In vivo transcranial cavitation detection during ultrasound-induced blood-brain barrier opening

Tung, Yu-Chi; Vlachos, Fotios; Choi, James J.; Thomas, Daniel; Selert, Kirsten; Konofagou, Elisa E.

doi:10.1109/ultsym.2010.5935953

Cited by 50 publications

(75 citation statements)

References 15 publications

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“…The rapid increase in TNFα and other proinflammatory factors indicates an acute involvement of NVU elements in response to hypoxia or injury (14,48). Previous studies have suggested that the mechanism of action by which pFUS+MB exposure results in BBBD was stable acoustic cavitation forces acting at the level of TJP (i.e., vessel centric) stretching apart endothelial cells (6,20,28,30,41). However, this proposed mechanism does not address how the cavitation forces interact directly with other cells in the NVU.…”

Section: Discussionmentioning

confidence: 99%

“…MRI-guided pulsed focused ultrasound (pFUS) combined with the infusion of contrast agent microbubbles (pFUS+MB) is a noninvasive technique that can cause transient BBBD in targeted brain regions and facilitate the delivery of large molecules into the parenchyma. Contrast-enhanced MR-guided pFUS+MB transiently opens the BBB in the targeted parenchyma without evidence of microhemorrhages (21,28). It has been postulated that the BBBD following pFUS+MB results from a combination of acoustic radiation forces [i.e., soft tissue displacement exerted by ultrasound (US)]…”

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confidence: 99%

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Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

332

388

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MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1-7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells. The BBB consists of specialized endothelial cells connected through various tight junction proteins (TJP), astrocyte endplates, and a basement membrane. These components form part of the neurovascular unit (NVU) that is comprised of vessels, pericytes, microglia, astrocytes, and neurons along with the extracellular matrix (1,3,4,8). BBBD secondary to ischemia or trauma leads to increases in endothelial caveolae and down-regulation of TJP, transcytosis of plasma proteins (i.e., albumin), and vasogenic edema (1,6,(8)(9)(10)(11). The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12-15). The release of CCTFs and inte...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

332

388

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“…Both stable and inertial cavitation have been observed to both mechanically agitate the microvascular wall (8) and cause extravasation of vascular agents (7,21). Previous reports using longer PLs of 10 or 20 ms have analyzed the acoustic emissions radiating from the acoustically driven microbubbles and have indicated that BBB disruption may occur with stable cavitation or nonviolent inertial cavitation (22)(23). However, it is difficult to infer to the type of cavitation activity present in our experiments due to the shorter duration of the PL used and the fact that we are operating at PRPs near the threshold of BBB disruption.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Choi¹,

Selert²,

Vlachos³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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135

141

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Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood-brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 μs) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound.F ocused ultrasound (FUS) and microbubble-based drug delivery systems (DDSs) can increase the dose of an agent in a target volume and has potential in applications such as blood-brain barrier (BBB) disruption for the treatment of neurological diseases (1, 2), molecular and viral treatment of tumors (3), gene therapy for treating heart conditions (4), and enhancement of renal ultrafiltration (5). In each method, biologically inert and preformed microbubbles, with a lipid or polymer shell, a stabilized gas core, and a diameter less than 10 μm, are systemically administered and subsequently exposed to noninvasively delivered FUS pulses. Microbubbles within the target volume are "acoustically activated" in a complex range of behaviors known as acoustic cavitation. In stable cavitation, the microbubbles expand and contract with the acoustic pressure rarefaction and compression over several cycles (6). This activity has been associated with a range of bioeffects including displacement of the vessel wall through dilation and contractions (7,8). Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8). Each type and magnitude of cavitation activity results...

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“…It has been shown that a passive cavitation detector (PCD) can be used to transcranially acquire the acoustic emissions stemming from the microbubble [13]. The frequency analysis of the backscattered signal and, more specifically the cavitation dose, has been proven relevant to characterizing the bubble-capillary interaction and potential damage in mice along with complete histological analysis [10,14].…”

Section: Introductionmentioning

confidence: 99%

Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates

Marquet

Tung

et al. 2012

2012 IEEE International Ultrasonics Symposium

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The delivery of drugs to specific neural targets faces two fundamental problems: (1) most drugs do not cross the bloodbrain barrier, and (2) those that do, spread to the entire brain. To date, there exists only one non-invasive methodology with the potential to solve these problems: selective blood-brain barrier (BBB) opening using micro-bubble enhanced focused ultrasound. We have recently developed a single-element 500-kHz spherical transducer ultrasound setup for targeted BBB opening in the non-human primate that does not require simultaneous MRI monitoring. So far, however, the targeting accuracy that can be achieved with this system has not been quantified systematically. In this paper, the accuracy of this system was tested by targeting caudate nucleus and putamen of the basal ganglia in two macaque monkeys. The average lateral targeting error of the system was ,2.5 mm while the axial targeting error, i.e., along the ultrasound path, was ,1.5 mm. We have also developed a real-time treatment monitoring technique based on cavitation spectral analysis. This technique also allowed for delineation of a safe and reliable acoustic parameter window for BBB opening. In summary, the targeting accuracy of the system was deemed to be suitable to reliably open the BBB in specific sub-structures of the basal ganglia even in the absence of MRI-based verification of opening volume and position. This establishes the method and the system as a potentially highly useful tool for brain drug delivery.

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In vivo transcranial cavitation detection during ultrasound-induced blood-brain barrier opening

Cited by 50 publications

References 15 publications

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates

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