Abstract
Blood-brain barrier (BBB) is an unique structure in the mammalian brain, which prevents poisonous substances from entering the brain and maintains the normal physiological activities of the brain. However, BBB also hinders the drug delivery into the brain, which further decreases the efficiency of treating cerebral diseases. Recently, blood-brain barrier disruption (BBBD) has been performed by focused ultrasound (FUS) combining with microbubbles (MBs), and has been approved to enhance the local drug or gene delivery. Furthermore, the BBBD effect has been widely observed by several biomedical imaging methods to broaden its clinical practicability. The magnetic resonance imaging (MRI) is one of the most commonly used tools to indicate the BBBD location via monitoring the contrast agent such as Gd-DTPA leakage into the brain tissues by T1-weighted sequences. Moreover, the intracerebral hemorrhage (ICH) caused by FUS sonication could be recognized by the MRI T2*-weighted sequence. However, the low temporal resolution property of MRI restricts the dynamic observation of physiological changes within the brain. Also, MRI fails to detect micro-circulation shortage induced by FUS with MBs. In this paper, we proposed a high-resolution ultrasound imaging system with destruction/reperfusion technique, which can be used to identify BBBD region and even brain tissue damage according to cerebral blood flow variation in the rat model. The BBB was disrupted by a 2 MHz FUS combining with MBs at 0.5 - 0.7 MPa (pulse repetition frequency: 1 Hz, pulse length: 1 ms, sonication time: 60 s). The D/R B-mode images were then acquired at three time points including (1) 15 min before; (2) 20 s after; and (3) 60 s after FUS sonication to dynamically investigate the relationship between BBBD and brain perfusion/damage. Finally, MRI images were used to further confirm the proposed technique and the results of this study. The results showed that the velocity of blood flow decreased after BBBD induced by FUS sonication. Particularly, the plateau of blood flow time-intensity curve (TIC) was higher at 20 s after MB destruction by FUS sonication than that obtained prior to sonication. Besides, the blood flow was found to be obstructed at 60 s after sonication due to blood coagulation. The pattern of hemorrhagic damage caused by FUS can be monitored by the TIC. In addition, we also observed that the location of blood flow velocity decrease was consistent with the areas of BBBD and the variation of blood flow depends on the applied acoustic pressure, and the extent of permeability presented by MRI Ktrans images were highly correlative with the blood flow variation measured by our methods. In conclusion, our proposed imaging technique provided a useful tool to monitor both the extent of BBBD and presence of hemorrhage by the flow velocity variation map and the TIC pattern, individually. The results can be used to establish an immediate-feedback control tool for preventing the induction of intracerebral hemorrhage during FUS treatment.