Focused Ultrasound-Induced Blood-Brain Barrier Opening: Association with Mechanical Index and Cavitation Index Analyzed by Dynamic Contrast-Enhanced Magnetic-Resonance Imaging

Abstract

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

Loud music and the specific sound stress open the blood-brain barrier: new fundamental, biomedical, and social aspects

“…There are numerous studies using infrasound or ultrasound for transient BBB opening. 10,[34][35][36][37][38] At present, infrasound (8 Hz, 90-120 dB, duration -2h) effectively opens BBB but induces significant brain injuries due to increased intracellular calcium concentration, induction of apoptosis and high expression of heat shock protein 70. 34,35 The currently focused ultrasound is one of the most promising methods to enhance drug penetration into the brain by disruption the TJ between capillary endothelial cells.…”

“…Indeed, currently over 70 different methods were suggested for overcoming BBB including physical, chemical and biological approaches [4][5][6] . Nevertheless, these methods are not widely applied in daily clinical practice due to many reasons including invasiveness (e.g., photodynamic opening of BBB that requires skull opening) 7 , challenge in performing (intraarterial injection of mannitol that only few specialists in clinics can usually do) 8 , limitation of drug concentration (intranasal drug delivery) 9 or small area of treatment (only 1-3 mm at usage of focused ultrasound that opens BBB with additional using of micro-bubbles) 10 . All these methods require further studies to improve the reproducibility and technological robustness as well as quantitative evaluation of BBB permeability.…”

Blood–brain barrier and laser technology for drug brain delivery

“…[51][52][53][54] However, no approaches for the opening of BBB, which are widely used in daily clinical practice due to their invasiveness and challenge in performing such as intra-arterial injection of mannitol, limitation of drug concentration using intranasal drug delivery or area of treatment (1-3 mm) using focused ultrasound. [55][56][57] Here, we discuss technology, which is used in clinical practice but with completely new view on this method as novel approach for the brain drug delivery. Photodynamic therapy (PDT) with using 5-aminolevulinic acid (5-ALA)-PDT is a valuable method for surgical navigation of glioblastoma.…”

Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control

“…(BBB) opening and albumin-based drug carriers that are MRI-visible to achieve 23 targeted drug delivery to the brain. FUS has gained attention as a tool for focal BBB 24 opening (BBBO) [4][5][6][7][8][9][10], and can penetrate the skull to safely open the BBB at specific 25 locations [5,[11][12][13][14][15][16]. It is an ideal tool for focal drug delivery due to its current use in 26 humans [17,18] and its non-invasive nature [19,20].…”

“…The BBB is generally an impediment to the delivery of therapeutic agents. FUS has 275 gained attention as a tool for focal BBB opening [4,[6][7][8][9][10]20] [12,16]. We investigated the use of FUS for non-invasive neuromodulation by combining 279 FUS-induced BBBO and nanocluster drug delivery.…”