via stimulation of NO pathways as discussed, or production of enhanced flow via acoustic streaming.…”

Treatment of acute stroke: an update

“…The CLOTBUST-ER trial was based on a previous Phase II trial (CLOTBUST) which showed an improved recanalization rate if alteplase was combined with continuous transcranial ultrasound monitoring as compared to alteplase alone [52]. Different mechanisms of action of ultrasound have been considered including better penetration of thrombolytic agents into the clot due to induction of 'microstreaming' in the residual flow around the thrombus or improvement of the microcirculation leading to decreased infarct volume [106].…”