Bi-modal confirmation of liposome delivery to the brain after focused ultrasound-induced blood-brain barrier opening.

Focused ultrasound-mediated opening of the blood-brain barrier offers a great opportunity to deliver therapeutics into hard-to-treat brain tumors such as glioblastoma multiforme or diffuse midline glioma. However, the potential of the technique to offer a time window for efficient nanomedicine delivery has not been thoroughly studied. Non-invasive and targeted delivery of large drug-loaded nanocarriers, such as liposomes, could offer a safe and scalable method of personalized therapy for the treatment of brain pathologies.

Focused ultrasound-mediated enhancement of blood-brain barrier permeability for brain tumor treatment: a systematic review of clinical trials.

Purpose: Brain tumors, particularly glioblastoma multiforme (GBM), present significant prognostic challenges despite multimodal therapies, including surgical resection, chemotherapy, and radiotherapy. One major obstacle is the limited drug delivery across the blood-brain barrier (BBB). Focused ultrasound (FUS) combined with systemically administered microbubbles has emerged as a non-invasive, targeted, and reversible approach to transiently open the BBB, thus enhancing drug delivery.

Alteration of functional connectivity in the cortex and major brain networks of non-human primates following focused ultrasound exposure in the dorsal striatum.

Background: Focused ultrasound (FUS) is a non-invasive neuromodulation technology that is being investigated for potential treatment of neurological and psychiatric disorders. FUS combined with microbubbles can temporarily open the intact blood-brain barrier (BBB) of animals and humans, and facilitate drug delivery. FUS exposure, either with or without microbubbles, has been demonstrated to alter the behavior of non-human primates (NHP), and previous studies have demonstrated the transient and long-term effects of FUS neuromodulation on functional connectivity using resting state functional MRI.

Focused ultrasound mitigates pathology and improves spatial memory in Alzheimer's mice and patients.

Bilateral sonication with focused ultrasound (FUS) in conjunction with microbubbles has been shown to separately reduce amyloid plaques and hyperphosphorylated tau protein in the hippocampal formation and the entorhinal cortex in different mouse models of Alzheimer's disease (AD) without any therapeutic agents. However, the two pathologies are expressed concurrently in human disease. Therefore, the objective of this study is to investigate the effects of repeated bilateral sonications in the presence of both pathologies.

Characterising the chemical and physical properties of phase-change nanodroplets.

Phase-change nanodroplets have attracted increasing interest in recent years as ultrasound theranostic nanoparticles. They are smaller compared to microbubbles and they may distribute better in tissues (e.g.

Natural aging and Alzheimer's disease pathology increase susceptibility to focused ultrasound-induced blood-brain barrier opening.

Focused Ultrasound (FUS) paired with systemically-injected microbubbles (μB) is capable of transiently opening the blood-brain barrier (BBBO) for noninvasive and targeted drug delivery to the brain. FUS-BBBO is also capable of modulating the neuroimmune system, further qualifying its therapeutic potential for neurodegenerative diseases like Alzheimer's disease (AD). Natural aging and AD impose significant strain on the brain and particularly the BBB, modifying its structure and subsequently, its functionality.

Real-Time Passive Acoustic Mapping With Enhanced Spatial Resolution in Neuronavigation-Guided Focused Ultrasound for Blood-Brain Barrier Opening.

Objective: Passive acoustic mapping (PAM) provides the spatial information of acoustic energy emitted from microbubbles during focused ultrasound (FUS), which can be used for safety and efficacy monitoring of blood-brain barrier (BBB) opening. In our previous work with a neuronavigation-guided FUS system, only part of the cavitation signal could be monitored in real time due to the computational burden although full-burst analysis is required to detect transient and stochastic cavitation activity. In addition, the spatial resolution of PAM can be limited for a small-aperture receiving array transducer.

Alteration of functional connectivity in the cortex and major brain networks of non-human primates following focused ultrasound exposure.

Focused ultrasound (FUS) is a non-invasive neuromodulation technology that is being investigated for potential treatment of neurological and psychiatric disorders. Focused ultrasound combined with microbubbles can temporarily open the intact blood-brain barrier (BBB) of animals and humans, and facilitate drug delivery. FUS exposure, either with or without microbubbles, has been demonstrated to alter the behavior of non-human primates, and previous work has demonstrated transient and long-term effects of FUS neuromodulation on functional connectivity using resting state functional MRI.

Deep Learning Enables Reduced Gadolinium Dose for Contrast-Enhanced Blood-Brain Barrier Opening.

Focused ultrasound (FUS) can be used to open the blood-brain barrier (BBB), and MRI with contrast agents can detect that opening. However, repeated use of gadolinium-based contrast agents (GBCAs) presents safety concerns to patients. This study is the first to propose the idea of modeling a volume transfer constant (Ktrans) through deep learning to reduce the dosage of contrast agents.

Evaluation of Non-invasive Optogenetic Stimulation with Transcranial Functional Ultrasound Imaging.

Optogenetics employs engineered viruses to genetically modify cells to express specific light-sensitive ion channels. The standard method for gene delivery in the brain involves invasive craniotomies that expose the brain and direct injections of viruses that invariably damage neural tissue along the syringe tract. A recently proposed alternative in which non-invasive optogenetics is performed with focused ultrasound (FUS)-mediated blood-brain barrier (BBB) openings has been found to non-invasively facilitate gene delivery for optogenetics in mice.

Non-invasive optogenetics with ultrasound-mediated gene delivery and red-light excitation.

Optogenetics has revolutionized the capability of controlling genetically modified neurons in vitro and in vivo and has become an indispensable neuroscience tool. Using light as a probe for selective neuronal activation or inhibition and as a means to read out neural activity has dramatically enhanced our understanding of complex neural circuits. However, a common limitation of optogenetic studies to date is their invasiveness and spatiotemporal range.

Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates.

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function.

Acoustic Holograms for Bilateral Blood-Brain Barrier Opening in a Mouse Model.

Transcranial focused ultrasound (FUS) in conjunction with circulating microbubbles injection is the sole non-invasive technique that temporally and locally opens the blood-brain barrier (BBB), allowing targeted drug delivery into the central nervous system (CNS). However, single-element FUS technologies do not allow the simultaneous targeting of several brain structures with high-resolution, and multi-element devices are required to compensate the aberrations introduced by the skull. In this work, we present the first preclinical application of acoustic holograms to perform a bilateral BBB opening in two mirrored regions in mice.

Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates.

An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood-brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied.

Focused ultrasound mediated blood-brain barrier opening is safe and feasible in a murine pontine glioma model.

Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brainstem. Given that the utility of FUS in brainstem malignancies remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model.

Contrast-Free Detection of Focused Ultrasound-Induced Blood-Brain Barrier Opening Using Diffusion Tensor Imaging.

Focused ultrasound (FUS) has emerged as a non-invasive technique to locally and reversibly disrupt the blood-brain barrier (BBB). Here, we investigate the use of diffusion tensor imaging (DTI) as a means of detecting FUS-induced BBB opening at the absence of an MRI contrast agent. A non-human primate (NHP) was repeatedly treated with FUS and preformed circulating microbubbles to transiently disrupt the BBB (n = 4).

Focused Ultrasound-Mediated Blood-Brain Barrier Opening Increases Delivery and Efficacy of Etoposide for Glioblastoma Treatment.

Purpose: Glioblastoma (GBM) is a devastating disease. With the current treatment of surgery followed by chemoradiation, outcomes remain poor, with median survival of only 15 months and a 5-year survival rate of 6.8%.

Doppler Passive Acoustic Mapping.

In therapeutic ultrasound using microbubbles, it is essential to drive the microbubbles into the correct type of activity and the correct location to produce the desired biological response. Although passive acoustic mapping (PAM) is capable of locating where microbubble activities are generated, it is well known that microbubbles rapidly move within the ultrasound beam. We propose a technique that can image microbubble movement by estimating their velocities within the focal volume.

Real-Time Passive Acoustic Mapping Using Sparse Matrix Multiplication.

Passive acoustic mapping enables the spatiotemporal monitoring of cavitation with circulating microbubbles during focused ultrasound (FUS)-mediated blood-brain barrier opening. However, the computational load for processing large data sets of cavitation maps or more complex algorithms limit the visualization in real-time for treatment monitoring and adjustment. In this study, we implemented a graphical processing unit (GPU)-accelerated sparse matrix-based beamforming and time exposure acoustics in a neuronavigation-guided ultrasound system for real-time spatiotemporal monitoring of cavitation.

Temporal stability of lipid-shelled microbubbles during acoustically-mediated blood-brain barrier opening.

Non-invasive blood-brain barrier (BBB) opening using focused ultrasound (FUS) is being tested as a means to locally deliver drugs into the brain. Such FUS therapies require injection of preformed microbubbles, currently used as contrast agents in ultrasound imaging. Although their behavior during exposure to imaging sequences has been well described, our understanding of microbubble stability within a therapeutic field is still not complete.

Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons.

The BRICHOS domain is found in human precursor proteins associated with cancer, dementia (Bri2) and amyloid lung disease (proSP-C). Recombinant human (rh) proSP-C and Bri2 BRICHOS domains delay amyloid-β peptide (Aβ) fibril formation and reduce associated toxicity in vitro and their overexpression reduces Aβ neurotoxicity in animal models of Alzheimer's disease. After intravenous administration in wild-type mice, rh Bri2, but not proSP-C, BRICHOS was detected in the brain parenchyma, suggesting that Bri2 BRICHOS selectively bypasses the blood-brain barrier (BBB).

Neuron labeling with rhodamine-conjugated Gd-based MRI contrast agents delivered to the brain via focused ultrasound.

Gadolinium-based magnetic resonance imaging contrast agents can provide information regarding neuronal function, provided that these agents can cross the neuronal cell membrane. Such contrast agents are normally restricted to extracellular domains, however, by attaching cationic fluorescent dyes, they can be made cell-permeable and allow for both optical and magnetic resonance detection. To reach neurons, these agents also need to cross the blood-brain barrier.