Histological Findings in the Brain after Focused Ultrasound Ablation Combined with Definity Using Parameters Suited for Transcranial Application

Abstract

Burst sonications (burst: 10 ms; pulse repetition frequency: 1 Hz; total exposure: 5 min or 1 min; acoustic power: 0.47–1.3 W) were applied transcranially to the brains of 12 rats using a 558 kHz single element focused transducer (D/ROC: 10/7.8 cm). Sonications were combined with ultrasound (US) contrast agent (Definity, 0.02 ml/kg). Additional experiments tested continuous‐wave exposures and bursts of 200 and 500 ms. Tissue effects were evaluated with MRI and light microscopy at 24 h, 48 h, and 7 d. No lesion was produced with the 1 min exposure. With 5 min exposures, at 0.47 W the probability of producing a lesion was 50%, at 0.59 W and higher, it was ∼100%. Some lesions with moderate hemorrhage were predominately characterized by ischemia, while others with more extensive hemorrhage exhibited hemorrhagic necrosis. At 7 days sonicated regions displayed necrosis with abundant macrophages. We surmised that ischemic lesions were presumably produced by the occlusion of capillary blood vessels (through formation of emboli and platelet aggregations) due to stable cavitation. Hemorrhagic lesions might be caused by mechanical damage to the blood vessels via inertial cavitation. Thus, FUS in conjunction with contrast agents can create localized lesions at reduced acoustical power. Future work will be necessary to optimize the exposure parameters to produce ischemic lesions without extensive hemorrhage, to monitor acoustic emissions, relating inertial and stable cavitation to tissue effects, and to optimize online detection of the lesions.